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  • CLASSES

    Miscellaneous Antidepressants

    BOXED WARNING

    Hepatic disease, hepatotoxicity, jaundice

    Cases of life-threatening hepatotoxicity, including hepatic failure, have been reported in patients treated with nefazodone. The prescriber should consider the risk of hepatic failure associated with nefazodone; other medications with lower risk of hepatotoxicity are generally more suitable first-line agents. Ordinarily, treatment with nefazodone should not be initiated in individuals with active hepatic disease or with elevated baseline serum transaminases. There is no evidence that pre-existing hepatic disease increases the likelihood of developing liver failure secondary to the drug, but baseline abnormalities can complicate patient monitoring. Nefazodone is contraindicated in patients who were withdrawn from nefazodone because of evidence of liver injury. Baseline liver function tests (LFTs) are recommended prior to initiation of treatment. Consider periodic liver function testing. Periodic testing has not been proven to prevent serious injury but it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery. Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels  more than 3 times the upper limit of normal (ULN) should be permanently withdrawn from the drug. Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them immediately if they occur. Nefazodone should be discontinued if clinical signs or symptoms suggest liver failure. Nefazodone is also contraindicated for concurrent use with certain medications because nefazodone inhibits hepatic CYP3A4, the isoenzyme that metabolizes these drugs. In some cases, these contraindicated drug combinations have been associated with QT prolongation and rare cases of serious cardiovascular adverse events.

    Children, suicidal ideation

    The safe and effective use of nefazodone has not been established in pediatric patients less than 18 years of age; few reports of nefazodone use in older pediatric patients are available. A boxed warning in the product label describes the risk of suicidality and suicidal ideation in children, adolescent, and young adult patients receiving antidepressants. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. The need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of nefazodone may be necessary in patients with emerging suicidality or worsening depression.

    DEA CLASS

    Rx

    DESCRIPTION

    Synthetic phenylpiperazine antidepressant; structurally similar to trazodone but exhibits less sedation and orthostasis
    Used for treating major depression in adults
    Boxed warning warns of risk of hepatotoxicity
    Requires close monitoring in pediatrics and young adults due to an increased risk of suicidality during the initial stages of treatment

    COMMON BRAND NAMES

    Serzone

    HOW SUPPLIED

    Nefazodone Hydrochloride/Serzone Oral Tab: 50mg, 100mg, 150mg, 200mg, 250mg

    DOSAGE & INDICATIONS

    For the treatment of major depression.
    Oral dosage
    Adults

    Initially, 100 mg PO twice daily. Initiate with 50 mg PO twice daily in debilitated adults. Increase in increments of 100 to 200 mg/day at weekly intervals as tolerated and needed. In controlled clinical trials, the effective dose range was 300 mg/day to 600 mg/day PO administered in 2 divided doses.

    Geriatric Adults

    Initially, 50 mg PO twice daily. Increase in increments of no more than 100 to 200 mg/day at intervals of no less than 1 week, as tolerated and needed. The usual effective adult dose range is 300 to 600 mg/day PO administered in 2 divided doses.

    Adolescents†

    Nefazodone is not FDA-approved for use in pediatric patients. Data are limited. One reference recommends the following: initially, 50 mg PO twice daily. Increase by 50 mg/day PO not more than every 3 days; do not exceed 600 mg/day PO administered in 2 divided doses.

    Children† 7 to 12 years

    Nefazodone is not FDA-approved for use in children. Data are limited. One reference recommends the following: initially, 50 mg PO twice daily. Increase by 50 mg/day PO not more than every 3 days; do not exceed 300 mg/day PO administered in 2 divided doses.

    For the treatment of panic disorder† or for social phobia (social anxiety disorder)†.
    Oral dosage
    Adults

    Initially, 50 mg PO twice daily. Dosage is titrated to an effective dose. Max: 600 mg/day PO, administered in 2 divided doses. In an open-label trial, 23 patients with generalized social phobia received this regimen for 12 weeks. Of the 21 patients completing the trial, 69.6% were considered to have moderate to marked improvement in social anxiety, avoidance, depression, and social functioning based on the results of standard assessment scales.

    For the treatment of posttraumatic stress disorder (PTSD)†.
    Oral dosage
    Adults

    Data are limited. Initially, 50 mg PO twice daily, titrated upward until a effective response. Max:600 mg/day PO, administered in 2 divided doses. One 12-week open label trial of 10 patients with combat-related PTSD reported PTSD symptom improvement in all patients treated; insomnia and anger outbursts were also improved.

    For the treatment of premenstrual dysphoric disorder (PMDD)†.
    Oral dosage
    Adult females

    In an open label study, an initial dose of 50 mg PO twice daily was administered and titrated up to a maximum dose of 300 mg PO twice daily as tolerated and needed. The Hamilton Rating Scale for Depression was used to assess symptoms. After 4 weeks of treatment and at an average dose of 245 mg/day, significant improvement was noted. Forty-seven (87%) of 54 patients completed 2 months of therapy. The average dose was 319 mg/day.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    600 mg/day PO.

    Elderly

    600 mg/day PO.

    Adolescents

    600 mg/day PO.

    Children

    >= 7 years: 300 mg/day PO has been suggested; limited data are available; not FDA-approved.
    <= 6 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Generally not recommended in hepatic disease. Dosage should be modified depending on clinical response and degree of hepatic impairment, but no quantitative recommendations are available. Elimination is reduced in patients with cirrhosis. Withdraw drug if evidence of hepatocellular injury such as active liver disease or increased LFT levels >3 times the upper limit of normal occurs (see Contraindications).

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Food decreases nefazodone bioavailability slightly; but does not prohibit the administration of nefazodone with food. May be taken without regard to meals.

    STORAGE

    Serzone:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Nefazodone should be avoided in patients with a history of a previous hypersensitivity reaction to nefazodone or other phenylpiperazine antidepressants (e.g., trazodone hypersensitivity).

    Bipolar disorder, mania

    All effective antidepressants can transform depression into mania or hypomania in predisposed individuals. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. If a patient develops manic symptoms, nefazodone should be withheld and appropriate therapy initiated to treat the manic symptoms. Depression may be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or suicidality. It should be noted that nefazodone is not approved for use in treating bipolar depression.

    Hepatic disease, hepatotoxicity, jaundice

    Cases of life-threatening hepatotoxicity, including hepatic failure, have been reported in patients treated with nefazodone. The prescriber should consider the risk of hepatic failure associated with nefazodone; other medications with lower risk of hepatotoxicity are generally more suitable first-line agents. Ordinarily, treatment with nefazodone should not be initiated in individuals with active hepatic disease or with elevated baseline serum transaminases. There is no evidence that pre-existing hepatic disease increases the likelihood of developing liver failure secondary to the drug, but baseline abnormalities can complicate patient monitoring. Nefazodone is contraindicated in patients who were withdrawn from nefazodone because of evidence of liver injury. Baseline liver function tests (LFTs) are recommended prior to initiation of treatment. Consider periodic liver function testing. Periodic testing has not been proven to prevent serious injury but it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery. Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels  more than 3 times the upper limit of normal (ULN) should be permanently withdrawn from the drug. Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them immediately if they occur. Nefazodone should be discontinued if clinical signs or symptoms suggest liver failure. Nefazodone is also contraindicated for concurrent use with certain medications because nefazodone inhibits hepatic CYP3A4, the isoenzyme that metabolizes these drugs. In some cases, these contraindicated drug combinations have been associated with QT prolongation and rare cases of serious cardiovascular adverse events.

    Children, suicidal ideation

    The safe and effective use of nefazodone has not been established in pediatric patients less than 18 years of age; few reports of nefazodone use in older pediatric patients are available. A boxed warning in the product label describes the risk of suicidality and suicidal ideation in children, adolescent, and young adult patients receiving antidepressants. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. The need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of nefazodone may be necessary in patients with emerging suicidality or worsening depression.

    MAOI therapy

    The concurrent administration of MAOI therapy and nefazodone is contraindicated. At least 14 days should elapse between the discontinuation of the MAO inhibitor and initiation of nefazodone (see Drug Interactions).

    Electroconvulsive therapy (ECT)

    There are not clinical studies of the combined use of nefazodone and electroconvulsive therapy (ECT). It is recommended to avoid concurrent use of these therapies.

    Angina, bradycardia, cardiac disease, cerebrovascular disease, dehydration, hypertension, hypotension, hypovolemia, myocardial infarction, stroke

    Nefazodone should be used cautiously in patients with a recent history of myocardial infarction or unstable cardiac disease because these patients have been excluded from clinical trials. Nefazodone is infrequently associated with clinically significant ECG changes; sinus bradycardia may occur in roughly 1.5% of patients. Postural hypotension (e.g., SBP <= 90 mmHg and >= 20 mmHg change from baseline) occurs in roughly 2—3% of patients. The risk of hypotension and syncope is less than for some antidepressants (e.g., tricyclics), however certain patients may have medical conditions that could be exacerbated by the presence of clinically significant hypotension (e.g., angina, cerebrovascular disease, ischemic stroke, or myocardial infarction). Patients with dehydration or hypovolemia, or patients with hypertension who are receiving antihypertensive agents, may be more at risk for hypotensive reactions.

    Infants, neonates, pregnancy

    Nefazodone should be used only if the benefit to the mother outweighs the potential risks to the fetus; patients should notify their health care professional if they become pregnant while on nefazodone. Clinicians should administer any serotonergic agent with caution during pregnancy, particularly during the third trimester. At doses 5-times the maximal human daily dose in mg/m2, no teratogenic effects have been noted in rats or rabbits. However, increased early pup mortality and decreased birth weights have occurred. There was no effect on pup mortality at doses 1.3 times the human dose in mg/m2. The effect of nefazodone exposure on neurological development during gestation is unknown. Neonates exposed to other serotonergic antidepressants late in the third trimester of pregnancy have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Symptoms have included respiratory distress, cyanosis, apnea, seizure activity, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. Features are consistent with either a direct toxic effect of serotonergic agents or, possibly, a neonatal abstinence syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. Animal studies have shown that selective serotonin reuptake inhibitors (SSRIs) downregulate serotonin receptors in the fetal cortex and that these changes can be present for a period of time after birth. The applicability of these animal findings to human gestation is unknown; some human epidemiologic studies have suggested that the cognitive and behavioral development of infants prenatally exposed to serotonergic agents does not differ from controls. The effects of nefazodone on labor and delivery are unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to nefazodone; information about the registry can be obtained at womensmentalhealth.org/research/pregnancyregistry or by calling 1-866-961-2388.

    Breast-feeding

    According to the manufacturer, caution is advisable when administering nefazodone to a woman who is breast-feeding an infant. Drowsiness, poor temperature regulation, and poor feeding have been associated with the use of nefazodone in at least one breast-fed infant; there are also concerns for potential hepatotoxic risk. The milk:plasma ratio for nefazodone was 0.27, and 0.02—0.19 for the three metabolites. The estimated infant dose relative to the weight-adjusted total daily maternal dose was 0.3% for nefazodone and 0.45% for the parent drug plus metabolites. Although the American Academy of Pediatrics (AAP) does not make specific recommendations regarding nefazodone use during breast-feeding, the AAP cautions that psychotropic medications affect neurotransmitter function in the developing central nervous system, and therefore, the accurate prediction of long-term adverse effects may not be possible. Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding. However, because a pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum, these agents may be the preferred antidepressants when initiating antidepressant therapy in a breast-feeding mother.] Patients should advise their physician of their intention to breast-feed. If breast-feeding is continued, the infant should be observed for evidence of adverse effects. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    Use of nefazodone in geriatric patients has shown that there is an increase in AUC and Cmax after initial dose administration in these patients. It is recommended to initiate nefazodone in elderly patients at one-half the normal initial adult dose but titration may occur as tolerated. The final effective dose in elderly patients may be the same as for other adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities. According to OBRA, the duration of therapy should be in accordance with pertinent literature for the condition being treated, including clinical practice guidelines. All residents being treated for depression with any antidepressant should be monitored closely for worsening of depression and/or suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, somnolence, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk for falls. Concurrent use of 2 or more antidepressants may increase the risk of side effects; in such cases there should be documentation of expected benefits that outweigh the associated risks and monitoring for any increase in side effects. Monitoring should consist of a review for continued need at least quarterly, and documentation of the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated.

    Seizures

    Rare occurrences of seizures have been reported with the use of nefazodone in both pre-market and post-market introductions. A causal relationship to nefazodone has not been established.

    Surgery

    Little is known regarding the potential for nefazodone to interact with general anesthetics. The manufacturer has recommended that nefazodone be discontinued as long as clinically feasible prior to elective surgery.

    Driving or operating machinery

    Patients should be warned to use caution when driving or operating machinery or performing other tasks that require mental alertness until they know how nefazodone will affect them.

    Closed-angle glaucoma, increased intraocular pressure

    Caution is recommended when prescribing nefazodone to patients with closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.

    Abrupt discontinuation

    Gradual tapering is advisable during discontinuation of antidepressants to minimize the occurrence of potential discontinuation symptoms. Frequent symptoms which have occurred with serotonin reuptake inhibitors include dizziness, vertigo, nausea, vomiting, flu-like symptoms, sensory disturbances (e.g., paresthesias, electric shock sensation), sleep disturbances, irritability, anxiety, and/or agitation. Antidepressants with short half-lives generally have an increased frequency and severity of symptoms. Two days after abrupt discontinuation of nefazodone, one patient experienced asthenia, fatigue, difficulty in maintaining sleep due to vivid nightmares, nocturnal twitching, muscle pains primarily located in legs, severe headache, nausea, vomiting, and anxiety combined with agitation. Five days after cessation of the drug, all symptoms resolved spontaneously.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 1.5-1.5
    keratoconjunctivitis / Early / 0.1-1.0
    peptic ulcer / Delayed / 0.1-1.0
    bronchospasm / Rapid / 0.1-1.0
    suicidal ideation / Delayed / 0.1-1.0
    neuroleptic malignant syndrome / Delayed / 0-0.1
    stroke / Early / 0-0.1
    night blindness / Delayed / 0-0.1
    hearing loss / Delayed / 0-0.1
    AV block / Early / 0-0.1
    heart failure / Delayed / 0-0.1
    GI bleeding / Delayed / 0-0.1
    oliguria / Early / 0-0.1
    serotonin syndrome / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known

    Moderate

    constipation / Delayed / 14.0-14.0
    blurred vision / Early / 9.0-9.0
    scotomata / Delayed / 7.0-7.0
    confusion / Early / 7.0-7.0
    memory impairment / Delayed / 4.0-4.0
    orthostatic hypotension / Delayed / 4.0-4.0
    peripheral edema / Delayed / 3.0-3.0
    ataxia / Delayed / 2.0-2.0
    hypotension / Rapid / 2.0-2.0
    vaginitis / Delayed / 2.0-2.0
    urinary retention / Early / 2.0-2.0
    mania / Early / 1.6-1.6
    hypertonia / Delayed / 1.0-1.0
    dysarthria / Delayed / 0.1-1.0
    myoclonia / Delayed / 0.1-1.0
    neuropathic pain / Delayed / 0.1-1.0
    photophobia / Early / 0.1-1.0
    conjunctivitis / Delayed / 0.1-1.0
    hyperacusis / Delayed / 0.1-1.0
    hypertension / Early / 0.1-1.0
    sinus tachycardia / Rapid / 0.1-1.0
    angina / Early / 0.1-1.0
    ejaculation dysfunction / Delayed / 0.1-1.0
    gastritis / Delayed / 0.1-1.0
    stomatitis / Delayed / 0.1-1.0
    esophagitis / Delayed / 0.1-1.0
    colitis / Delayed / 0.1-1.0
    oral ulceration / Delayed / 0.1-1.0
    cystitis / Delayed / 0.1-1.0
    nephrolithiasis / Delayed / 0.1-1.0
    hematuria / Delayed / 0.1-1.0
    vaginal bleeding / Delayed / 0.1-1.0
    urinary incontinence / Early / 0.1-1.0
    atopic dermatitis / Delayed / 0.1-1.0
    hallucinations / Early / 0.1-1.0
    hostility / Early / 0.1-1.0
    euphoria / Early / 0.1-1.0
    gout / Delayed / 0.1-1.0
    dehydration / Delayed / 0.1-1.0
    lymphadenopathy / Delayed / 0.1-1.0
    leukopenia / Delayed / 0.1-1.0
    anemia / Delayed / 0.1-1.0
    hypotonia / Delayed / 0-0.1
    hyperesthesia / Delayed / 0-0.1
    candidiasis / Delayed / 0-0.1
    dysphagia / Delayed / 0-0.1
    glossitis / Early / 0-0.1
    hypoglycemia / Early / 0-0.1
    hypercholesterolemia / Delayed / 0-0.1
    impotence (erectile dysfunction) / Delayed / 1.0
    dyspnea / Early / 1.0
    priapism / Early / Incidence not known
    hyperprolactinemia / Delayed / Incidence not known
    galactorrhea / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    edema / Delayed / Incidence not known

    Mild

    headache / Early / 36.0-36.0
    drowsiness / Early / 25.0-25.0
    xerostomia / Early / 25.0-25.0
    nausea / Early / 22.0-22.0
    dizziness / Early / 17.0-17.0
    insomnia / Early / 11.0-11.0
    asthenia / Delayed / 11.0-11.0
    dyspepsia / Early / 9.0-9.0
    diarrhea / Early / 8.0-8.0
    infection / Delayed / 8.0-8.0
    pharyngitis / Delayed / 6.0-6.0
    appetite stimulation / Delayed / 5.0-5.0
    flushing / Rapid / 4.0-4.0
    paresthesias / Delayed / 4.0-4.0
    cough / Delayed / 3.0-3.0
    influenza / Delayed / 3.0-3.0
    tremor / Early / 2.0-2.0
    psychomotor impairment / Early / 2.0-2.0
    tinnitus / Delayed / 2.0-2.0
    dysgeusia / Early / 2.0-2.0
    vomiting / Early / 2.0-2.0
    increased urinary frequency / Early / 2.0-2.0
    pruritus / Rapid / 2.0-2.0
    rash / Early / 2.0-2.0
    chills / Rapid / 2.0-2.0
    fever / Early / 2.0-2.0
    vertigo / Early / 0.1-1.0
    diplopia / Early / 0.1-1.0
    mydriasis / Early / 0.1-1.0
    otalgia / Early / 0.1-1.0
    xerophthalmia / Early / 0.1-1.0
    syncope / Early / 0.1-1.0
    libido increase / Delayed / 0.1-1.0
    libido decrease / Delayed / 1.0-1.0
    eructation / Early / 0.1-1.0
    gingivitis / Delayed / 0.1-1.0
    halitosis / Early / 0.1-1.0
    weight loss / Delayed / 0.1-1.0
    mastalgia / Delayed / 1.0-1.0
    amenorrhea / Delayed / 0.1-1.0
    menorrhagia / Delayed / 0.1-1.0
    breast enlargement / Delayed / 0.1-1.0
    nocturia / Early / 0.1-1.0
    polyuria / Early / 0.1-1.0
    urinary urgency / Early / 0.1-1.0
    laryngitis / Delayed / 0.1-1.0
    epistaxis / Delayed / 0.1-1.0
    hiccups / Early / 0.1-1.0
    acne vulgaris / Delayed / 0.1-1.0
    photosensitivity / Delayed / 0.1-1.0
    xerosis / Delayed / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    alopecia / Delayed / 0.1-1.0
    maculopapular rash / Early / 0.1-1.0
    paranoia / Early / 0.1-1.0
    arthropathy / Delayed / 0.1-1.0
    arthralgia / Delayed / 1.0-1.0
    polydipsia / Early / 1.0-1.0
    ecchymosis / Delayed / 0.1-1.0
    hyperkinesis / Delayed / 0-0.1
    ptosis / Delayed / 0-0.1
    hypersalivation / Early / 0-0.1
    pallor / Early / 0-0.1
    orgasm dysfunction / Delayed / 0-0.1
    yawning / Early / 0-0.1
    hyperventilation / Early / 0-0.1
    ocular pain / Early / 1.0
    gynecomastia / Delayed / Incidence not known
    agitation / Early / Incidence not known
    pelvic pain / Delayed / Incidence not known
    malaise / Early / Incidence not known

    DRUG INTERACTIONS

    Abemaciclib: (Major) If coadministration with nefazodone is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If nefazodone is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of nefazodone. Abemaciclib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
    Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and nefazodone; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Acebutolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of dihydrocodeine with nefazodone may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinue dihydrocodeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Nefazodone is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Acetaminophen; Chlorpheniramine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with nefazodone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinue codeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nefazodone is a strong inhibitor of CYP3A4.
    Acetaminophen; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Diphenhydramine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Acetaminophen; Hydrocodone: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Acetaminophen; Oxycodone: (Major) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of nefazodone is necessary. If nefazodone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like nefazodone has resulted in serotonin syndrome. In addition, oxycodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nefazodone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If nefazodone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Acetaminophen; Pamabrom; Pyrilamine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Acetaminophen; Pentazocine: (Moderate) Concomitant use of pentazocine with other CNS depressants, such as nefazodone, can potentiate respiratory depression, CNS depression, and sedation.
    Acetaminophen; Propoxyphene: (Moderate) Concomitant use of propoxyphene with other CNS depressants, such as nefazodone, can potentiate respiratory depression and/or sedation. Use with caution.
    Acrivastine; Pseudoephedrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Ado-Trastuzumab emtansine: (Major) Avoid coadministration of nefazodone with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until nefazodone has cleared from the circulation (approximately 3 half-lives of nefazodone) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; nefazodone is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Aldesleukin, IL-2: (Moderate) Aldesleukin may cause nephrotoxicity. Concurrent administration of drugs possessing hepatotoxic effects with Aldesleukin, such as nefazodone, may increase the risk of liver dysfunction. In addition, reduced liver function secondary to Aldesleukin treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs.
    Alfentanil: (Moderate) Certain opiate agonists, such as alfentanil, are metabolized via cytochrome P450 3A4. Nefazodone inhibits the metabolism of these agents and may lead to excessive opiate agonist effects.
    Alfuzosin: (Contraindicated) Alfuzosin is contraindicated for use with nefazodone due to the potential for serious/life-threatening reactions, including hypotension. Coadministration is expected to reduce the metabolism and increase systemic exposure to alfuzosin. Alfuzosin is primarily metabolized by CYP3A4; nefazodone is a strong inhibitor of this enzyme. Coadministration of another strong CYP3A4 inhibitor increased the alfuzosin AUC by 2.5-fold to 3.2-fold.
    Aliskiren: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Aliskiren; Amlodipine: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Aliskiren; Valsartan: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with nefazodone is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and nefazodone should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
    Alosetron: (Moderate) Alosetron is partially metabolized by CYP3A4. Nefazodone inhibits this enzyme and may decrease the metabolism of alosetron resulting in increased alosetron plasma concentrations. Coadministration of alosetron with nefazodone has not been studied.
    Alprazolam: (Major) Avoid coadministration of alprazolam and nefazodone due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with nefazodone, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and nefazodone is a moderate CYP3A4 inhibitor. Coadministration with nefazodone increased alprazolam exposure by 1.98-fold.
    Amiloride: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Amiloride; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Amiodarone: (Major) Administer amiodarone and nefazodone together with caution. Nefazodone is a potent inhibitor of CYP3A4, and amiodarone is a substrate of CYP3A4. Clinically significant increases in plasma concentrations of other CYP3A4 substrates (e.g., alprazolam, atorvastatin, lovastatin, simvastatin, triazolam) have been reported. If nefazodone and amiodarone are administered concomitantly, increased amiodarone plasma concentrations may occur, which could result in a potential for serious or life-threatening reactions, including cardiac arrhythmias. Furthermore, due to the long half-life of amiodarone, a drug interactions is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as nefazodone. Both nefazodone and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Cases of serotonin syndrome or serotonin-related adverse events have been observed during concurrent use of serotonergic antidepressants and nefazodone. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Amlodipine: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Atorvastatin: (Major) Caution should be used if nefazodone is administered in combination with HMG-CoA reductase inhibitors that are metabolized by CYP3A4, and dosage adjustments of these HMG-CoA reductase inhibitors are recommended. There have been reports of rhabdomyolysis and myopathy when nefazodone has been administered to patients receiving statins metabolized by CYP3A4. Consider alternative therapy. Since pravastatin and rosuvastatin are not substantially metabolized and fluvastatin is a minor CYP3A4 substrate (20%), these statins are less likely to be significantly affected by CYP3A4 inhibitors such as nefazodone. (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Benazepril: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Amlodipine; Celecoxib: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Olmesartan: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Amlodipine; Valsartan: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Amphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and nefazodone. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and nefazodone. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Amphetamine; Dextroamphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and nefazodone. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Angiotensin II receptor antagonists: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Angiotensin-converting enzyme inhibitors: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Apalutamide: (Moderate) Monitor for decreased efficacy of nefazodone and an increase in apalutamide-related adverse reactions if coadministration is necessary. Nefazodone is a substrate and strong inhibitor of CYP3A4. Apalutamide is a substrate and strong inducer of CYP3A4. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%. Use of apalutamide with a strong CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide). No initial dose adjustment of apalutamide is required, although the dose of apalutamide may need to be reduced based upon tolerability.
    Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants, including nefazodone, could result in additive depressant effects. Careful monitoring is recommended during combined use of a CNS depressant and apomorphine. A dose reduction of one or both drugs may be warranted.
    Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of nefazodone with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased nefazodone exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in nefazodone- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Nefazodone is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of a single oral dose of aprepitant (125 mg) on day 5 of a 10-day ketoconazole regimen (strong CYP3A4 inhibitor) increased the aprepitant AUC approximately 5-fold, and increased the mean terminal half-life by approximately 3-fold. Nefazodone is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may additionally increase plasma concentrations of nefazodone. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aripiprazole: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as nefazodone. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving Aristada 882 mg every 6 weeks or 1,064 mg every 2 months, reduce the dose to 441 mg every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs and receiving a strong CYP3A4 inhibitor for more than 14 days should have their Aristada dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg; no dosage adjustment is necessary in patients receiving 441 mg of Aristada, if tolerated. Avoid use of combination therapy with a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days in patients receiving 662 mg, 882 mg, or 1,064 mg of Aristada; no dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.
    Armodafinil: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as nefazodone are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Artemether; Lumefantrine: (Moderate) Nefazodone is a substrate/inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Nefazodone is a substrate/inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Asciminib: (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with nefazodone is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with nefazodone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinue codeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nefazodone is a strong inhibitor of CYP3A4.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of dihydrocodeine with nefazodone may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinue dihydrocodeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Nefazodone is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with nefazodone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinue codeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nefazodone is a strong inhibitor of CYP3A4.
    Aspirin, ASA; Oxycodone: (Major) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of nefazodone is necessary. If nefazodone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like nefazodone has resulted in serotonin syndrome. In addition, oxycodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nefazodone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If nefazodone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Atazanavir: (Major) Nefazodone and atazanavir are both substrates and inhibitors of CYP3A4. Coadministration could result in increased plasma concentrations of either drug; caution and close monitoring are recommended.
    Atazanavir; Cobicistat: (Major) Nefazodone and atazanavir are both substrates and inhibitors of CYP3A4. Coadministration could result in increased plasma concentrations of either drug; caution and close monitoring are recommended. (Moderate) Caution is warranted when cobicistat is administered with nefazodone as there is a potential for elevated nefazodone and cobicistat concentrations. Both nefazodone and cobicistat are substrates and strong inhibitors of CYP3A4.
    Atenolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Atenolol; Chlorthalidone: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Atogepant: (Major) Limit the dose of atogepant to 10 mg PO once daily if coadministered with nefazodone. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and nefazodone is a strong CYP3A inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant exposure and a 2.15-fold increase in atogepant peak concentration.
    Atorvastatin: (Major) Caution should be used if nefazodone is administered in combination with HMG-CoA reductase inhibitors that are metabolized by CYP3A4, and dosage adjustments of these HMG-CoA reductase inhibitors are recommended. There have been reports of rhabdomyolysis and myopathy when nefazodone has been administered to patients receiving statins metabolized by CYP3A4. Consider alternative therapy. Since pravastatin and rosuvastatin are not substantially metabolized and fluvastatin is a minor CYP3A4 substrate (20%), these statins are less likely to be significantly affected by CYP3A4 inhibitors such as nefazodone.
    Atorvastatin; Ezetimibe: (Major) Caution should be used if nefazodone is administered in combination with HMG-CoA reductase inhibitors that are metabolized by CYP3A4, and dosage adjustments of these HMG-CoA reductase inhibitors are recommended. There have been reports of rhabdomyolysis and myopathy when nefazodone has been administered to patients receiving statins metabolized by CYP3A4. Consider alternative therapy. Since pravastatin and rosuvastatin are not substantially metabolized and fluvastatin is a minor CYP3A4 substrate (20%), these statins are less likely to be significantly affected by CYP3A4 inhibitors such as nefazodone.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Concurrent use of intravenous methylene blue with nefazodone may increase the risk of serotonin syndrome. Methylene blue is a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and nefazodone increases central serotonin effects. Cases of serotonin syndrome have been reported with IV methylene blue given as a visualizing agent in patients receiving serotonergic agents like SSRIs, SNRIs, and clomipramine. It is not known if patients receiving other serotonergic psychiatric agents are at a comparable risk. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. For patients requiring urgent treatment with IV methylene blue, it may be wise to discontinue nefazodone and monitor the patient until 24 hours after the last dose of methylene blue IV; nefazodone can then be re-initiated 24 hours after the last dose of methylene blue.
    Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of nefazodone is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
    Avanafil: (Major) Concomitant use of avanafil and nefazodone is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; nefazodone is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; nefazodone would be expected to have similar effects.
    Avapritinib: (Major) Avoid coadministration of avapritinib with nefazodone due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
    Axitinib: (Major) Avoid coadministration of axitinib with nefazodone due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after nefazodone is discontinued. Axitinib is a CYP3A4/5 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including nefazodone.
    Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and nefazodone is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including nefazodone.
    Azilsartan: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Azilsartan; Chlorthalidone: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Bedaquiline: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as nefazodone, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, nefazodone may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Nefazodone may reduce the metabolism of ergotamine via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness of the extremities or other serious effects). In addition, serotonin syndrome has been reported or may be possible with the use of ergot alkaloids like ergotamine, particularly in combination with other serotonin-augmenting drugs. Avoid coadministration of ergotamine with nefazodone when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable. (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with phenobarbital is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
    Benazepril: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Benazepril; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Bendroflumethiazide; Nadolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Benzhydrocodone; Acetaminophen: (Major) Concurrent use of benzhydrocodone with nefazodone may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of nefazodone in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Nefazodone is a strong inhibitor of CYP3A4. Concomitant use of opioid agonists with nefazodone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking nefazodone, reduce initial dosage and titrate to clinical response. If nefazodone is prescribed in a patient taking an opioid agonist, use a lower initial dose of nefazodone and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and nefazodone because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone is serotonin syndrome is suspected. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Concurrent use of intravenous methylene blue with nefazodone may increase the risk of serotonin syndrome. Methylene blue is a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and nefazodone increases central serotonin effects. Cases of serotonin syndrome have been reported with IV methylene blue given as a visualizing agent in patients receiving serotonergic agents like SSRIs, SNRIs, and clomipramine. It is not known if patients receiving other serotonergic psychiatric agents are at a comparable risk. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. For patients requiring urgent treatment with IV methylene blue, it may be wise to discontinue nefazodone and monitor the patient until 24 hours after the last dose of methylene blue IV; nefazodone can then be re-initiated 24 hours after the last dose of methylene blue.
    Benzphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and nefazodone. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Bepridil: (Major) Nefazodone is a CYP3A4 inhibitors which theoretically may decrease hepatic metabolism of bepridil, a CYP3A4 substrate.
    Beta-blockers: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Betamethasone: (Moderate) Monitor for corticosteroid-related adverse effects if coadministration is necessary. Nefazodone is a strong CYP3A4 inhibitor and betamethasone is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
    Betaxolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Bisoprolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering nefazodone with boceprevir due to an increased potential for nefazodone-related adverse events. If nefazodone dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of nefazodone and boceprevir. Both nefazodone and boceprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4. When used in combination, the plasma concentrations of both medications may be elevated.
    Bortezomib: (Minor) Bortezomib is a significant substrate for CYP3A4. Nefazodone inhibits CYP3A4 and may increase the exposure to bortezomib and increase the risk for toxicity.
    Bosentan: (Moderate) Nefazodone is a CYP3A4 inhibitor, and may increase the risk of toxicity from bosentan which is partially metabolized by CYP3A4 isoenzymes. Excessive bosentan dosage can result in hypotension or elevated hepatic enzymes.
    Bosutinib: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, and nefazodone, a strong CYP3A4 inhibitor, as bosutinib plasma exposure may increase.
    Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as nefazodone. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. Because brexpiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a moderate to strong CYP3A4 inhibitor and moderate to strong CYP2D6 inhibitor should have their brexpiprazole dose reduced to one-quarter (25%) of the usual dose. If the co-administered CYP inhibitor is discontinued, adjust the brexpiprazole dose to its original level.
    Brigatinib: (Major) Avoid coadministration of brigatinib with nefazodone if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of nefazodone, resume the brigatinib dose that was tolerated prior to initiation of nefazodone. Brigatinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Brimonidine; Timolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with nefazodone ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; nefazodone is a strong inhibitor of CYP3A4.
    Brompheniramine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Brompheniramine; Phenylephrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Brompheniramine; Pseudoephedrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Budesonide: (Moderate) Avoid coadministration of oral budesonide and nefazodone due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
    Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and nefazodone due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of oral budesonide and nefazodone due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
    Bumetanide: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as nefazodone, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Bupivacaine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as nefazodone, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Bupivacaine; Epinephrine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as nefazodone, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and nefazodone may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; nefazodone inhibits CYP3A4. (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as nefazodone, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Bupivacaine; Meloxicam: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as nefazodone, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Buprenorphine: (Major) The plasma concentrations of CYP3A4 substrates such as buprenorphine and its metabolite, norbuprenorphine, may be elevated when administered concurrently with strong CYP3A4 inhibitors such as nefazodone. If concurrent use of nefazodone and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
    Buprenorphine; Naloxone: (Major) The plasma concentrations of CYP3A4 substrates such as buprenorphine and its metabolite, norbuprenorphine, may be elevated when administered concurrently with strong CYP3A4 inhibitors such as nefazodone. If concurrent use of nefazodone and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
    Buspirone: (Major) The administration of nefazodone with buspirone has resulted in marked increases in plasma buspirone concentrations most likely due to CYP3A4 inhibition by nefazodone. Some patients receiving both drugs concurrently have reported lightheadedness, asthenia, dizziness, and drowsiness. If buspirone is to be administered concurrently with nefazodone, a low dose of buspirone, such as 2.5 mg PO twice daily, is recommended. Subsequent dosage adjustments should be based on clinical response.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with nefazodone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinue codeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nefazodone is a strong inhibitor of CYP3A4.
    Butorphanol: (Moderate) Concomitant use of butorphanol with other central nervous system (CNS) depressants, such as nefazodone, can potentiate the effects of the butorphanol and may lead to additive CNS or respiratory depression. Prior to concurrent use of butorphanol in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with nefazodone if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and nefazodone is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
    Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering nefazodone with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nefazodone is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Cabozantinib: (Major) Avoid concomitant use of cabozantinib and nefazodone due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with nefazodone 2 to 3 days after discontinuation of nefazodone. Cabozantinib is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Calcifediol: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with nefazodone. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with nefazodone. Nefazodone, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
    Candesartan: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Candesartan; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Capmatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with nefazodone is necessary. Capmatinib is a CYP3A substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Captopril: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Captopril; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Carbamazepine: (Contraindicated) Coadministration of carbamazepine and nefazodone is contraindicated; use together may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Nefazodone may also increase plasma concentrations of carbamazepine. Nefazodone and carbamazepine are both substrates of CYP3A4; however, carbamazepine is a strong CYP3A4 inducer while nefazodone is a strong CYP3A4 inhibitor.
    Carbetapentane; Chlorpheniramine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbetapentane; Pyrilamine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants.
    Carbidopa; Levodopa; Entacapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as nefazodone, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Carbinoxamine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Carbinoxamine; Phenylephrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Carbinoxamine; Pseudoephedrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. When a strong CYP3A4 inhibitor, such as nefazodone, is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For adult patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased. When initiating cariprazine in a patient who is stable on a strong CYP3A4 inhibitor, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased.
    Carteolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Carvedilol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with nefazodone is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concurrent use of nefazodone, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and nefazodone. Concurrent use may result in additive CNS depression.
    Ceritinib: (Major) Avoid concomitant use of ceritinib with nefazodone due to increased ceritinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is necessary, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg and monitor for ceritinib-related adverse reactions. After nefazodone is discontinued, resume the dose of ceritinib taken prior to initiating nefazodone. Ceritinib is a CYP3A substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold.
    Cerivastatin: (Major) Caution should be used if nefazodone is administered in combination with HMG-CoA reductase inhibitors that are metabolized by CYP3A4, and dosage adjustments of these HMG-CoA reductase inhibitors are recommended. There have been reports of rhabdomyolysis and myopathy when nefazodone has been administered to patients receiving statins metabolized by CYP3A4. Cerivastatin is metabolized by CYP2C8 and CYP3A4. Administration of cerivastatin with a potent inhibitor of CYP3A4 has increased cerivastatin exposure by approximately 1.5-fold.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with nefazodone should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with nefazodone should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Chlophedianol; Dexbrompheniramine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Chlorcyclizine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Chlordiazepoxide; Amitriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as nefazodone. Both nefazodone and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Cases of serotonin syndrome or serotonin-related adverse events have been observed during concurrent use of serotonergic antidepressants and nefazodone. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Chlorothiazide: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Chlorpheniramine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Chlorpheniramine; Codeine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Concomitant use of codeine with nefazodone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinue codeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nefazodone is a strong inhibitor of CYP3A4.
    Chlorpheniramine; Dextromethorphan: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of dihydrocodeine with nefazodone may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinue dihydrocodeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Nefazodone is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of dihydrocodeine with nefazodone may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinue dihydrocodeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Nefazodone is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Chlorpheniramine; Hydrocodone: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Chlorpheniramine; Phenylephrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Chlorpheniramine; Pseudoephedrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Chlorthalidone: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Chlorthalidone; Clonidine: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Cilostazol: (Major) Decrease cilostazol dose to one half of the recommended dosage when coadministered with nefazodone. Coadministration may increase cilostazol serum concentrations and increase the risk for adverse reactions. Cilostazol is extensively metabolized by hepatic isoenzyme CYP3A4; nefazodone is a strong inhibitor of CYP3A4. In a drug interaction study, coadministration of another strong CYP3A4 inhibitor and cilostazol increased cilostazol Cmax by 94% and AUC by 117%.
    Cinacalcet: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include nefazodone. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Cisapride: (Contraindicated) Postmarketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes and death, when known and potent inhibitors of CYP3A4 are coadministered with cisapride. Because of the potential severity of these drug interactions (increased plasma cisapride concentrations and QT prolongation), nefazodone, which inhibits CYP3A4 isoenzymes, is contraindicated for use with cisapride.
    Citalopram: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as nefazodone and citalopram. In addition, nefazodone is a strong inhibitor of CYP3A4 and citalopram is a partial CYP3A4 substrate. Concurrent use may increase the risk of citalopram-related adverse effects such as QT prolongation and torsade de pointes (TdP). Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least one case report of serotonin syndrome from the concurrent use of nefazodone and a selective serotonin reuptake inhibitor (i.e., paroxetine) has been published. Additionally, when a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient serotonin-related adverse events. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Clemastine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Clindamycin: (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of nefazodone as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; nefazodone is a strong inhibitor of CYP3A4.
    Clomipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as nefazodone. Both nefazodone and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Cases of serotonin syndrome or serotonin-related adverse events have been observed during concurrent use of serotonergic antidepressants and nefazodone. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Clonazepam: (Moderate) Use nefazodone cautiously and carefully monitor patients receiving concurrent clonazepam due to impaired metabolism of clonazepam leading to exaggerated concentrations and adverse effects, such as CNS and/or respiratory depression. Clonazepam is a CYP3A4 substrate. Nefazodone is a CYP3A4 inhibitor.
    Clorazepate: (Moderate) Nefazodone is a CYP3A4 inhibitor and may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity.
    Clozapine: (Major) Caution is advisable during concurrent use of nefazodone and clozapine. Nefazodone is a potent inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias or other adverse effects. In one case report, nefazodone 300 mg/day was started in a patient receiving clozapine who subsequently developed dizziness, elevated anxiety, and hypotension. Clozapine and norclozapine plasma concentrations were 75% and 89% higher, respectively, after starting nefazodone. Lowering the nefazodone dose to 200 mg/day resolved the adverse effects, and the serum concentrations of clozapine declined. In contrast, other studies have not shown an interaction between clozapine and nefazodone. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with nefazodone as there is a potential for elevated nefazodone and cobicistat concentrations. Both nefazodone and cobicistat are substrates and strong inhibitors of CYP3A4.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with nefazodone due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate in vitro, and nefazodone is a strong inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
    Cocaine: (Major) Concomitant use of cocaine with drugs that have CNS serotonergic properties, such as nefazodone, could potentiate serotonin neurotransmission, and result in the serotonin syndrome. Symptoms may include mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia or fever.
    Codeine: (Moderate) Concomitant use of codeine with nefazodone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinue codeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nefazodone is a strong inhibitor of CYP3A4.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with nefazodone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinue codeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nefazodone is a strong inhibitor of CYP3A4.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with nefazodone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinue codeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nefazodone is a strong inhibitor of CYP3A4.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with nefazodone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinue codeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nefazodone is a strong inhibitor of CYP3A4.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with nefazodone may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinue codeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nefazodone is a strong inhibitor of CYP3A4.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and nefazodone in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Nefazodone can inhibit colchicine's metabolism via CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken nefazodone in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    COMT inhibitors: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as nefazodone, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Conivaptan: (Contraindicated) Coadministration of conivaptan and nefazodone is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; nefazodone is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with nefazodone, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro.
    Copanlisib: (Major) Avoid the concomitant use of copanlisib and nefazodone if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; nefazodone is a strong CYP3A inhibitor.
    Crizotinib: (Major) Avoid concomitant use of nefazodone and crizotinib due to increased plasma concentrations of crizotinib, which may increase the incidence and severity of adverse reactions. If concomitant use is necessary for patients with non-small cell lung cancer, reduce the dose of crizotinib to 250 mg PO once daily. If concomitant use is necessary for patients with anaplastic large cell lymphoma, reduce the dose of crizotinib to 250 mg PO twice daily for BSA of 1.7 m2 or more; 200 mg PO twice daily for BSA of 1.17 to 1.69 m2; and 250 mg PO once daily for BSA of 0.81 to 1.16 m2; do not use this combination in patients with a BSA of 0.6 to 0.8 m2. Resume the original crizotinib dose after discontinuation of nefazodone. Crizotinib is a CYP3A substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC of single-dose crizotinib by 216%. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC of crizotinib by 57% compared to crizotinib alone.
    Cyclizine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Cyclobenzaprine: (Major) Coadministration of medications that increase central serotonergic activity, such as cyclobenzaprine and nefazodone, may increase the risk of serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical treatment should be implemented. In addition, in vitro data indicate that CYP3A4 and CYP1A2 are primarily responsible for the metabolism of cyclobenzaprine, and concurrent use of a CYP3A4 inhibitor such as nefazodone could theoretically result in elevated cyclobenzaprine plasma concentrations. Patients should be observed for enhanced side effects, such as CNS depression, if cyclobenzaprine and nefazodone are coadministered.
    Cyclosporine: (Major) Both nefazodone and cyclosporine are substrates and inhibitors of CYP3A4. Nefazodone is known to increase cyclosporine serum concentrations by inhibiting cyclosporine metabolism. A single case report is noted of increasing cyclosporine concentrations after the addition of nefazodone; the cyclosporine concentration returned to previous levels after the discontinuation of nefazodone. The manufacturer has also received reports of this interaction. In some cases cyclosporine levels have been seven-times their baseline after nefazodone administration. Because of the potential toxicity of cyclosporine, nefazodone should be used cautiously, if at all, in patients receiving cyclosporine. Monitoring of serum cyclosporine concentrations is recommended.
    Cyproheptadine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Dabrafenib: (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and moderate CYP3A4 inducer, and nefazodone, a strong CYP3A4 inhibitor and a CYP3A4 substrate, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity and for loss of nefazodone efficacy.
    Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as nefazodone. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Dapagliflozin; Saxagliptin: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP 3A4/5 inhibitor such as nefazodone.
    Darifenacin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with nefazodone due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor.
    Darunavir: (Major) Nefazodone inhibits the metabolism of anti-retroviral protease inhibitors. Nefazodone has been used to treat depression in patients on these medications concurrently. However, the potential drug interactions with anti-retroviral agents indicate that it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects of either the anti-retroviral or nefazodone treatment.
    Darunavir; Cobicistat: (Major) Nefazodone inhibits the metabolism of anti-retroviral protease inhibitors. Nefazodone has been used to treat depression in patients on these medications concurrently. However, the potential drug interactions with anti-retroviral agents indicate that it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects of either the anti-retroviral or nefazodone treatment. (Moderate) Caution is warranted when cobicistat is administered with nefazodone as there is a potential for elevated nefazodone and cobicistat concentrations. Both nefazodone and cobicistat are substrates and strong inhibitors of CYP3A4.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Nefazodone inhibits the metabolism of anti-retroviral protease inhibitors. Nefazodone has been used to treat depression in patients on these medications concurrently. However, the potential drug interactions with anti-retroviral agents indicate that it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects of either the anti-retroviral or nefazodone treatment. (Moderate) Caution is warranted when cobicistat is administered with nefazodone as there is a potential for elevated nefazodone and cobicistat concentrations. Both nefazodone and cobicistat are substrates and strong inhibitors of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Elevated plasma concentrations of nefazodone and ritonavir may occur. Both ritonavir and nefazodone are CYP3A4 substrates/potent inhibitors. Cardiac and neurologic events have been reported when ritonavir was concurrently administered with nefazodone. If coadministration of these drugs is warranted, do so with caution and careful monitoring. A 50% reduction in the nefazodone dose may be warranted. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs with potential bradycardic effects has not been evaluated. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with nefazodone is necessary. Paritaprevir is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with other strong CYP3A inhibitors increased paritaprevir exposure by 2.2- to 2.9-fold.
    Dasatinib: (Major) Avoid coadministration of dasatinib and nefazodone due to the potential for increased dasatinib exposure and subsequent toxicity. An alternative to nefazodone with no or minimal enzyme inhibition potential is recommended if possible. If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Concomitant use of nefazodone is not recommended in patients receiving dasatinib 60 mg or 40 mg daily. If dasatinib is not tolerated after dose reduction, consider alternative therapies. If nefazodone is stopped, allow a washout of approximately 1 week before increasing the dasatinib dose. Dasatinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with nefazodone. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; nefazodone is a strong inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
    Delavirdine: (Major) Both nefazodone and delavirdine are inhibitors and substrates of CYP3A4. Elevated plasma concentrations of both medications may occur during concurrent use. It is essential to evaluate for appropriate dosing of both agents to avoid adverse effects.
    Desipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as nefazodone. Both nefazodone and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Cases of serotonin syndrome or serotonin-related adverse events have been observed during concurrent use of serotonergic antidepressants and nefazodone. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as nefazodone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as nefazodone, may have additive effects and worsen drowsiness or sedation.
    Dexbrompheniramine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Dexbrompheniramine; Pseudoephedrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Dexchlorpheniramine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextroamphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and nefazodone. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Quinidine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Quinidine causes a dose-dependent QT prolongation and is metabolized via CYP3A4. Concurrent use of quinidine with moderate CYP3A4 inhibitors, such as nefazodone, may result in elevated quinidine plasma concentrations with the potential for enhanced QT-prolonging effects.
    Diazepam: (Moderate) Diazepam is metabolized by oxidative metabolism, specifically, the hepatic isozymes CYP2C19 and CYP3A4. As a result, diazepam is susceptible to interactions with drugs that inhibit these hepatic enzymes including nefazodone.
    Digoxin: (Major) Coadministration of digoxin and nefazodone increases the serum concentration and AUC of digoxin by 27% and 15%, respectively. Measure serum digoxin concentrations before initiating nefazodone. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of dihydrocodeine with nefazodone may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Additionally, the concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinue dihydrocodeine if serotonin syndrome occurs. Discontinuation of nefazodone could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Nefazodone is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Dihydroergotamine: (Contraindicated) Nefazodone may reduce the metabolism of dihydroergotamine via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness of the extremities or other serious effects). In addition, serotonin syndrome has been reported or may be possible with the use of ergot alkaloids like dihydroergotamine. particularly in combination with other serotonin-augmenting drugs. Avoid coadministration with nefazodone when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Diltiazem: (Moderate) Nefazodone is an inhibitor of CYP3A4 and may theoretically increase diltiazem serum concentrations with potential for toxicity.
    Dimenhydrinate: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Diphenhydramine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Diphenhydramine; Ibuprofen: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Diphenhydramine; Naproxen: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Diphenhydramine; Phenylephrine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Disopyramide: (Moderate) CYP3A4 inhibitors, such as nefazodone, may increase serum plasma concentrations of disopyramide, a CYP3A4 substrate. Caution should be used when CYP3A4 inhibitors are co-administered with disopyramide; monitor clinical response and serum disopyramide concentrations.
    Docetaxel: (Major) Avoid coadministration of docetaxel with nefazodone if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
    Dofetilide: (Major) Nefazodone may reduce the metabolism of dofetilide via CYP3A4 inhibition. This interaction may result in increased dofetilide plasma concentrations and risk for QTc prolongation.
    Dolutegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering nefazodone with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nefazodone is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Donepezil: (Minor) Monitor for increased donepezil effects if coadministered with nefazodone. Nefazodone is a strong CYP3A4 inhibitor; donepezil is partially metabolized by CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Donepezil; Memantine: (Minor) Monitor for increased donepezil effects if coadministered with nefazodone. Nefazodone is a strong CYP3A4 inhibitor; donepezil is partially metabolized by CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Doravirine: (Minor) Coadministration of doravirine and nefazodone may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; nefazodone is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Minor) Coadministration of doravirine and nefazodone may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; nefazodone is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
    Dorzolamide; Timolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Doxazosin: (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with nefazodone. Nefazodone is a strong CYP3A4 inhibitor; doxazosin is a CYP3A4 substrate. Coadministration of doxazosin with a moderate CYP3A4 inhibitor resulted in a 10% increase in mean AUC and an insignificant increase in mean Cmax and mean half-life of doxazosin. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution.
    Doxepin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as nefazodone. Both nefazodone and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Cases of serotonin syndrome or serotonin-related adverse events have been observed during concurrent use of serotonergic antidepressants and nefazodone. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Doxorubicin Liposomal: (Major) Nefazodone is a potent CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of nefazodone and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Doxorubicin: (Major) Nefazodone is a potent CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of nefazodone and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Doxylamine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Doxylamine; Pyridoxine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Dronabinol: (Major) Use caution if coadministration of dronabinol with nefazodone is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; nefazodone is a strong inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Contraindicated) The concomitant use of dronedarone and nefazodone is contraindicated due to the potential for increased exposure to dronedarone; nefazodone concentrations may also increase. Dronedarone is metabolized by CYP3A and is a moderate inhibitor of CYP3A. Nefazodone is a strong inhibitor of CYP3A4 and is a CYP3A substrate. Repeated doses of another strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. No data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. The effects of dronedarone on the pharmacokinetics of nefazodone have not been described, although an increase in nefazodone serum concentrations is possible.
    Droperidol: (Major) Central nervous system depressants, such as nefazodone, have additive or potentiating effects with droperidol. Following administration of droperidol, lower doses of the other CNS depressant should be used.
    Drospirenone: (Minor) Nefazodone is a strong CYP3A4 inhibitor. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when CYP3A4 inhibitors are coadministered with drospirenone; estradiol. An interaction has been reported clinically, but more study is needed to determine the clinical significance of this interaction in the general population. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly.
    Drospirenone; Estetrol: (Minor) Nefazodone is a strong CYP3A4 inhibitor. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when CYP3A4 inhibitors are coadministered with drospirenone; estradiol. An interaction has been reported clinically, but more study is needed to determine the clinical significance of this interaction in the general population. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly.
    Drospirenone; Estradiol: (Minor) Nefazodone is a strong CYP3A4 inhibitor. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when CYP3A4 inhibitors are coadministered with drospirenone; estradiol. An interaction has been reported clinically, but more study is needed to determine the clinical significance of this interaction in the general population. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly.
    Drospirenone; Ethinyl Estradiol: (Minor) Nefazodone is a strong CYP3A4 inhibitor. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when CYP3A4 inhibitors are coadministered with drospirenone; estradiol. An interaction has been reported clinically, but more study is needed to determine the clinical significance of this interaction in the general population. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Nefazodone is a strong CYP3A4 inhibitor. Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when CYP3A4 inhibitors are coadministered with drospirenone; estradiol. An interaction has been reported clinically, but more study is needed to determine the clinical significance of this interaction in the general population. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly.
    Duloxetine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as nefazodone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Dutasteride: (Moderate) Dutasteride is metabolized by CYP3A4 enzyme. The clearance of dutasteride may be reduced when co-administered with CYP3A4 inhibitors including nefazodone.
    Dutasteride; Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of nefazodone. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use with a strong CYP3A4 inhibitor, such as nefazodone, should be avoided. (Moderate) Dutasteride is metabolized by CYP3A4 enzyme. The clearance of dutasteride may be reduced when co-administered with CYP3A4 inhibitors including nefazodone.
    Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with nefazodone. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; nefazodone is a strong CYP3A inhibitor. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as nefazodone.
    Efavirenz: (Major) Nefazodone inhibits the CYP3A4 metabolism of efavirenz. Nefazodone has been used to treat depression in patients on antiretroviral medications concurrently. However, it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Nefazodone inhibits the CYP3A4 metabolism of efavirenz. Nefazodone has been used to treat depression in patients on antiretroviral medications concurrently. However, it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Nefazodone inhibits the CYP3A4 metabolism of efavirenz. Nefazodone has been used to treat depression in patients on antiretroviral medications concurrently. However, it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects.
    Elagolix: (Major) Concomitant use of elagolix 200 mg twice daily and nefazodone for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and nefazodone to 6 months. Elagolix is a CYP3A substrate; nefazodone is a strong inhibitor of CYP3A. Coadministration may increase elagolix plasma concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Concomitant use of elagolix 200 mg twice daily and nefazodone for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and nefazodone to 6 months. Elagolix is a CYP3A substrate; nefazodone is a strong inhibitor of CYP3A. Coadministration may increase elagolix plasma concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively.
    Elbasvir; Grazoprevir: (Major) Concurrent administration of elbasvir with nefazodone should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvirr, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Nefazodone is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with nefazodone should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentration grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Nefazodone is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, plasma concentrations of nefazodone (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
    Eletriptan: (Contraindicated) Eletriptan is contraindicated with recent use (i.e., within 72 hours) of nefazodone due to the potential for increased eletriptan exposure. Eletriptan is a sensitive substrate of CYP3A4; nefazodone is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the Cmax and AUC of eletriptan by 3-fold and 6-fold, respectively. In addition, although clinical data for some interactions is lacking, medications that augment release, decrease the metabolism of, or decrease the reuptake of serotonin (e.g., serotonin-receptor agonists) may interact with nefazodone by causing serotonin-related side effects, including serotonin syndrome.
    Elexacaftor; tezacaftor; ivacaftor: (Major) If nefazodone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate, and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor when coadministered with nefazodone; coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 2 elexacaftor/tezacaftor/ivacaftor combination tablets twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive substrate); nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with nefazodone; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); nefazodone is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
    Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of nefazodone and eliglustat is contraindicated. In extensive CYP2D6 metabolizer (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both nefazodone and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Nefazodone is a strong CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors, such as nefazodone, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with nefazodone as there is a potential for elevated nefazodone and cobicistat concentrations. Both nefazodone and cobicistat are substrates and strong inhibitors of CYP3A4.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with nefazodone as there is a potential for elevated nefazodone and cobicistat concentrations. Both nefazodone and cobicistat are substrates and strong inhibitors of CYP3A4.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering nefazodone with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nefazodone is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Close clinical monitoring is advised when administering nefazodone with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nefazodone is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Enalapril, Enalaprilat: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Enalapril; Felodipine: (Moderate) Nefazodone is a CYP3A4 inhibitor which theoretically may decrease hepatic clearance and enhance oral bioavailability of felodipine, a CYP3A4 substrate. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Enalapril; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Encorafenib: (Major) Avoid coadministration of encorafenib and nefazodone due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of nefazodone. If nefazodone is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of nefazodone. Encorafenib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Entacapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as nefazodone, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Entrectinib: (Major) Avoid coadministration of entrectinib with nefazodone due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If nefazodone is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of nefazodone. Entrectinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Enzalutamide: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with enzolutamide is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
    Eplerenone: (Contraindicated) Coadministration of nefazodone and eplerenone is contraindicated. Nefazodone potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Eprosartan: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Erdafitinib: (Major) Avoid coadministration of erdafitinib and nefazodone due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If nefazodone is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. The mean ratios for the Cmax and AUC of erdafitinib were 105% and 134%, respectively, when coadministered with another strong CYP3A4 inhibitor.
    Ergonovine: (Major) Nefazodone should be used cautiously, if at all, in patients taking certain ergot alkaloids. Nefazodone may reduce the metabolism of ergot alkaloids via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. In addition, serotonin syndrome has been reported or may be possible, particularly in combination with other serotonin-augmenting drugs. Avoid coadministration of ergonovine with nefazodone when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Ergotamine: (Major) Nefazodone may reduce the metabolism of ergotamine via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness of the extremities or other serious effects). In addition, serotonin syndrome has been reported or may be possible with the use of ergot alkaloids like ergotamine, particularly in combination with other serotonin-augmenting drugs. Avoid coadministration of ergotamine with nefazodone when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Ergotamine; Caffeine: (Major) Nefazodone may reduce the metabolism of ergotamine via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness of the extremities or other serious effects). In addition, serotonin syndrome has been reported or may be possible with the use of ergot alkaloids like ergotamine, particularly in combination with other serotonin-augmenting drugs. Avoid coadministration of ergotamine with nefazodone when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Erlotinib: (Major) Avoid coadministration of erlotinib with nefazodone if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Escitalopram: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as nefazodone and escitalopram. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least one case report of serotonin syndrome from the concurrent use of nefazodone and a selective serotonin reuptake inhibitor (i.e., paroxetine) has been published. Additionally, when a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient serotonin-related adverse events. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Esketamine: (Major) Closely monitor patients receiving esketamine and nefazodone for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
    Esmolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Estazolam: (Moderate) Nefazodone is a CYP3A4 inhibitor and may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with nefazodone, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro.
    Estradiol; Progesterone: (Moderate) Use caution if coadministration of nefazodone with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Nefazodone is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Estramustine: (Moderate) It is not known if nefazodone interacts with estrasmustine, but the interaction seems theoretically possible since estramustine contains an estradiol molecule linked to nornitrogen mustard and nefazodone inhibits the hepatic CYP3A4 isoenzyme which is responsible for the metabolism of estrogens. Until more data are available, monitor for potential estrogen-related side effects, such as increased nausea and fluid-retention.
    Eszopiclone: (Major) The adult dose of eszopiclone should not exceed 2 mg/day during co-administration of potent CYP3A4 inhibitors, such as nefazodone. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day psychomotor or memory impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Ethacrynic Acid: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
    Everolimus: (Major) Avoid coadministration of everolimus with nefazodone due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Nefazodone is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Ezetimibe; Simvastatin: (Contraindicated) Nefazodone is contraindicated during simvastatin therapy due to the increased risk of myopathy. Nefazodone may reduce the metabolism of simvastatin via inhibition of the hepatic CYP3A4 isoenzyme. Both rhabdomyolysis and myositis have been reported in the literature secondary to concurrent administration of nefazodone with simvastatin.
    Fedratinib: (Major) Avoid coadministration of fedratinib with nefazodone as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If nefazodone is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Felodipine: (Moderate) Nefazodone is a CYP3A4 inhibitor which theoretically may decrease hepatic clearance and enhance oral bioavailability of felodipine, a CYP3A4 substrate.
    Fenfluramine: (Moderate) Use fenfluramine and nefazodone with caution due to an increased risk of serotonin syndrome and additive CNS depression. Monitor for excessive sedation, somnolence, and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Fentanyl: (Major) Concomitant use of opioid agonists with nefazodone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. If nefazodone is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nefazodone can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If nefazodone is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Fesoterodine: (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with nefazodone. Avoid use of fesoterodine and nefazodone in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine.
    Finerenone: (Contraindicated) Concomitant use of finerenone and nefazodone is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%.
    Flibanserin: (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors, such as nefazodone, is contraindicated. Strong CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a strong CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a strong CYP3A4 inhibitor following flibanserin use, start the strong CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
    Fluoxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as nefazodone and fluoxetine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least one case report of serotonin syndrome from the concurrent use of nefazodone and a selective serotonin reuptake inhibitor (i.e., paroxetine) has been published. Additionally, when a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient serotonin-related adverse events. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Flurazepam: (Moderate) Nefazodone is a CYP3A4 inhibitor and may reduce the metabolism of flurazepam and increase the potential for benzodiazepine toxicity.
    Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and nefazodone is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
    Fluticasone; Salmeterol: (Major) Avoid concomitant use of salmeterol with nefazodone. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Coadministration of inhaled fluticasone propionate and nefazodone is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
    Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and nefazodone is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) The coadministration of vilanterol with strong CYP3A4 inhibitors such as nefazodone can result in elevated vilanterol plasma concentrations and increased risk for adverse reactions.
    Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and nefazodone is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) The coadministration of vilanterol with strong CYP3A4 inhibitors such as nefazodone can result in elevated vilanterol plasma concentrations and increased risk for adverse reactions.
    Fluvoxamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as nefazodone and fluvoxamine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least one case report of serotonin syndrome from the concurrent use of nefazodone and a selective serotonin reuptake inhibitor (i.e., paroxetine) has been published. Additionally, when a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient serotonin-related adverse events. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with nefazodone. Nefazodone is an inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with nefazodone, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Formoterol; Mometasone: (Moderate) Concomitant administration of nefazodone and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with nefazodone long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor.
    Fosamprenavir: (Major) Nefazodone inhibits the metabolism of anti-retroviral protease inhibitors. Nefazodone has been used to treat depression in patients on these medications concurrently. However, the potential drug interactions with anti-retroviral agents indicate that it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects of either the anti-retroviral or nefazodone treatment.
    Fosinopril: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Fosphenytoin: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with fosphenytoin is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
    Fostamatinib: (Moderate) Monitor for fostamatinib toxicities that may require fostamatinib dose reduction (i.e., elevated hepatic enzymes, neutropenia, high blood pressure, severe diarrhea) if given concurrently with a strong CYP3A4 inhibitor. Concomitant use of fostamatinib with a strong CYP3A4 inhibitor increases exposure to the major active metabolite, R406, which may increase the risk of adverse reactions. R406 is extensively metabolized by CYP3A4; nefazodone is a strong CYP3A4 inhibitor. Coadministration of fostamatinib with another strong CYP3A4 inhibitor increased R406 AUC by 102% and Cmax by 37%.
    Frovatriptan: (Major) Medications that augment release, decrease the metabolism of, or decrease the reuptake of serotonin, like the serotonin-receptor agonists, may interact with nefazodone by causing serotonin-related side effects, including serotonin syndrome. Whenever possible, these drug combinations should be avoided. If serotonin-syndrome is suspected, offending agents should be discontinued.
    Furosemide: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Gabapentin: (Major) Initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of gabapentin and nefazodone. Concomitant use of gabapentin with nefazodone may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
    Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with nefazodone is necessary. Gefitinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Gilteritinib: (Major) Consider an alternative to nefazodone during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Glasdegib: (Major) Consider an alternative to nefazodone during treatment with glasdegib. Concurrent use may increase glasdegib exposure resulting in treatment-related adverse events including QT prolongation. If coadministration cannot be avoided, monitor for increased adverse events; more frequent ECG monitoring is recommended. Glasdegib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Guaifenesin; Hydrocodone: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Guanfacine: (Major) Nefazodone may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If nefazodone is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and nefazodone is a strong CYP3A4 inhibitor.
    Halofantrine: (Moderate) Drugs which significantly inhibit cytochrome CYP3A4, such as nefazodone, may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity. If concurrent use of halofantrine and a CYP3A4 inhibitor is warranted, it would be prudent to use caution and monitor the ECG periodically.
    Haloperidol: (Moderate) Nefazodone is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of haloperidol. In one study, concurrent use of nefazodone and haloperidol resulted in a 36%, 13%, and 37% increase in mean AUC, highest concentration, and 12-h concentration values for haloperidol, respectively; however, only the increase in AUC was statistically significant. Elevated haloperidol concentrations occurring through inhibition of CYP3A4 may increase the risk of adverse effects, including QT prolongation or additive CNS effects. A lower doses of haloperidol may be required in some patients receiving this combination.
    Homatropine; Hydrocodone: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Hydrochlorothiazide, HCTZ; Moexipril: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Hydrocodone: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Hydrocodone; Ibuprofen: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Hydrocodone; Phenylephrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Hydrocodone; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and nefazodone because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with nefazodone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nefazodone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nefazodone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. nefazodone is a strong inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Hydromorphone: (Major) Concomitant use of opioid agonists with nefazodone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hydroxyzine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Concurrent use of intravenous methylene blue with nefazodone may increase the risk of serotonin syndrome. Methylene blue is a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and nefazodone increases central serotonin effects. Cases of serotonin syndrome have been reported with IV methylene blue given as a visualizing agent in patients receiving serotonergic agents like SSRIs, SNRIs, and clomipramine. It is not known if patients receiving other serotonergic psychiatric agents are at a comparable risk. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. For patients requiring urgent treatment with IV methylene blue, it may be wise to discontinue nefazodone and monitor the patient until 24 hours after the last dose of methylene blue IV; nefazodone can then be re-initiated 24 hours after the last dose of methylene blue.
    Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with nefazodone. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of ibrexafungerp by 5.8-fold and 2.5-fold, respectively.
    Ibrutinib: (Major) Avoid concomitant use of ibrutinib and nefazodone; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Ibuprofen; Oxycodone: (Major) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of nefazodone is necessary. If nefazodone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like nefazodone has resulted in serotonin syndrome. In addition, oxycodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nefazodone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If nefazodone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Idelalisib: (Contraindicated) Concomitant use of idelalisib, a CYP3A4 substrate, and nefazodone, a strong CYP3A4 inhibitor, may increase the exposure of idelalisib. Additionally, idelalisib is a strong CYP3A inhibitor while nefazodone is a CYP3A substrate. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. Avoid concomitant use of idelalisib and nefazodone.
    Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with nefazodone is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Nefazodone is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Iloperidone: (Major) Reduce the iloperidone dose by one-half if coadministered with nefazodone. If nefazodone is discontinued, increase the iloperidone dose to the previous level. Increased iloperidone exposure may occur with concurrent use. Iloperidone is a CYP3A4 substrate. Nefazodone is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively.
    Imatinib: (Moderate) Inhibitors of cytochrome P450 3A4, such as nefazodone, may decrease metabolism and increase imatinib, STI-571 concentrations leading to adverse reactions. However, interactions have not been studied.
    Imipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as nefazodone. Both nefazodone and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Cases of serotonin syndrome or serotonin-related adverse events have been observed during concurrent use of serotonergic antidepressants and nefazodone. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Indinavir: (Major) Nefazodone inhibits the metabolism of anti-retroviral protease inhibitors. Nefazodone has been used to treat depression in patients on these medications concurrently. However, the potential drug interactions with anti-retroviral agents indicate that it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects of either the anti-retroviral or nefazodone treatment.
    Infigratinib: (Major) Avoid concomitant use of infigratinib and nefazodone. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%.
    Irbesartan: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Irinotecan Liposomal: (Major) Avoid administration of nefazodone during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Irinotecan: (Major) Avoid administration of nefazodone during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Isavuconazonium: (Contraindicated) Concomitant use of isavuconazonium with nefazodone is contraindicated due to the risk for increased isavuconazole serum concentrations and serious adverse reactions, such as hepatic toxicity. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; nefazodone is a strong inhibitor of this enzyme. According to the manufacturer, coadministration of isavuconazole with strong CYP3A4 inhibitors is contraindicated. Isavuconazole serum concentrations were increased 5-fold when codadministered with another strong CYP3A4 inhibitor, ketoconazole. Elevated nefazodone concentrations would also be expected with coadministration, as nefazodone is a CYP3A4 substrate and isavuconazole is a moderate CYP3A4 inhibitor.
    Isocarboxazid: (Contraindicated) Nefazodone is considered contraindicated for concurrent use with MAOIs. Because nefazodone inhibits the reuptake of serotonin and, to a lesser extent, norepinephrine, combination with a MAOI could possibly produce confusion, delirium, coma, seizures, hyperthermia, or other, less severe, symptoms. Although severe reactions have been seen when drugs with a pharmacological profile similar to nefazodone were used with MAOI therapy, no controlled trials have been done with nefazodone. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of nefazodone therapy, or at least 1 week should elapse between the discontinuation of nefazodone and the initiation of a MAOI.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with rifampin is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
    Isoniazid, INH; Rifampin: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with rifampin is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
    Isradipine: (Moderate) Caution should be used when CYP3A4 inhibitors, such as nefazodone, are co-administered with isradipine a CYP3A4 substrate.
    Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with nefazodone as istradefylline exposure and adverse effects may increase. Nefazodone is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
    Ivabradine: (Contraindicated) Coadministration of ivabradine and nefazodone is contraindicated. Ivabradine is primarily metabolized by CYP3A4; nefazodone is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivacaftor: (Major) If nefazodone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate, and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with nefazodone if possible due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If nefazodone is discontinued, wait at least 5 half-lives of nefazodone before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
    Ixabepilone: (Major) Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with strong CYP3A4 inhibitors such as nefazodone should be avoided. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. If concurrent treatment with a strong CYP3A4 inhibitor is necessary, strongly consider an ixabepilone dose reduction. Closely monitor patients for ixabepilone-related toxicities. If a strong CYP3A4 inhibitor is discontinued, allow 7 days to elapse before increasing the ixabepilone dose.
    Labetalol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Lapatinib: (Major) Avoid coadministration of lapatinib with nefazodone due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If nefazodone is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold.
    Larotrectinib: (Major) Avoid coadministration of larotrectinib with nefazodone due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If nefazodone is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of nefazodone. Larotrectinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Lasmiditan: (Moderate) Monitor for excessive sedation, somnolence, and serotonin syndrome during coadministration of lasmiditan and nefazodone. Inform patients taking this combination of the risks and symptoms of excessive CNS depression and serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Lefamulin: (Major) Avoid coadministration of nefazodone with oral lefamulin due to increased lefamulin exposure; nefazodone may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
    Lemborexant: (Major) Avoid coadministration of lemborexant and nefazodone as concurrent use may increase lemborexant exposure and the risk of adverse effects. Additive CNS effects are also possible. Lemborexant is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of lemborexant with another strong CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of nefazodone; monitor for potential reduction in efficacy. Nefazodone is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of nefazodone; monitor for potential reduction in efficacy. Nefazodone is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Levamlodipine: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored.
    Levobetaxolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Levobunolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Levobupivacaine: (Minor) Nefazodone may inhibit the metabolism of levobupivacaine through CYP3A4. Concurrent administration of nefazodone and levobupivacaine may result in increased systemic levels of levobupivacaine resulting in toxicity.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with nefazodone should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Levomethadyl: (Major) Nefazodone inhibits hepatic cytochrome P450 CYP3A4 and may decrease the metabolism of levomethadyl, increase levomethadyl levels, and may precipitate severe arrhythmias including torsade de pointes.
    Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as nefazodone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Levorphanol: (Major) Concomitant use of opioid agonists with nefazodone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial dose of levorphanol by approximately 50% or more. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and nefazodone may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; nefazodone inhibits CYP3A4.
    Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and nefazodone may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; nefazodone inhibits CYP3A4.
    Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and nefazodone may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; nefazodone inhibits CYP3A4.
    Linezolid: (Major) Linezolid should generally not be administered to patients taking serotonergic agents, such as nefazodone, due to the potential for serious CNS reactions, such as serotonin syndrome. Serotonin syndrome has been reported when linezolid has been administerd with certain serotonergic agents. In theory, serotonin syndome could occur with the concomitant use of nefazodone; however, the FDA states that it is unclear if concomitant use of linezolid and agents with lesser degrees of serotonergic activity would pose a comparable risk. Linezolid is an antibiotic that is also a reversible, non-selective MAO inhibitor. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Lisdexamfetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and nefazodone. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Lisinopril: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Lofexidine: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and nefazodone. Lofexidine can potentiate the effects of CNS depressants.
    Lomitapide: (Contraindicated) Concomitant use of nefazodone and lomitapide is contraindicated. If treatment with nefazodone is unavoidable, lomitapide should be stopped during the course of treatment. Nefazodone is a strong CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor.
    Lonafarnib: (Contraindicated) Coadministration of lonafarnib and nefazodone is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
    Loop diuretics: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 substrate, may be increased when administered concurrently with nefazodone, a potent CYP3A4 inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 substrate, may be increased when administered concurrently with nefazodone, a potent CYP3A4 inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Major) Elevated plasma concentrations of nefazodone and ritonavir may occur. Both ritonavir and nefazodone are CYP3A4 substrates/potent inhibitors. Cardiac and neurologic events have been reported when ritonavir was concurrently administered with nefazodone. If coadministration of these drugs is warranted, do so with caution and careful monitoring. A 50% reduction in the nefazodone dose may be warranted. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs with potential bradycardic effects has not been evaluated. (Moderate) Elevated lopinavir plasma concentrations may occur when administered concurrently with nefazodone. Nefazodone is a potent inhibitor of CYP3A4; lopinavir is a CYP3A4 substrate. Lopinavir also prolongs the PR interval in some patients; however, the impact on the PR interval when administered with other drugs that have potential bradycardic effects has not been evaluated.
    Lorlatinib: (Major) Avoid coadministration of lorlatinib with nefazodone due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If nefazodone is discontinued, resume the original dose of lorlatinib after 3 half-lives of nefazodone. Lorlatinib is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Losartan: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Losartan; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Lovastatin: (Contraindicated) Concurrent use of lovastatin and nefazodone is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is substantially increased if lovastatin is administered concomitantly with nefazodone. Lovastatin is a substrate of CYP3A4 and nefazodone is a strong inhibitor of CYP3A4; therefore, coadministration may result in substantial increases in plasma concentrations of lovastatin.
    Lovastatin; Niacin: (Contraindicated) Concurrent use of lovastatin and nefazodone is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is substantially increased if lovastatin is administered concomitantly with nefazodone. Lovastatin is a substrate of CYP3A4 and nefazodone is a strong inhibitor of CYP3A4; therefore, coadministration may result in substantial increases in plasma concentrations of lovastatin.
    Lumacaftor; Ivacaftor: (Major) If nefazodone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate, and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of nefazodone; avoid concurrent use if possible. If concomitant use of nefazodone is necessary, monitor for efficacy and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when nefazodone is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking nefazodone, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other dayfor the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking nefazodone. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Nefazodone is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of nefazodone and decrease its therapeutic efficacy. Although nefazodone is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of nefazodone; avoid concurrent use if possible. If concomitant use of nefazodone is necessary, monitor for efficacy and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when nefazodone is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking nefazodone, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other dayfor the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking nefazodone. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Nefazodone is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of nefazodone and decrease its therapeutic efficacy. Although nefazodone is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Lumateperone: (Major) Avoid coadministration of lumateperone and nefazodone as concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold. In addition, additive CNS depressant effects may occur.
    Lurasidone: (Contraindicated) Concurrent use of lurasidone with strong CYP3A4 inhibitors, such as nefazodone, is contraindicated. Lurasidone is primarily metabolized by CYP3A4. Increased lurasidone plasma concentrations are expected when the drug is co-administered with inhibitors of CYP3A4.
    Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and nefazodone due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. Lurbinectedin is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor.
    Macitentan: (Major) Avoid concurrent use of macitentan and nefazodone. Nefazodone is a strong inhibitor of CYP3A4. Coadminsitration of macitentan with another strong CYP3A4 inhibitor (ketoconazole) approximately doubles macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with nefazodone is necessary.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as nefazodone. Caution should be exercised when using these agents concurrently.
    Maraviroc: (Major) Coadministration of maraviroc, a CYP3A substrate, with nefazodone, a strong CYP3A4 inhibitor, may result in increased maraviroc concentrations. Reduce the dose of maraviroc when coadministered with strong CYP3A inhibitors; coadministration of maraviroc with strong CYP3A inhibitors is contraindicated in patients with CrCl less than 30 mL/min. Adjust the maraviroc dosage as follows when administered with nefazodone (with or without a concomitant CYP3A inducer): adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily; children weighing 2 to 9 kg: use not recommended.
    Mecamylamine: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Meclizine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Medroxyprogesterone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with nefazodone, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro.
    Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Nefazodone is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure.
    Meperidine: (Major) Concomitant use of meperidine with nefazodone may cause excessive sedation and somnolence. Limit the use of meperidine with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of meperidine and nefazodone is necessary; less frequent dosing of meperidine may be required. Concomitant use of meperidine and nefazodone may increase the plasma concentration of meperidine, resulting in increased or prolonged opioid effects. If nefazodone is discontinued, consider increasing the meperidine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Meperidine is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Meperidine; Promethazine: (Major) Concomitant use of meperidine with nefazodone may cause excessive sedation and somnolence. Limit the use of meperidine with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of meperidine and nefazodone is necessary; less frequent dosing of meperidine may be required. Concomitant use of meperidine and nefazodone may increase the plasma concentration of meperidine, resulting in increased or prolonged opioid effects. If nefazodone is discontinued, consider increasing the meperidine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Meperidine is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Metformin; Repaglinide: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Nefazodone is an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Metformin; Saxagliptin: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP 3A4/5 inhibitor such as nefazodone.
    Methadone: (Major) Concomitant use of methadone with nefazodone may cause excessive sedation and somnolence. Limit the use of methadone with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of methadone and nefazodone is necessary; less frequent dosing of methadone may be required. Concomitant use of methadone and nefazodone may increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects. If nefazodone is discontinued, consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Methamphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as methamphetamine and nefazodone. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Concurrent use of intravenous methylene blue with nefazodone may increase the risk of serotonin syndrome. Methylene blue is a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and nefazodone increases central serotonin effects. Cases of serotonin syndrome have been reported with IV methylene blue given as a visualizing agent in patients receiving serotonergic agents like SSRIs, SNRIs, and clomipramine. It is not known if patients receiving other serotonergic psychiatric agents are at a comparable risk. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. For patients requiring urgent treatment with IV methylene blue, it may be wise to discontinue nefazodone and monitor the patient until 24 hours after the last dose of methylene blue IV; nefazodone can then be re-initiated 24 hours after the last dose of methylene blue.
    Methyclothiazide: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Methylene Blue: (Major) Concurrent use of intravenous methylene blue with nefazodone may increase the risk of serotonin syndrome. Methylene blue is a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and nefazodone increases central serotonin effects. Cases of serotonin syndrome have been reported with IV methylene blue given as a visualizing agent in patients receiving serotonergic agents like SSRIs, SNRIs, and clomipramine. It is not known if patients receiving other serotonergic psychiatric agents are at a comparable risk. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. For patients requiring urgent treatment with IV methylene blue, it may be wise to discontinue nefazodone and monitor the patient until 24 hours after the last dose of methylene blue IV; nefazodone can then be re-initiated 24 hours after the last dose of methylene blue.
    Methylergonovine: (Contraindicated) Nefazodone should be used cautiously, if at all, in patients taking certain ergot alkaloids. Nefazodone may reduce the metabolism of ergot alkaloids via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. In addition, serotonin syndrome has been reported or may be possible with the use of ergot alkaloids like ergotamine or dihydroergotamine, particularly in combination with other serotonin-augmenting drugs. Avoid coadministration of methylergonovine with nefazodone when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Methylphenidate Derivatives: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate derivatives and nefazodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Methylprednisolone: (Moderate) It appears that nefazodone inhibits the metabolism of methylprednisolone. In addition, concomitant nefazodone prolongs the duration of methylprednisolone induced cortisol suppression. If nefazodone and methylprednisolone are to be coadministered, care should be taken with regards to the potential for prolonged corticosteroid exposure.
    Methysergide: (Contraindicated) Nefazodone should be used cautiously, if at all, in patients taking methysergide. Nefazodone may reduce the metabolism of methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects.
    Metolazone: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Metoprolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Midazolam: (Major) Nefazodone inhibits the hepatic CYP3A4 isoenzyme and substantially increases the plasma concentrations of some benzodiazepines. Although not studied, a similar interaction may occur with oral midazolam. If possible, this drug combination is best avoided due to the narrow therapeutic index for midazolam. If concurrent use of these drugs is necessary, it would be prudent to reduce the midazolam dosage and monitor the clinical response more closely.
    Midostaurin: (Major) Avoid the concomitant use of midostaurin and nefazodone due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
    Mifepristone: (Major) Caution is advised when administering nefazodone with mifepristone because increased serum concentrations of either drug may occur. When mifepristone is used in the treatment of Cushing's syndrome, coadministration with nefazodone should be done only when necessary, and in such cases the dose of mifepristone should be limited to a maximum dose of 900 mg per day. In a patient already receiving nefazodone, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with nefazodone is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with nefazodone is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with nefazodone is initiated in a patient already receiving 900 mg, reduce dose of mifepristone to 600 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with nefazodone is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and nefazodone are substrates and strong inhibitors of CYP3A4.
    Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as nefazodone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as nefazodone. Caution should be exercised when using these agents concurrently.
    Mirtazapine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering mirtazapine with other drugs that have serotonergic properties such as nefazodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Additive sedative effects are also possible. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Mirtazapine should be discontinued if a patient develops a combination of symptoms suggestive of serotonin syndrome.
    Mitapivat: (Major) Avoid coadministration of mitapivat with nefazodone due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold.
    Mitotane: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with mitotane is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
    Mobocertinib: (Major) Avoid concomitant use of mobocertinib and nefazodone. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions such as QT prolongation. Mobocertinib is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Use of a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%.
    Modafinil: (Moderate) Modafinil is extensively metabolized by the CYP3A4 hepatic isoenzyme, which nefazodone inhibits. Modafinil concentrations may increase with concurrent nefazodone use. Because modafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 enzyme inhibition by other medications may be complex and difficult to predict.
    Moexipril: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Mometasone: (Moderate) Concomitant administration of nefazodone and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with nefazodone long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor.
    Monoamine oxidase inhibitors: (Contraindicated) Nefazodone is considered contraindicated for concurrent use with MAOIs. Because nefazodone inhibits the reuptake of serotonin and, to a lesser extent, norepinephrine, combination with a MAOI could possibly produce confusion, delirium, coma, seizures, hyperthermia, or other, less severe, symptoms. Although severe reactions have been seen when drugs with a pharmacological profile similar to nefazodone were used with MAOI therapy, no controlled trials have been done with nefazodone. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of nefazodone therapy, or at least 1 week should elapse between the discontinuation of nefazodone and the initiation of a MAOI.
    Morphine: (Major) Concomitant use of opioid agonists with nefazodone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at one-third to one-half the recommended starting dosage. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Morphine; Naltrexone: (Major) Concomitant use of opioid agonists with nefazodone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at one-third to one-half the recommended starting dosage. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Nabilone: (Moderate) Concomitant use of nabilone with nefazodone can potentiate the effects of cannabinoids on drowsiness and CNS depression.
    Nadolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Nalbuphine: (Major) Concomitant use of opioid agonists with nefazodone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with nefazodone. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor.
    Naloxegol: (Contraindicated) Concomitant use of naloxegol with nefazodone is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as nefazodone, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with nefazodone is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as nefazodone. Nefazodone may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Naratriptan: (Major) Medications that augment release, decrease the metabolism of, or decrease the reuptake of serotonin, like the serotonin-receptor agonists, may interact with nefazodone by causing serotonin-related side effects, including serotonin syndrome. Whenever possible, these drug combinations should be avoided. If serotonin-syndrome is suspected, offending agents should be discontinued.
    Nebivolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Nebivolol; Valsartan: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Nelfinavir: (Major) Nefazodone inhibits the metabolism of anti-retroviral protease inhibitors. Nefazodone has been used to treat depression in patients on these medications concurrently. However, the potential drug interactions with anti-retroviral agents indicate that it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects of either the anti-retroviral or nefazodone treatment.
    Neratinib: (Major) Avoid concomitant use of nefazodone with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Nefazodone is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as nefazodone can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
    Nevirapine: (Moderate) Nevirapine is an inducer of the cytochrome P4503A enzyme. Concomitant administration of nevirapine with drugs that are extensively metabolized by this enzyme, such as nefazodone, may require dosage adjustments.
    Niacin; Simvastatin: (Contraindicated) Nefazodone is contraindicated during simvastatin therapy due to the increased risk of myopathy. Nefazodone may reduce the metabolism of simvastatin via inhibition of the hepatic CYP3A4 isoenzyme. Both rhabdomyolysis and myositis have been reported in the literature secondary to concurrent administration of nefazodone with simvastatin.
    Nicardipine: (Moderate) Caution should be used when CYP3A4 inhibitors, such as nefazodone, are co-administered with nicardipine, a CYP3A4 substrate and inhibitor.
    Nifedipine: (Moderate) Nefazodone is a CYP3A4 inhibitor which theoretically may decrease hepatic clearance and enhance oral bioavailability of nifedipine, a CYP3A4 substrate. In addition, although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and nefazodone. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If nefazodone is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and nefazodone is a strong inhibitor of CYP3A4.
    Nimodipine: (Moderate) Nefazodone is a CYP3A4 inhibitor which theoretically may decrease hepatic metabolism of nimodipine, a CYP3A4 substrate.
    Nirmatrelvir; Ritonavir: (Major) Elevated plasma concentrations of nefazodone and ritonavir may occur. Both ritonavir and nefazodone are CYP3A4 substrates/potent inhibitors. Cardiac and neurologic events have been reported when ritonavir was concurrently administered with nefazodone. If coadministration of these drugs is warranted, do so with caution and careful monitoring. A 50% reduction in the nefazodone dose may be warranted. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs with potential bradycardic effects has not been evaluated.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with nefazodone due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor.
    Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antidepressants. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with antidepressants.
    Nortriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as nefazodone. Both nefazodone and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Cases of serotonin syndrome or serotonin-related adverse events have been observed during concurrent use of serotonergic antidepressants and nefazodone. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Olanzapine; Fluoxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as nefazodone and fluoxetine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least one case report of serotonin syndrome from the concurrent use of nefazodone and a selective serotonin reuptake inhibitor (i.e., paroxetine) has been published. Additionally, when a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient serotonin-related adverse events. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Olaparib: (Major) Avoid coadministration of olaparib with nefazodone due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after nefazodone is discontinued. Olaparib is a CYP3A substrate and nefazodone is a strong CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A inhibitor increased the olaparib Cmax by 42% and the AUC by 170%.
    Oliceridine: (Major) Concomitant use of oliceridine with nefazodone may cause excessive sedation and somnolence. Limit the use of oliceridine with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and nefazodone is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and nefazodone may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If nefazodone is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Olmesartan: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Elevated plasma concentrations of nefazodone and ritonavir may occur. Both ritonavir and nefazodone are CYP3A4 substrates/potent inhibitors. Cardiac and neurologic events have been reported when ritonavir was concurrently administered with nefazodone. If coadministration of these drugs is warranted, do so with caution and careful monitoring. A 50% reduction in the nefazodone dose may be warranted. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs with potential bradycardic effects has not been evaluated. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with nefazodone is necessary. Paritaprevir is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with other strong CYP3A inhibitors increased paritaprevir exposure by 2.2- to 2.9-fold.
    Opicapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as nefazodone, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Oritavancin: (Moderate) Nefazodone is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of nefazodone may be reduced if these drugs are administered concurrently.
    Osilodrostat: (Major) Reduce the dose of osilodrostat by one-half during coadministration of nefazodone; concurrent use may increase osilodrostat exposure and the risk of osilodrostat-related adverse reactions. Osilodrostat is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor.
    Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A4. Inhibitors of the CYP3A4 enzyme, such as nefazodone, may increase the serum concentrations of oxybutynin. The manufacturer recommends caution when oxybutynin is co-administered with CYP3A4 inhibitors.
    Oxycodone: (Major) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of nefazodone is necessary. If nefazodone is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like nefazodone has resulted in serotonin syndrome. In addition, oxycodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nefazodone can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If nefazodone is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Oxymorphone: (Major) Concomitant use of opioid agonists with nefazodone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial oxymorphone dosage by one-third to one-half. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Ozanimod: (Major) Coadministration of ozanimod with nefazodone is not recommended due to the potential for hypertensive crisis. If coadministration is necessary, closely monitor patients for hypertension. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis. Nefazodone may increase blood pressure by increasing serotonin concentrations.
    Paclitaxel: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Inhibitors of these enzymes, such as nefazodone, may cause increased serum concentration and side effects of paclitaxel. Closely monitor patients for toxicity when administering paclitaxel with any of these agents.
    Pacritinib: (Contraindicated) Concurrent use of pacritinib with nefazodone is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor.
    Palbociclib: (Major) Avoid coadministration of nefazodone with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If nefazodone is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of nefazodone) to the dose used before initiation of nefazodone. Palbociclib is primarily metabolized by CYP3A4 and nefazodone is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
    Panobinostat: (Major) Use caution when administering panobinostat and nefazodone together; reduce the initial panobinostat dose from 20 mg PO to 10 mg PO. Nefazodone is a strong CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor.
    Paricalcitol: (Moderate) Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as nefazodone. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
    Paroxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as nefazodone and paroxetine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least one case report of serotonin syndrome from the concurrent use of nefazodone and a selective serotonin reuptake inhibitor (i.e., paroxetine) has been published. Additionally, when a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient serotonin-related adverse events. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Pazopanib: (Major) Avoid administering pazopanib with strong CYP3A4 inhibitors, such as nefazodone. If co-administration with a strong CYP3A4 inhibitor is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur. The concomitant use of pazopanib, a weak CYP3A4 inhibitor and a CYP3A4 substrate, and nefazodone, a strong CYP3A4 inhibitor and CYP3A4 substrate, may result in increased pazopanib and/or nefazodone concentrations.
    Pemigatinib: (Major) Avoid coadministration of pemigatinib and nefazodone due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If nefazodone is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of nefazodone. Pemigatinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased pemigatinib exposure by 88%.
    Penbutolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Pentazocine: (Moderate) Concomitant use of pentazocine with other CNS depressants, such as nefazodone, can potentiate respiratory depression, CNS depression, and sedation.
    Pentazocine; Naloxone: (Moderate) Concomitant use of pentazocine with other CNS depressants, such as nefazodone, can potentiate respiratory depression, CNS depression, and sedation.
    Perampanel: (Moderate) Concomitant use of perampanel and nefazodone, a potent CYP3A4 inhibitor, may increase exposure to perampanel, a CYP3A4 substrate. Monitor patients for increases in adverse effects such as anger anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Perindopril: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Perindopril; Amlodipine: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Perphenazine; Amitriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as nefazodone. Both nefazodone and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Cases of serotonin syndrome or serotonin-related adverse events have been observed during concurrent use of serotonergic antidepressants and nefazodone. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Pexidartinib: (Major) Avoid coadministration of pexidartinib with nefazodone as concurrent use may increase pexidartinib exposure. If concurrent use cannot be avoided, reduce the dose of pexidartinib. If nefazodone is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of nefazodone. Dose adjustments are as follows: 800 mg/day or 600 mg/day of pexidartinib, reduce to 200 mg twice daily; 400 mg/day of pexidartinib, reduce to 200 mg once daily. Pexidartinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased pexidartinib exposure by 70%.
    Phenelzine: (Contraindicated) Nefazodone is considered contraindicated for concurrent use with MAOIs. Because nefazodone inhibits the reuptake of serotonin and, to a lesser extent, norepinephrine, combination with a MAOI could possibly produce confusion, delirium, coma, seizures, hyperthermia, or other, less severe, symptoms. Although severe reactions have been seen when drugs with a pharmacological profile similar to nefazodone were used with MAOI therapy, no controlled trials have been done with nefazodone. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of nefazodone therapy, or at least 1 week should elapse between the discontinuation of nefazodone and the initiation of a MAOI.
    Phenobarbital: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with phenobarbital is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with phenobarbital is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
    Phenytoin: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with phenytoin is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
    Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as nefazodone. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Pimozide: (Contraindicated) Nefazodone inhibits the hepatic CYP3A4 isoenzyme. Post-marketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes and death, when known and potent inhibitors of CYP3A4 are coadministered with pimozide. Because of the potential severity of these drug interactions, nefazodone is contraindicated for use with these medications.
    Pindolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of nefazodone due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; nefazodone is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
    Ponatinib: (Major) Avoid coadministration of ponatinib and nefazodone due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of nefazodone and consider alternative therapy. After nefazodone has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting nefazodone. Ponatinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Posaconazole: (Moderate) Posaconazole and nefazodone should be coadministered with caution due to an increased potential for nefazodone-related adverse events. Both posaconazole and nefazodone are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of nefazodone. These drugs used in combination may result in elevated nefazodone plasma concentrations, causing an increased risk for nefazodone-related adverse events.
    Potassium-sparing diuretics: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Pralsetinib: (Major) Avoid coadministration of nefazodone with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. Pralsetinib is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with a combined P-gp and strong CYP3A inhibitor increased the AUC of pralsetinib by 251%.
    Pregabalin: (Major) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and nefazodone. Concomitant use of pregabalin with nefazodone may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
    Primidone: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with primidone is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
    Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and nefazodone in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Nefazodone can inhibit colchicine's metabolism via CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken nefazodone in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Progesterone: (Moderate) Use caution if coadministration of nefazodone with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Nefazodone is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Promethazine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Propafenone: (Moderate) Nefazodone is a CYP3A4 inhibitors which theoretically may decrease the hepatic metabolism of propafenone.
    Propoxyphene: (Moderate) Concomitant use of propoxyphene with other CNS depressants, such as nefazodone, can potentiate respiratory depression and/or sedation. Use with caution.
    Propranolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Propranolol; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Protriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as nefazodone. Both nefazodone and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Cases of serotonin syndrome or serotonin-related adverse events have been observed during concurrent use of serotonergic antidepressants and nefazodone. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Pseudoephedrine; Triprolidine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Pyrilamine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Quazepam: (Moderate) Nefazodone inhibits the hepatic CYP3A4 isoenzyme and thus substantially increases the plasma concentrations of many benzodiazepines that undergo oxidative metabolism.
    Quetiapine: (Major) Nefazodone may inhibit the CYP3A4 metabolism of quetiapine, resulting in elevated quetiapine plasma concentrations. If administration of nefazodone is required in a patient taking quetiapine, reduce the quetiapine dose to one sixth of the current dose and monitor for quetiapine-related adverse events. If nefazodone is discontinued, increase the quetiapine dose by 6-fold.
    Quinapril: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Quinapril; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Quinidine: (Moderate) Quinidine causes a dose-dependent QT prolongation and is metabolized via CYP3A4. Concurrent use of quinidine with moderate CYP3A4 inhibitors, such as nefazodone, may result in elevated quinidine plasma concentrations with the potential for enhanced QT-prolonging effects.
    Ramipril: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Ranolazine: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including nefazodone. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes.
    Rasagiline: (Major) It is recommended to avoid concurrent use of rasagiline and antidepressants, including nefazodone. Severe CNS toxicity with hyperpyrexia has been reported during concurrent use of antidepressants and selective or non-selective MAOIs. During postmarketing use of rasagiline, non-fatal cases of serotonin syndrome have been reported during concomitant antidepressant administration. At least 2 weeks should elapse between stopping rasagiline treatment and beginning therapy with nefazodone. Conversely, when discontinuing nefazodone, it is advisable to wait the length of 4 to 5 half-lives of the drug prior to initiation with rasagiline.
    Red Yeast Rice: (Contraindicated) Nefazodone may reduce the metabolism of certain HMG-CoA reductase inhibitors (e.g., atorvastatin, cerivastatin, lovastatin) via inhibition of the hepatic CYP3A4 isoenzyme. Coadministration of nefazodone is not recommended with lovastatin. Both rhabdomyolysis and myositis have been reported in the literature secondary to concurrent administration of nefazodone with lovastatin. Since pravastatin and rosuvastatin are not substantially metabolized and fluvastatin is a minor CYP3A4 substrate (20%), these statins are less likely to be significantly affected by CYP3A4 inhibitors such as nefazodone. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, red yeast rice should not be used in combination with nefazodone.
    Regorafenib: (Major) Avoid coadministration of regorafenib with nefazodone due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Remifentanil: (Major) Concomitant use of opioid agonists with nefazodone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Repaglinide: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Nefazodone is an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Reserpine: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as nefazodone, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate.
    Ribociclib: (Major) Avoid coadministration of nefazodone with ribociclib if possible due to increased ribociclib exposure resulting in a risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ribociclib to 400 mg PO once daily; monitor ECGs for QT prolongation and monitor electrolytes. If nefazodone is discontinued, the original dose of ribociclib may be resumed after at least 5 half-lives of nefazodone. Ribociclib is a CYP3A4 substrate and strong inhibitor, that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Nefazodone is a strong CYP3A4 inhibitor as well as a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased ribociclib exposure in healthy subjects by 3.2-fold.
    Ribociclib; Letrozole: (Major) Avoid coadministration of nefazodone with ribociclib if possible due to increased ribociclib exposure resulting in a risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ribociclib to 400 mg PO once daily; monitor ECGs for QT prolongation and monitor electrolytes. If nefazodone is discontinued, the original dose of ribociclib may be resumed after at least 5 half-lives of nefazodone. Ribociclib is a CYP3A4 substrate and strong inhibitor, that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Nefazodone is a strong CYP3A4 inhibitor as well as a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased ribociclib exposure in healthy subjects by 3.2-fold.
    Rifampin: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with rifampin is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
    Rifapentine: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with rifapentine is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
    Rilpivirine: (Moderate) Close clinical monitoring is advised when administering nefazodone with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nefazodone is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Rimegepant: (Major) Avoid coadministration of rimegepant with nefazodone; concurrent use may significantly increase rimegepant exposure. Rimegepant is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration of rimegepant with another strong CYP3A4 inhibitor increased rimegepant exposure by 4-fold.
    Riociguat: (Moderate) Concomitant use of riociguat with strong cytochrome CYP3A inhibitors may result in hypotension. Nefazodone is a potent inhibitor of CYP3A4. In addition, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with riociguat. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
    Ripretinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with nefazodone. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
    Ritonavir: (Major) Elevated plasma concentrations of nefazodone and ritonavir may occur. Both ritonavir and nefazodone are CYP3A4 substrates/potent inhibitors. Cardiac and neurologic events have been reported when ritonavir was concurrently administered with nefazodone. If coadministration of these drugs is warranted, do so with caution and careful monitoring. A 50% reduction in the nefazodone dose may be warranted. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs with potential bradycardic effects has not been evaluated.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and nefazodone may result in increases in rivaroxaban exposure and may increase bleeding risk. Nefazodone is a potent inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Rizatriptan: (Major) Medications that augment release, decrease the metabolism of, or decrease the reuptake of serotonin, like the serotonin-receptor agonists, may interact with nefazodone by causing serotonin-related side effects, including serotonin syndrome. Whenever possible, these drug combinations should be avoided. If serotonin-syndrome is suspected, offending agents should be discontinued.
    Romidepsin: (Moderate) The concomitant use of romidepsin, a CYP3A4 substrate, and nefazodone, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as nefazodone, may occur during concurrent use with rufinamide.
    Ruxolitinib: (Major) Reduce the ruxolitinib dosage when coadministered with nefazodone in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of nefazodone in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. Ruxolitinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor.
    Sacubitril; Valsartan: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Salmeterol: (Major) Avoid concomitant use of salmeterol with nefazodone. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Saquinavir: (Major) The concurrent use of saquinavir boosted with ritonavir and nefazodone should be avoided if possible due to the potential for elevated saquinavir plasma concentrations and associated adverse effects. Both saquinavir boosted with ritonavir and nefazodone are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation. The use of saquinavir/ritonavir with nefazodone may result in large increases in saquinavir plasma concentrations, which could cause adverse events such as life threatening cardiac arrhythmias (e.g., torsade de pointes [TdP]).
    Saxagliptin: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP 3A4/5 inhibitor such as nefazodone.
    Sedating H1-blockers: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Segesterone Acetate; Ethinyl Estradiol: (Minor) Coadministration of segesterone and strong CYP3A4 inhibitors such as nefazodone may increase the serum concentration of segesterone.
    Selegiline: (Contraindicated) Nefazodone is contraindicated for use with selegiline, a selective monoamine oxidase type B inhibitor (MAO-B inhibitor). At least 14 days should elapse between discontinuation of selegiline and initiation of treatment with nefazodone. After stopping treatment with nefazodone, a time period equal to 4 to 5 half-lives of nefazodone or any active metabolite should elapse before starting therapy with selegiline. Serotonin syndrome has occurred in patients receiving selective MAO-B inhibitors and sertonoergic antidepressants simultaneously.
    Selpercatinib: (Major) Avoid coadministration of selpercatinib and nefazodone due to the risk of increased selpercatinib exposure which may increase the risk of adverse reactions, including QT prolongation. If coadministration is unavoidable, reduce the dose of selpercatinib to 40 mg PO twice daily if original dose was 120 mg twice daily, and to 80 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If nefazodone is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of nefazodone. Selpercatinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selpercatinib exposure by 133%.
    Selumetinib: (Major) Avoid coadministration of selumetinib and nefazodone due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If nefazodone is discontinued, resume the original selumetinib dose after 3 elimination half-lives of nefazodone. Selumetinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
    Serotonin norepinephrine reuptake inhibitors: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as nefazodone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Sertraline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as nefazodone and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least one case report of serotonin syndrome from the concurrent use of nefazodone and a selective serotonin reuptake inhibitor (i.e., paroxetine) has been published. Additionally, when a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient serotonin-related adverse events. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Sibutramine: (Major) Concomitant use of two serotonin-augmenting drugs, such as nefazodone and sibutramine, may be associated with serotonin syndrome. Avoid concomitant adminsitration of these drugs.
    Sildenafil: (Major) Coadministration of nefazodone is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving nefazodone. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Nefazodone is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Silodosin: (Moderate) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4. In theory, drugs that inhibit CYP3A4 such as nefazodone may cause significant increases in silodosin plasma concentrations.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and nefazodone. Inhibition of CYP3A4 by nefazodone may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of nefazodone, a CYP3A4 substrate.
    Simvastatin: (Contraindicated) Nefazodone is contraindicated during simvastatin therapy due to the increased risk of myopathy. Nefazodone may reduce the metabolism of simvastatin via inhibition of the hepatic CYP3A4 isoenzyme. Both rhabdomyolysis and myositis have been reported in the literature secondary to concurrent administration of nefazodone with simvastatin.
    Simvastatin; Sitagliptin: (Contraindicated) Nefazodone is contraindicated during simvastatin therapy due to the increased risk of myopathy. Nefazodone may reduce the metabolism of simvastatin via inhibition of the hepatic CYP3A4 isoenzyme. Both rhabdomyolysis and myositis have been reported in the literature secondary to concurrent administration of nefazodone with simvastatin.
    Siponimod: (Moderate) Concomitant use of siponimod and nefazodone may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
    Sirolimus: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as nefazodone. Nefazodone may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as nefazodone. Caution should be exercised when using these agents concurrently.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with nefazodone. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Nefazodone is a potent CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with nefazodone. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Nefazodone is a potent CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
    Solifenacin: (Moderate) Use caution and reduce the solifenacin dose to 5 mg per day when used concomitantly with nefazodone. Solifenacin is significantly metabolized via the CYP3A4 pathway; nefazodone is a strong CYP3A4 inhibitor. Pharmacokinetic studies of the use of solifenacin concomitantly with all CYP3A4 inhibitors have not been performed. The interaction between solifenacin and ketoconazole has been studied. Following the administration of solifenacin 10 mg and ketoconazole 400 mg PO, the peak concentration and AUC increased 150% and 270%, respectively.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and nefazodone; sonidegib exposure may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
    Sotalol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Spironolactone: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    St. John's Wort, Hypericum perforatum: (Moderate) Concurrent use of nefazodone and St. John's wort may increase the risk of serotonin syndrome or decrease the efficacy of nefazodone. Inform patients of the possible risk for serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, monitor for decreased efficacy of nefazodone if coadministration with St. John's wort is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
    Sufentanil: (Major) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if nefazodone must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of nefazodone is necessary. If nefazodone is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like nefazodone has resulted in serotonin syndrome. In addition, sufentanil is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nefazodone can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If nefazodone is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Sumatriptan: (Major) Medications that augment release, decrease the metabolism of, or decrease the reuptake of serotonin, like the serotonin-receptor agonists, may interact with nefazodone by causing serotonin-related side effects, including serotonin syndrome. Whenever possible, these drug combinations should be avoided. If serotonin-syndrome is suspected, offending agents should be discontinued.
    Sumatriptan; Naproxen: (Major) Medications that augment release, decrease the metabolism of, or decrease the reuptake of serotonin, like the serotonin-receptor agonists, may interact with nefazodone by causing serotonin-related side effects, including serotonin syndrome. Whenever possible, these drug combinations should be avoided. If serotonin-syndrome is suspected, offending agents should be discontinued.
    Sunitinib: (Major) Avoid coadministration of nefazodone with sunitinib if possible due to increased sunitinib exposure, which may increase the risk of QT prolongation. If concomitant use is unavoidable, monitor the QT interval more frequently and consider reducing the daily dose of sunitinib to a minimum of 37.5 mg for patients with GIST or RCC, and to a minimum of 25 mg for patients with pNET. Sunitinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%.
    Suvorexant: (Major) Coadministration of suvorexant and nefazodone is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate. Nefazodone is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the suvorexant AUC by 2.8-fold.
    Tacrolimus: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with nefazodone if necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Delirium, renal failure, and high tacrolimus serum concentrations (46.4 ng/ml) were reported in a patient receiving tacrolimus and nefazodone. The patient discontinued nefazodone and was started on paroxetine instead. Three days after stopping the nefazodone the tacrolimus level was 10.2 ng/ml. In a separate report, a patient on stable doses of tacrolimus for 2 years developed headache, confusion and 'gray areas' in her vision without ophthalmologic findings 1 week after switching from sertraline to nefazodone for persistent depression. Her serum creatinine increased 1.5 mg/dl from baseline and her 12-hour trough tacrolimus level was greater than 30 ng/ml. The tacrolimus was held for 4 days and the patient restarted on sertraline with resolution of symptoms. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; nefazodone is a strong CYP3A4 inhibitor.
    Tadalafil: (Moderate) Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme and inhibitors of CYP3A4, such as nefazodone, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of nefazodone. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use with a strong CYP3A4 inhibitor, such as nefazodone, should be avoided.
    Tapentadol: (Major) Concomitant use of opioid agonists with nefazodone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Tasimelteon: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as nefazodone, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Tazemetostat: (Major) Avoid coadministration of tazemetostat with nefazodone as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
    Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and nefazodone, due to the theoretical risk of serious CNS reactions, such as serotonin sydrome. Animal studies did not predict serontoneric effects with tedizolid. Addtionally, tedizolid is an antibiotic that is also a weak reversible, non-selective MAO inhibitor. Serotonin syndrome has been reported when linezolid, which is structurally similar to tedizolid, has been administerd with certain serotonergic agents. In theory, serotonin syndome could occur with the concomitant use of nefazodone; however, the FDA states that it is unclear if concomitant use of linezolid and agents with lesser degrees of serotonergic activity would pose a comparable risk. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering nefazodone with telaprevir due to an increased potential for nefazodone-related adverse events. If nefazodone dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of nefazodone and telaprevir. Both nefazodone and telaprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4. When used in combination, the plasma concentrations of both medications may be elevated.
    Telithromycin: (Moderate) Concentrations of telithromycin and nefazodone may be increased with coadministration, as both agents are CYP3A4 substrates and inhibitors. Patients should be monitored for increased side effects.
    Telmisartan: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Telmisartan; Amlodipine: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Temsirolimus: (Major) Avoid coadministration of nefazodone with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of nefazodone before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering nefazodone. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; nefazodone is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
    Tezacaftor; Ivacaftor: (Major) If nefazodone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate, and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with nefazodone; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); nefazodone is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
    Thalidomide: (Major) Avoid the concomitant use of thalidomide with other central nervous system depressants such as nefazodone due to the potential for additive sedative effects.
    Thiazide diuretics: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Thiotepa: (Major) Avoid the concomitant use of thiotepa and nefazodone if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; nefazodone is a strong CYP3A4 inhibitor.
    Ticagrelor: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as nefazodone. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with nefazodone substantially increases ticagrelor exposure which may increase the bleeding risk.
    Timolol: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Tipranavir: (Major) Nefazodone inhibits the metabolism of anti-retroviral protease inhibitors. Nefazodone has been used to treat depression in patients on these medications concurrently. However, the potential drug interactions with anti-retroviral agents indicate that it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects of either the anti-retroviral or nefazodone treatment.
    Tisotumab Vedotin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with nefazodone is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
    Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with nefazodone. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with nefazodone. Nefazodone is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
    Tolcapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as nefazodone, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Tolterodine: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with nefazodone. Concurrent use may increase tolterodine exposure. Nefazodone is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
    Tolvaptan: (Contraindicated) The concomitant use of tolvaptan and nefazodone is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; nefazodone is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Toremifene: (Major) Avoid coadministration of nefazodone with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Torsemide: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Trabectedin: (Major) Avoid the concomitant use of trabectedin with nefazodone due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with nefazodone is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concurrent use of nefazodone, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with nefazodone is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concurrent use of nefazodone, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Trandolapril: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Trandolapril; Verapamil: (Moderate) Nefazodone is an inhibitor of CYP3A4, and may theoretically increase verapamil serum concentrations. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Tranylcypromine: (Contraindicated) Nefazodone is considered contraindicated for concurrent use with MAOIs. Because nefazodone inhibits the reuptake of serotonin and, to a lesser extent, norepinephrine, combination with a MAOI could possibly produce confusion, delirium, coma, seizures, hyperthermia, or other, less severe, symptoms. Although severe reactions have been seen when drugs with a pharmacological profile similar to nefazodone were used with MAOI therapy, no controlled trials have been done with nefazodone. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of nefazodone therapy, or at least 1 week should elapse between the discontinuation of nefazodone and the initiation of a MAOI.
    Trazodone: (Moderate) Coadministration of trazodone and nefazodone may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue nefazodone and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Triamcinolone: (Moderate) Nefazodone may inhibit the CYP3A4 metabolism of triamcinolone, resulting in increased plasma triamcinolone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving another strong CYP3A4 inhibitor with triamcinolone, resulting in systemic corticosteroid effects including, but not limited to, Cushing syndrome and adrenal suppression. Consider the benefit-risk of concomitant use and monitor for systemic corticosteroid side effects. Consider using an alternative treatment to triamcinolone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). In some patients, a corticosteroid dose adjustment may be needed. If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
    Triamterene: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Triamterene; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary.
    Triazolam: (Contraindicated) Coadministration of triazolam, a primary CYP3A4 substrate, with strong CYP3A4 inhibitors, such as nefazodone, is contraindicated by the manufacturer of triazolam due to the risk for increased and prolonged sedation and respiratory depression. Triazolam AUC and half-life are increased 4-fold by the addition of nefazodone. Nefazodone does not appear to interact with benzodiazepines that are eliminated through conjugation, such as lorazepam, oxazepam or temazepam.
    Tricyclic antidepressants: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as nefazodone. Both nefazodone and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Cases of serotonin syndrome or serotonin-related adverse events have been observed during concurrent use of serotonergic antidepressants and nefazodone. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Trimipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as nefazodone. Both nefazodone and TCAs inhibit the central reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Cases of serotonin syndrome or serotonin-related adverse events have been observed during concurrent use of serotonergic antidepressants and nefazodone. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Triprolidine: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone.
    Ubrogepant: (Contraindicated) Coadministration of ubrogepant and nefazodone is contraindicated as concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor resulted in a 9.7-fold increase in the exposure of ubrogepant.
    Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and nefazodone is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
    Umeclidinium; Vilanterol: (Moderate) The coadministration of vilanterol with strong CYP3A4 inhibitors such as nefazodone can result in elevated vilanterol plasma concentrations and increased risk for adverse reactions.
    Upadacitinib: (Major) Do not exceed an upadacitinib induction dose of 30 mg PO once daily for 8 weeks and a maintenance dose of 15 mg once daily if coadministered with nefazodone in patients with Ulcerative Colitis. Do not exceed an upadacitinib dose of 15 mg PO once daily if coadministered with nefazodone in patients with arthritis or dermatitis. Monitor closely for adverse reactions. Concurrent use may increase upadacitinib exposure. Upadacitinib is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Concurrent use of a strong inhibitor increased upadacitinib exposure by 75%.
    Valbenazine: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as nefazodone. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
    Valsartan: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring and dosage adjustments of either drug may be necessary. (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with nefazodone due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; nefazodone is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
    Vemurafenib: (Major) Avoid the concomitant use of vemurafenib and nefazodone; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with nefazodone cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
    Venetoclax: (Major) Coadministration of nefazodone with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of nefazodone. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
    Venlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as nefazodone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Verapamil: (Moderate) Nefazodone is an inhibitor of CYP3A4, and may theoretically increase verapamil serum concentrations.
    Vilazodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vilazodone with other drugs that have serotonergic properties such as nefazodone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone, and nefazodone is a strong inhibitor of CYP3A4. The manufacturer of vilazodone recommends that the daily dose not exceed 20 mg/day during concurrent use of a strong CYP3A4 inhibitor. The original vilazodone dose can be resumed when the CYP3A4 inhibitor is discontinued.
    Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with nefazodone is necessary. Vinblastine is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with nefazodone is necessary. Vinorelbine is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor.
    Voclosporin: (Contraindicated) Concomitant use of voclosporin and nefazodone is contraindicated; concomitant use may increase the exposure of voclosporin and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Voclosporin is a sensitive CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased voclosporin exposure by approximately 19-fold.
    Vorapaxar: (Major) Avoid coadministration of vorapaxar and nefazodone. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with nefazodone, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: (Moderate) Voriconazole is metabolized by CYP3A4 and, theoretically, inhibitors of CYP3A4, such as nefazodone, could lead to increased serum levels of voriconazole.
    Vortioxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vortioxetine with other drugs that have serotonergic properties such as nefazodone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving nefazodone in combination with vortioxetine should be monitored for the emergence of serotonin syndrome or other adverse effects. If serotonin syndrome is suspected, vortioxetine and concurrent serotonergic agents should be discontinued.
    Voxelotor: (Major) Avoid coadministration of voxelotor and nefazodone as concurrent use may increase voxelotor exposure and lead to increased toxicity. If coadministration is unavoidable, reduce voxelotor dosage to 1,000 mg PO once daily. Voxelotor is a substrate of CYP3A4; nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase voxelotor exposure by 42% to 83%.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with nefazodone is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Nefazodone is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
    Zaleplon: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as nefazodone, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
    Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with nefazodone. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of nefazodone, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. The AUC of zanubrutinib was increased by 278% when coadministered with another strong CYP3A4 inhibitor.
    Ziconotide: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as nefazodone. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
    Ziprasidone: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme system. Decreased metabolism of ziprasidone may lead to clinically important side effects. Drugs having the potential to decrease the elimination of ziprasidone via inhibition of CYP3A4 include nefazodone.
    Zolmitriptan: (Major) Medications that augment release, decrease the metabolism of, or decrease the reuptake of serotonin, like the serotonin-receptor agonists, may interact with nefazodone by causing serotonin-related side effects, including serotonin syndrome. Whenever possible, these drug combinations should be avoided. If serotonin-syndrome is suspected, offending agents should be discontinued.
    Zolpidem: (Moderate) Consider decreasing the dose of zolpidem if coadministration with nefazodone is necessary. Zolpidem is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.

    PREGNANCY AND LACTATION

    Pregnancy

    Nefazodone should be used only if the benefit to the mother outweighs the potential risks to the fetus; patients should notify their health care professional if they become pregnant while on nefazodone. Clinicians should administer any serotonergic agent with caution during pregnancy, particularly during the third trimester. At doses 5-times the maximal human daily dose in mg/m2, no teratogenic effects have been noted in rats or rabbits. However, increased early pup mortality and decreased birth weights have occurred. There was no effect on pup mortality at doses 1.3 times the human dose in mg/m2. The effect of nefazodone exposure on neurological development during gestation is unknown. Neonates exposed to other serotonergic antidepressants late in the third trimester of pregnancy have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Symptoms have included respiratory distress, cyanosis, apnea, seizure activity, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. Features are consistent with either a direct toxic effect of serotonergic agents or, possibly, a neonatal abstinence syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. Animal studies have shown that selective serotonin reuptake inhibitors (SSRIs) downregulate serotonin receptors in the fetal cortex and that these changes can be present for a period of time after birth. The applicability of these animal findings to human gestation is unknown; some human epidemiologic studies have suggested that the cognitive and behavioral development of infants prenatally exposed to serotonergic agents does not differ from controls. The effects of nefazodone on labor and delivery are unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to nefazodone; information about the registry can be obtained at womensmentalhealth.org/research/pregnancyregistry or by calling 1-866-961-2388.

    MECHANISM OF ACTION

    Mechanism of Action: The pharmacologic actions of nefazodone involve both the serotonergic and, to a lesser extent, the noradrenergic systems. Within the serotonergic system, nefazodone is a potent antagonist at type 2 serotonin (5-HT2) post-synaptic receptors. Nefazodone also inhibits pre-synaptic serotonin (5-HT) reuptake (similar to fluoxetine-type antidepressants) but this mechansim is secondary in importance. Both mechanisms increase the amount of serotonin available to interact with 5-HT receptors. Within the noradrenergic system, nefazodone inhibits norepinephrine uptake minimally and this effect is lost with chronic dosing. In addition, nefazodone has been shown to antagonize alpha1-adrenergic receptors. Blockade of alpha1-adrenergic receptors produces sedation, muscle relaxation, and cardiovascular effects such as hypotension, reflex tachycardia, and minor changes in ECG patterns. Nefazodone has no significant affinity for benzodiazepine, cholinergic, dopaminergic, histaminic, or beta or alpha2-adrenergic receptors. As with other antidepressants, nefazodone's antidepressant effects may not be noticeable for several weeks. Nefazodone does not inhibit REM sleep.

    PHARMACOKINETICS

    Nefazodone is administered orally. Nefazodone is distributed in most body tissues including the central nervous system. Protein binding is approximately 99% and metabolism occurs by n-dealkylation and aliphatic and aromatic hydroxylation via the hepatic microsomal CYP3A4 isoenzyme. At least 2 major active metabolites have been identified: hydroxynefazodone and triazoledione. Hydroxynefazodone has the same pharmacologic profile as the parent drug whereas the triazoledione metabolite has one-seventh the activity of nefazodone at 5HT-2A receptors and no serotonin reuptake activity. One minor metabolite, mCPP, also exists and has nonselective serotonin agonist activity at 5HT-1A, 5HT-1C, and 5HT-3 receptors. Nefazodone's half life ranges from 2 to 4 hours. The half-lives of the metabolites are 1.5—4 hours for hydroxynefazodone, 4 to 8 hours for mCPP, and 18 hours for triazoledione. Excretion of nefazodone and its metabolites occur through both the urine (55%) and feces (20 to 30%).
     
    Affected cytochrome P450 (CYP450) enzymes and drug transporters: CYP3A4, CYP1A2, CYP2D6, CYP2C
    In vitro data indicate that CYP3A4 is primarily responsible for the metabolism of nefazodone and its metabolites hydroxynefazodone and triazoledione, while the metabolite mCPP is primarily metabolized by CYP2D6. Nefazodone is a potent inhibitor of CYP3A4 and a weak inhibitor of CYP1A2, CYP2D6, and CYP2C. The metabolite mCPP is a weak inhibitor of CYP2D6.

    Oral Route

    Following oral administration, nefazodone is rapidly and completely absorbed. Absolute bioavailability is only 20% due to extensive first-pass metabolism. Food delays the absorption of nefazodone and further decreases bioavailability by roughly 20%. Peak plasma concentrations of nefazodone occur in 1 hour; with steady-state concentrations achieved in about 4—5 days of twice daily dosing.