PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Tetracyclic Antidepressants

    BOXED WARNING

    Children, suicidal ideation

    Mirtazapine is not FDA-approved for the treatment of depression in adolescents or children; safety and efficacy have not been established. Two manufacturer-sponsored, randomized, double-blind, placebo-controlled clinical trials in pediatric patients 7 to 18 years of age with major depressive disorder (n = 259) failed to demonstrate significant differences between mirtazapine and placebo with regard to the primary endpoint and all secondary endpoints. In October 2004, the FDA directed manufacturers of all antidepressants to add a boxed warning to their product labels detailing the risk of suicide in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4,400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment with antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in pediatrics or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of starting therapy or during dose changes. It is unknown if the suicidality risk in children or young adults extends to longer-term therapy. The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment should be closely monitored during treatment with mirtazapine. In patients who exhibit worsening of depression or suicidality, a decision should be made to change or discontinue treatment. If discontinuing, the medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdose.

    DEA CLASS

    Rx

    DESCRIPTION

    Tetracyclic serotonergic and noradrenergic antidepressant unrelated to other classes of antidepressants
    Used for the treatment of major depressive disorder in adults
    Increased risk of suicidality during the initial stages of treatment in pediatric and young adult patients

    COMMON BRAND NAMES

    Remeron, Remeron SolTab

    HOW SUPPLIED

    Mirtazapine/Remeron Oral Tab: 7.5mg, 15mg, 30mg, 45mg
    Mirtazapine/Remeron SolTab Oral Tab Orally Dis: 15mg, 30mg, 45mg

    DOSAGE & INDICATIONS

    For the treatment of major depression.
    Oral dosage
    Adults

    15 mg PO once daily at bedtime, initially. If needed, may titrate no sooner than every 1 to 2 weeks. Geriatric patients may need slower titration schedules. The effective dose range is 15 to 45 mg/day. Max: 45 mg/day PO. Periodically reassess the need for continued treatment. Guidance on the appropriate length of treatment is available through the American Psychiatric Association treatment guidelines for patients with major depressive disorder.

    For the treatment of resting tremor†, benign familial tremor† (essential tremor†) or for the treatment of levodopa-induced dyskinesias†.
    Oral dosage
    Adults

    Initially 15 mg PO at bedtime. Adjust dose no more than every 1 to 2 weeks; geriatric patients may need slower titration schedules. In limited reports the effective dose, after titration, was 30 mg PO at bedtime.

    For the treatment of pruritus†.
    For the treatment of intractable pruritus†.
    Oral dosage
    Adults

    Case reports suggest that 15 to 30 mg PO once daily may be effective. In a case series of 4 patients with pruritus not relieved by other antipruritic therapy, mirtazapine resulted in reduction or elimination of pruritus. All 4 patients presented with advanced cancer. In addition to the reported malignancies, 3 patients presented with other conditions known to cause pruritus including hepatic disease and renal failure.

    For the treatment of nocturnal itch associated with chronic pruritus†.
    Oral dosage
    Adults

    Case reports suggest 15 mg PO once daily may be effective. In 2 patients with nocturnal itch associated with chronic pruritus, mirtazapine resulted in significant improvement in nocturnal pruritic symptoms and sleep in as early as 1 day after starting therapy. Both patients experienced a return of symptoms upon withdrawal of therapy, which resolved within 1 to 2 weeks after restarting mirtazapine.

    Adolescents

    A single case report suggests that 15 mg PO once daily may be effective. A significant reduction in nocturnal pruritic symptoms, regression in prurigo nodules, and improved quality of life occurred in an adolescent female with severe atopic eczema following treatment with mirtazapine. Improvement in symptoms was noted 5 days after of initiation of therapy, and was maintained during 6 months of follow up.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    45 mg/day PO.

    Geriatric

    45 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    A dose reduction may be necessary in patients with hepatic impairment due to decreased clearance of mirtazapine in these populations.

    Renal Impairment

    CrCl less than 40 mL/minute: A dose reduction may be necessary in patients with moderate to severe renal impairment due to decreased clearance of mirtazapine in these populations.

    ADMINISTRATION

    Oral Administration

    May be administered without regard to meals.
    The preferred administration time is in the evening prior to sleep.

    Oral Solid Formulations

    Orally disintegrating tablets (e.g., Remeron SolTab):
    The tablet should remain in the blister pack until ready to be taken.
    Use dry hands to open the blister.
    The tablet should not be chewed, crushed, or split.
    After removal from the blister pack, immediately place the tablet on the patient's tongue and allow it to dissolve with saliva. The tablet will disintegrate in saliva so that it can be swallowed. It does not need to be administered with water.

    STORAGE

    Generic:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Remeron:
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Remeron SolTab:
    - Product should always be stored in the blister and only removed immediately before use
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Mirtazapine is contraindicated for use in any patient hypersensitive to mirtazapine or any component of the formulation. Severe skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have been reported following the use of mirtazapine. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue mirtazapine immediately if DRESS or another serious hypersensitivity reaction is suspected and institute appropriate treatment; do not rechallenge.

    Abrupt discontinuation

    Abrupt discontinuation of mirtazapine should be avoided when possible. Adverse effects have been reported upon discontinuation of the drug including nausea, vomiting, agitation, sensory disturbances, sweating, and headache. Symptoms are generally mild and self-limiting; however, a gradual reduction in dosage over several weeks is recommended if possible during treatment discontinuation. It should be noted that these symptoms may be due to the underlying medical condition in some cases.

    Children, suicidal ideation

    Mirtazapine is not FDA-approved for the treatment of depression in adolescents or children; safety and efficacy have not been established. Two manufacturer-sponsored, randomized, double-blind, placebo-controlled clinical trials in pediatric patients 7 to 18 years of age with major depressive disorder (n = 259) failed to demonstrate significant differences between mirtazapine and placebo with regard to the primary endpoint and all secondary endpoints. In October 2004, the FDA directed manufacturers of all antidepressants to add a boxed warning to their product labels detailing the risk of suicide in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4,400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment with antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in pediatrics or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of starting therapy or during dose changes. It is unknown if the suicidality risk in children or young adults extends to longer-term therapy. The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment should be closely monitored during treatment with mirtazapine. In patients who exhibit worsening of depression or suicidality, a decision should be made to change or discontinue treatment. If discontinuing, the medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdose.

    MAOI therapy

    Mirtazapine is contraindicated for use in combination with monoamine oxidase inhibitors (MAOI therapy). Therefore, mirtazapine should not be used in combination with MAOIs, including the antibiotic linezolid and the thiazine dye methylthioninium blue (methylene blue), which are less well-known examples of MAOIs or within a minimum of 2 weeks of terminating treatment with MAOIs. Treatment with mirtazipine should then be initiated cautiously and dosage increased gradually until optimal response is reached. MAOIs should not be introduced within 2 weeks of cessation of therapy with mirtazipine. There have been reports of serious, sometimes fatal, reactions presenting with features resembling serotonin syndrome or neuroleptic malignant syndrome when mirtazapine and other antidepressants that affect serotonergic transmitters have been used in combination with an MAOI. Caution should be exercised in combining mirtazapine with other drugs or agents that may affect the serotonergic neurotransmitter systems (e.g., tryptophan, serotonin agonists (triptans), serotonin reuptake inhibitors (SSRIs or SNRIs), lithium, tramadol, or St. John’s Wort) as the risk of serotonin syndrome may increase.

    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. In U.S. studies, approximately 0.2% of mirtazapine-treated patients developed mania/hypomania. If a patient develops manic symptoms, mirtazapine should be withheld and appropriate therapy initiated to treat the manic symptoms. Depression may also 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.

    Agranulocytosis, bone marrow suppression, fever, neutropenia

    Bone marrow suppression, usually presenting as neutropenia or agranulocytosis, has been reported during treatment with most antidepressants, including mirtazapine. This mostly appears after 4 to 6 weeks of treatment and is in general reversible after termination of treatment. During clinical trials of mirtazapine, agranulocytosis defined as an absolute neutrophil count (ANC) less than 500/mm3 with associated signs and symptoms developed in 2 out of 2,796 patients being treated with mirtazapine. A third patient developed severe neutropenia (ANC less than 500/mm3 without symptoms). For these patients, the onset of severe neutropenia was detected on days 9, 14, and 61 of treatment, respectively. Following discontinuation of mirtazapine, all patients recovered. During postmarketing, very rare cases of agranulocytosis havebeen reported, mostly reversible, but in some cases fatal. Fatal cases have mostly concerned patients above 65 years of age, although there has been at least 1 such fatality in a younger patient. Patients receiving mirtazapine should be warned about the risk of developing agranulocytosis, and advised to contact their physician if they experience any indication of infection such as fever, chills, sore throat, mucous membrane ulceration. If a patient develops a sore throat, fever, stomatitis or other signs of infection, along with a low WBC count, treatment with mirtazapine should be discontinued and the patient should be closely monitored. Fever may increase the risk of prolonging the QT interval when using mirtazapine.

    Angina, apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, cerebrovascular disease, females, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, hypovolemia, long QT syndrome, myocardial infarction, orthostatic hypotension, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)

    Mirtazapine is considered as a drug with a possible risk for QT prolongation and torsade de pointes (TdP). In placebo-controlled trials, there were no clinically significant ECG abnormalities reported with mirtazapine use and prolongation of the QT interval does not appear to be a significant risk. However, because TdP, including ventricular fibrillation and sudden death, have been reported rarely with postmarketing use, it may be possible for these events to occur under certain situations during treatment. Most reports occurred in association with overdose or in patients with other risk factors for QT prolongation, including concomitant use of QT prolonging medicines. Use mirtazapine with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Mirtazapine may induce orthostatic hypotension. During pharmacology trials, orthostatic hypotension was observed in normal volunteers, however, orthostatic hypotension was infrequently observed in clinical trials of depressed patients. Mirtazapine should be used with caution in patients with known cardiac disease or cerebrovascular disease that could be exacerbated by hypotension, such as a history of angina, ischemic stroke, or a history of myocardial infarction. Conditions that might predispose patients to hypotension include hypovolemia or being dehydrated, or pharmacologic antihypertensive therapy.

    Dehydration, hyponatremia

    Low sodium concentrations leading to hyponatremia have been reported very rarely during mirtazapine administration. Elderly patients , those receiving medications known to cause hyponatremia (e.g., diuretics), patients prone to dehydration, or those who are otherwise volume depleted may be at greatest risk. Hyponatremia may manifest as headache, difficulty concentrating or confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, convulsion, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.

    Seizure disorder

    In premarketing studies, mirtazapine was associated with a rare incidence of seizures (1 out of 2,796 mirtazapine-treated patients). No controlled studies have been carried out in patients with a history of seizures. As with other antidepressants, use with caution in patients with a history of a seizure disorder.

    Renal failure, renal impairment

    Mirtazapine should be used cautiously in patients with renal impairment or renal failure. Increased plasma concentrations of mirtazapine occur in patients with moderate and severe renal impairment. Choose initial dosing cautiously and use care in dosage titration.

    Hepatic disease, jaundice

    Mirtazapine should be used cautiously in patients with hepatic disease. Increased plasma concentrations of mirtazapine occur in patients with moderate and severe hepatic impairment. In such patients, upward dosage titration should be cautious and carefully monitored. During short-term U.S. controlled trials, clinically significant hepatic transaminase elevations of ALT to 3 times the normal range were observed in 2% of mirtazapine-treated patients compared to 0% of placebo-treated patients. Most patients did not develop signs or symptoms associated with impaired hepatic function. Mirtazapine was discontinued in some patients while in other cases, the enzyme levels returned to normal even with continued treatment with mirtazapine. If jaundice occurs during treatment, mirtazapine should be discontinued.

    Diabetes mellitus, hypercholesterolemia, hypertriglyceridemia

    Mirtazapine should be used cautiously in patients with hypercholesterolemia or hypertriglyceridemia. In U.S. short-term controlled studies, non-fasting cholesterol increases of more than 20% above the upper limits of normal were observed in 15% of patients taking mirtazapine compared to 7% for placebo. In these same studies, non-fasting triglycerides increased to more than 500 mg/dL in 6% of patients taking mirtazapine compared to 3% for placebo. In addition, mirtazapine may cause weight gain. Care should be taken in patients with diabetes mellitus. In patients with diabetes, antidepressants may alter glycemic control. Antidiabetic agent dosage may need to be adjusted and close monitoring is recommended.

    Prostatic hypertrophy

    Mirtazapine exhibits very weak anticholinergic activity. While problems are not expected, it should be used cautiously in patients who might be more susceptible to these effects, such as those micturation disturbances like prostatic hypertrophy.

    Closed-angle glaucoma, increased intraocular pressure

    Caution is recommended when prescribing mirtazapine to patients with closed-angle glaucoma. The pupillary dilation that can occur with mirtazapine 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.

    Akathisia

    The use of antidepressants have been associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental. In some cases, the drug will need to be discontinued.

    Driving or operating machinery, ethanol ingestion

    Mirtazapine may impair concentration and alertness; drowsiness and dizziness may occur. Patients should avoid the driving or operating machinery or other dangerous tasks requiring concentration, until the effects of the drug are known. The impairment of mental and motor skills produced by mirtazapine have been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid ethanol ingestion while taking mirtazapine.

    Neonates, pregnancy

    Mirtazapine should be used during pregnancy only after careful consideration of the possible fetal risks from drug exposure and potential harm to the mother from untreated depression (e.g., relapse). Available data from prolonged experience with mirtazapine have not established an increased risk of major birth defects, miscarriage, or adverse maternal and fetal outcomes. Postnatal adaptation syndrome (PNAS) has been reported in neonates with third-trimester exposure to some serotonergic antidepressants (e.g., SSRIs, SNRIs); however, there is no clear evidence of an association between mirtazapine and PNAS. The effects of mirtazapine during labor and delivery are unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to mirtazapine; information about the registry can be obtained at womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants or by calling 1-866-961-2388 or 1-844-405-6185.

    Breast-feeding

    Caution should be exercised when administering mirtazapine to breast-feeding women. Mirtazapine is present in breast milk in low concentrations, ranging from 0.6% to 2.8% of the maternal weight-adjusted dose in published literature. In a pooled analysis of 8 breast-feeding women, no adverse effects were noted in any of the breastfed infants. There are no data on the effects of mirtazapine on milk production. Psychotropic medications affect neurotransmitter function in the developing central nervous system, and therefore, the accurate prediction of long-term adverse effects to the infant from exposure during breast-feeding 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, paroxetine, and nortriptyline 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.

    Geriatric

    Mirtazapine should be used cautiously in geriatric patients. The elderly exhibit reduced drug clearance and need lower initial doses and slower dosage titration compared to younger adults. Geriatric patients may also be at increased risk for developing a prolonged QT interval when taking mirtazapine. According to the Beers Criteria, mirtazapine is considered a potentially inappropriate medication (PIM) in older adults; use with caution as mirtazapine can cause or exacerbate hyponatremia and SIADH and the elderly are at increased risk of developing these conditions. Sodium levels should be closely monitored when starting or changing dosages in older adults.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities; the duration of therapy is determined by pertinent literature and clinical practice guidelines for the condition being treated. Monitor closely for worsening of depression and suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Monitor for drug-related side effects; some side effects can increase the risk of falls. A review for continued need of the antidepressant should occur at least quarterly along with 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. Before discontinuation, it is recommended that mirtazapine is tapered to avoid a withdrawal/discontinuation syndrome.[60742]

    Lactase deficiency, phenylketonuria

    Remeron SolTab (mirtazapine) oral disentegrating tablets should be used cautiously in patients with phenylketonuria. The tablets contain phenylalanine in amounts of 2.6, 5.2, and 7.8 mg per 15, 30, and 45 mg tablet, respectively. The regular mirtazapine tablets do not contain phenylalanine. Lactose is an ingredient in mirtazapine tablets. Therefore, patients with rare hereditary problems of galactose intolerance or glucose-galactose malabsorption (lactase deficiency) should not take mirtazapine tablets.

    ADVERSE REACTIONS

    Severe

    cholecystitis / Delayed / 0.1-1.0
    bronchospasm / Rapid / 0.1-1.0
    bradycardia / Rapid / 0.1-1.0
    myocardial infarction / Delayed / 0.1-1.0
    exfoliative dermatitis / Delayed / 0.1-1.0
    ocular hypertension / Delayed / 0.1-1.0
    keratoconjunctivitis / Early / 0.1-1.0
    hearing loss / Delayed / 0.1-1.0
    muscle paralysis / Delayed / 0-0.1
    seizures / Delayed / 0-0.1
    dementia / Delayed / 0-0.1
    GI obstruction / Delayed / 0-0.1
    pancreatitis / Delayed / 0-0.1
    cirrhosis / Delayed / 0-0.1
    tendon rupture / Delayed / 0-0.1
    bone fractures / Delayed / 0-0.1
    asphyxia / Early / 0-0.1
    pneumothorax / Early / 0-0.1
    pulmonary embolism / Delayed / 0-0.1
    heart failure / Delayed / 0-0.1
    pancytopenia / Delayed / 0-0.1
    serotonin syndrome / Delayed / 0-0.1
    suicidal ideation / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    diabetic ketoacidosis / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known

    Moderate

    hypercholesterolemia / Delayed / 15.0-15.0
    constipation / Delayed / 13.0-13.0
    hypertriglyceridemia / Delayed / 6.0-6.0
    confusion / Early / 2.0-2.0
    elevated hepatic enzymes / Delayed / 0-2.0
    peripheral edema / Delayed / 2.0-2.0
    hyperreflexia / Delayed / 0.1-1.0
    delirium / Early / 0.1-1.0
    dysarthria / Delayed / 0.1-1.0
    ataxia / Delayed / 0.1-1.0
    migraine / Early / 0.1-1.0
    mania / Early / 0.1-1.0
    hostility / Early / 0.1-1.0
    hallucinations / Early / 0.1-1.0
    depression / Delayed / 0-1.0
    euphoria / Early / 0.1-1.0
    dyskinesia / Delayed / 0.1-1.0
    dystonic reaction / Delayed / 0.1-1.0
    stomatitis / Delayed / 0.1-1.0
    colitis / Delayed / 0.1-1.0
    glossitis / Early / 0.1-1.0
    dyspnea / Early / 1.0-1.0
    angina / Early / 0.1-1.0
    hypotension / Rapid / 0.1-1.0
    dehydration / Delayed / 0.1-1.0
    cystitis / Delayed / 0.1-1.0
    dysuria / Early / 0.1-1.0
    nephrolithiasis / Delayed / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    vaginitis / Delayed / 0.1-1.0
    impotence (erectile dysfunction) / Delayed / 0.1-1.0
    urinary incontinence / Early / 0.1-1.0
    hematuria / Delayed / 0.1-1.0
    hyperacusis / Delayed / 0.1-1.0
    conjunctivitis / Delayed / 0.1-1.0
    edema / Delayed / 1.0-1.0
    aphasia / Delayed / 0-0.1
    nystagmus / Delayed / 0-0.1
    myoclonia / Delayed / 0-0.1
    hypotonia / Delayed / 0-0.1
    akathisia / Delayed / 0-0.1
    psychosis / Early / 0-0.1
    gastritis / Delayed / 0-0.1
    oral ulceration / Delayed / 0-0.1
    candidiasis / Delayed / 0-0.1
    bone pain / Delayed / 0-0.1
    phlebitis / Rapid / 0-0.1
    lymphadenopathy / Delayed / 0-0.1
    lymphocytosis / Delayed / 0-0.1
    thrombocytopenia / Delayed / 0-0.1
    leukopenia / Delayed / 0-0.1
    anemia / Delayed / 0-0.1
    gout / Delayed / 0-0.1
    hyponatremia / Delayed / 0-0.1
    diabetes mellitus / Delayed / 0-0.1
    skin ulcer / Delayed / 0-0.1
    ejaculation dysfunction / Delayed / 0-0.1
    goiter / Delayed / 0-0.1
    hypothyroidism / Delayed / 0-0.1
    blepharitis / Early / 0-0.1
    withdrawal / Early / 0-0.1
    amnesia / Delayed / 1.0
    myasthenia / Delayed / 1.0
    peripheral vasodilation / Rapid / 1.0
    hypertension / Early / 1.0
    orthostatic hypotension / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    neutropenia / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    hyperprolactinemia / Delayed / Incidence not known
    galactorrhea / Delayed / Incidence not known

    Mild

    drowsiness / Early / 54.0-54.0
    weight gain / Delayed / 7.5-49.0
    xerostomia / Early / 25.0-25.0
    appetite stimulation / Delayed / 17.0-17.0
    asthenia / Delayed / 8.0-8.0
    dizziness / Early / 7.0-7.0
    influenza / Delayed / 5.0-5.0
    abnormal dreams / Early / 4.0-4.0
    tremor / Early / 2.0-2.0
    back pain / Delayed / 2.0-2.0
    myalgia / Early / 2.0-2.0
    increased urinary frequency / Early / 2.0-2.0
    libido increase / Delayed / 0.1-1.0
    emotional lability / Early / 0.1-1.0
    paranoia / Early / 0.1-1.0
    eructation / Early / 0.1-1.0
    weight loss / Delayed / 0.1-1.0
    nausea / Early / 0.1-1.0
    epistaxis / Delayed / 0.1-1.0
    syncope / Early / 0.1-1.0
    fever / Early / 0.1-1.0
    alopecia / Delayed / 0.1-1.0
    xerosis / Delayed / 0.1-1.0
    acne vulgaris / Delayed / 0.1-1.0
    leukorrhea / Delayed / 0.1-1.0
    amenorrhea / Delayed / 0.1-1.0
    dysmenorrhea / Delayed / 0.1-1.0
    mastalgia / Delayed / 0.1-1.0
    otalgia / Early / 0.1-1.0
    ocular pain / Early / 0.1-1.0
    chills / Rapid / 0.1-1.0
    headache / Early / 0-0.1
    diplopia / Early / 0-0.1
    tongue discoloration / Delayed / 0-0.1
    hypersalivation / Early / 0-0.1
    laryngitis / Delayed / 0-0.1
    hiccups / Early / 0-0.1
    petechiae / Delayed / 0-0.1
    seborrhea / Delayed / 0-0.1
    urticaria / Rapid / 0-0.1
    urinary urgency / Early / 0-0.1
    menorrhagia / Delayed / 0-0.1
    breast enlargement / Delayed / 0-0.1
    polyuria / Early / 0-0.1
    parosmia / Delayed / 0-0.1
    dysgeusia / Early / 0-0.1
    paresthesias / Delayed / 1.0
    hyperkinesis / Delayed / 1.0
    hypoesthesia / Delayed / 1.0
    vertigo / Early / 1.0
    agitation / Early / 1.0
    anxiety / Delayed / 1.0
    abdominal pain / Early / 1.0
    vomiting / Early / 1.0
    anorexia / Delayed / 1.0
    arthralgia / Delayed / 1.0
    sinusitis / Delayed / 1.0
    cough / Delayed / 1.0
    polydipsia / Early / 1.0
    photosensitivity / Delayed / 1.0
    pruritus / Rapid / 1.0
    rash / Early / 1.0
    malaise / Early / 1.0
    somnambulism / Early / Incidence not known
    infection / Delayed / Incidence not known
    gynecomastia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as phenyltoloxamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as phenyltoloxamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Acetaminophen; Chlorpheniramine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as phenyltoloxamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Acetaminophen; Codeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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.
    Acetaminophen; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as doxylamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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 mirtazapine. 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 mirtazapine. 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 mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as diphenhydramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine.
    Acetaminophen; Oxycodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as pyrilamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Acetaminophen; Pentazocine: (Major) Concomitant use of pentazocine with other CNS depressants can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously in any patient receiving mirtazapine.
    Acetaminophen; Propoxyphene: (Moderate) Concomitant use of propoxyphene with other CNS depressants, such as mirtazapine, can potentiate the effects of propoxyphene on respiratory depression and/or sedation. Use together with caution.
    Acrivastine; Pseudoephedrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as acrivastine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Alfentanil: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Alfuzosin: (Moderate) Use caution when using mirtazapine in combination with alfuzosin. Both alfuzosin and mirtazapine have been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing in treatment with mirtazapine, primarily in overdose or in patients with other risk factors for QT prolongation.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Almotriptan: (Major) Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when mirtazapine is coadministered with other drugs that may affect these neurotransmitter systems, including the serotonin-receptor agonists ("triptans"). The co-use of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
    Alprazolam: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Amiloride: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Amiodarone: (Major) Concomitant use of amiodarone and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
    Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with mirtazapine. Amisulpride causes dose- and concentration- dependent QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Amitriptyline: (Major) Concomitant use of mirtazapine and tricyclic antidepressants (TCAs) may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose prescription therapy (elevated serum concentrations). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and TCAs have central serotonin-enhancing effects, and case reports with other antidepressants (e.g., SSRIs) suggest that serotonin syndrome is possible. 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 treatment should be implemented. While one small study in healthy subjects (n = 24) reported that the combination of mirtazapine with a TCA may be tolerated and result in only minor alterations in the pharmacokinetics of either agent, the authors still recommended caution and the need for further human data, including safety data and evidence of combined treatment efficacy. Both mirtazapine and TCAs can have significant CNS depressant effects that may be additive. Patients should be advised to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Amobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Amoxapine: (Major) Monitor for excessive sedation and somnolence during coadministration of amoxapine and mirtazapine. Concurrent use may result in additive CNS depression.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and clarithromycin. Coadminister with caution. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Coadministration of mirtazapine with amphetamines may increase the risk of serotonin syndrome. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Amprenavir: (Moderate) Concurrent administration of mirtazapine and amprenavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
    Anagrelide: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and anagrelide. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary.
    Anticholinergics: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Anxiolytics; Sedatives; and Hypnotics: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including anxiolytics, sedatives, and hypnotics.
    Apalutamide: (Moderate) Monitor for decreased efficacy of mirtazapine if coadministration with apalutamide is necessary; a dosage adjustment of mirtazapine may be necessary. Mirtazapine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers increased mirtazapine clearance by approximately 2-fold, decreasing the average mirtazapine plasma concentrations by 45% to 60%.
    Apomorphine: (Major) Exercise caution when administering apomorphine concomitantly with mirtazapine as concurrent use may increase the risk of QT prolongation and CNS depression. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Additive sedation may also occur.
    Aripiprazole: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and aripiprazole. Coadminister with caution. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with other drugs that may cause QT prolongation such as mirtazapine; discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant use is unavoidable, frequently monitor electrocardiograms. TdP, QT prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Artemether; Lumefantrine: (Major) Artemether; lumefantrine is associated with QT prolongation and should be avoided if possible in combination with other QT prolonging drugs, such as mirtazapine. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. (Major) Artemether; lumefantrine is associated with QT prolongation and should be avoided if possible in combination with other QT prolonging drugs, such as mirtazapine. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Because llumefantrine is a CYP2D6 inhibitor and mirtazapine is partially metabolized by CYP2D6, coadministration may lead to increased mirtazapine concentrations. Monitor for mirtazapine-related side effects such as dizziness, somnolence, xerostomia, and constipation.
    Asenapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and asenapine. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have these effects. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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. (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Skeletal muscle relaxants like orphenadrine may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
    Aspirin, ASA; Carisoprodol: (Moderate) Skeletal muscle relaxants like carisoprodol may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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. (Moderate) Skeletal muscle relaxants like carisoprodol may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Atazanavir: (Moderate) Concurrent administration of mirtazapine and atazanavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
    Atazanavir; Cobicistat: (Moderate) Concurrent administration of mirtazapine and atazanavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4. (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor and an inhibitor of CYP2D6, while mirtazapine is a CYP3A4 and CYP2D6 substrate. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%
    Atenolol; Chlorthalidone: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Atomoxetine: (Moderate) Concomitant use of atomoxetine and mirtazapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Atropine: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) According to the manufacturer of mirtazapine, treatment initiation with mirtazapine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than mirtazapine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving mirtazapine and requiring urgent treatment with intravenous methylene blue, mirtazapine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Mirtazapine may be re-initiated 24 hours after the last dose of methylene blue Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and mirtazapine increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. 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. (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Atropine; Difenoxin: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including diphenoxylate/difenoxin. (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Atropine; Edrophonium: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including mirtazapine.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including mirtazapine.
    Azilsartan; Chlorthalidone: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Azithromycin: (Major) Concomitant use of azithromycin and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Baclofen: (Moderate) Skeletal muscle relaxants like baclofen may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
    Barbiturates: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Bedaquiline: (Major) Coadministration of mirtazapine and bedaquiline may result in additive or synergistic prolongation of the QT interval. Coadminister with caution. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression. (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
    Belladonna; Opium: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with mirtazapine 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. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Bendroflumethiazide; Nadolol: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with mirtazapine 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. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Benzodiazepines: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) According to the manufacturer of mirtazapine, treatment initiation with mirtazapine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than mirtazapine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving mirtazapine and requiring urgent treatment with intravenous methylene blue, mirtazapine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Mirtazapine may be re-initiated 24 hours after the last dose of methylene blue Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and mirtazapine increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. 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. (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Benzphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and mirtazapine. 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.
    Benztropine: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and mirtazapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and mirtazapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering mirtazapine with boceprevir due to an increased potential for mirtazapine-related adverse events. If mirtazapine 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 pathway of mirtazapine. Mirtazapine is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated mirtazapine plasma concentrations.
    Brexpiprazole: (Moderate) Due to the CNS effects of brexpiprazole, caution is advisable when brexpiprazole is given in combination with other centrally-acting medications including mirtazapine.
    Brompheniramine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as brompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as brompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as brompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as brompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as brompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as brompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Brompheniramine; Phenylephrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as brompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Brompheniramine; Pseudoephedrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as brompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as brompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Bumetanide: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Buprenorphine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), serotonin syndrome, or CNS depression during concurrent use of mirtazapine and buprenorphine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. The labeling of some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as mirtazapine, has resulted in 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. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments; discontinue serotonergic agents if serotonin syndrome occurs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during coadministration of buprenorphine and other CNS depressants. Prior to use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, the patient's overall response to treatment, and potential 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.
    Buprenorphine; Naloxone: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), serotonin syndrome, or CNS depression during concurrent use of mirtazapine and buprenorphine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. The labeling of some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as mirtazapine, has resulted in 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. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments; discontinue serotonergic agents if serotonin syndrome occurs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during coadministration of buprenorphine and other CNS depressants. Prior to use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, the patient's overall response to treatment, and potential 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.
    Buspirone: (Moderate) The use of mirtazapine with buspirone may increase the risk for serotonin syndrome. Both medications have serotonergic effects. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome.
    Butabarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Butalbital; Acetaminophen: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Butalbital; Acetaminophen; Caffeine: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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. (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation. Butorphanol should be used cautiously in any patient receiving these agents, which may include mirtazapine.
    Cabotegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with mirtazapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and mirtazapine. CNS depressants can potentiate the effects of cannabidiol.
    Capsaicin; Metaxalone: (Moderate) Coadministration of mirtazapine with metaxalone may result in additive CNS-depressant effects, such as sedation, and may increase the risk for serotonin syndrome. Use with caution and monitor for the emergence of excessive sedation or serotonin syndrome. If serotonin syndrome is suspected, serotonergic agents should be discontinued and appropriate medical treatment instituted.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Carbamazepine: (Moderate) As carbamazepine is known to induce CYP1A2 and CYP3A4, serum concentrations of mirtazapine may be decreased because of CYP enzyme induction. Increased dosages of mirtazapine may be needed.
    Carbetapentane; Chlorpheniramine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as diphenhydramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as pyrilamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Carbetapentane; Pyrilamine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as pyrilamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Carbidopa; Levodopa; Entacapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as mirtazapine, 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as carbinoxamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as carbinoxamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as carbinoxamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as carbinoxamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Carbinoxamine; Phenylephrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as carbinoxamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Carbinoxamine; Pseudoephedrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as carbinoxamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution is advisable when cariprazine is given in combination with other centrally-acting medications including mirtazapine.
    Carisoprodol: (Moderate) Skeletal muscle relaxants like carisoprodol may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
    Celecoxib; Tramadol: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and mirtazapine. Concurrent use may result in additive CNS depression.
    Ceritinib: (Major) Avoid coadministration of ceritinib with mirtazapine if possible due to the risk of QT prolongation; plasma concentrations of mirtazapine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Mirtazapine is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; torsade de pointes (TdP) has also been reported in postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation. Ceritinib is a strong CYP3A4 inhibitor that is also associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
    Cetirizine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with cetirizine, a low-sedating antihistamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Cetirizine; Pseudoephedrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with cetirizine, a low-sedating antihistamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlophedianol; Dexbrompheniramine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as dexbrompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as dexchlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorcyclizine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorcyclizine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlordiazepoxide: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Chlordiazepoxide; Amitriptyline: (Major) Concomitant use of mirtazapine and tricyclic antidepressants (TCAs) may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose prescription therapy (elevated serum concentrations). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and TCAs have central serotonin-enhancing effects, and case reports with other antidepressants (e.g., SSRIs) suggest that serotonin syndrome is possible. 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 treatment should be implemented. While one small study in healthy subjects (n = 24) reported that the combination of mirtazapine with a TCA may be tolerated and result in only minor alterations in the pharmacokinetics of either agent, the authors still recommended caution and the need for further human data, including safety data and evidence of combined treatment efficacy. Both mirtazapine and TCAs can have significant CNS depressant effects that may be additive. Patients should be advised to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Chlordiazepoxide; Clidinium: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines. (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Chloroquine: (Major) Avoid coadministration of chloroquine with mirtazapine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Chlorothiazide: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Chlorpheniramine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorpheniramine; Codeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorpheniramine; Phenylephrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Chlorpromazine: (Major) Coadministration may increase the risk of QT prolongation, torsade de pointes, and CNS depression. Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of chlorpromazine and mirtazapine. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Both drugs also have CNS depressant properties, and patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of the effects of the combination.
    Chlorthalidone: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Chlorthalidone; Clonidine: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions. (Moderate) Monitor closely for loss of blood pressure control or other loss of effect of clonidine if these agents are used together. Mirtazapine and clonidine have pharmacologic actions that potentially oppose one another. Mirtazapine inhibits central alpha-2 autoreceptors (located presynaptically on noradrenergic neurons) and stimulating norepinephrine and stimulates the serotonergic system through antagonism at alpha-2 heteroreceptors. Clonidine exerts its antihypertensive effect by stimulating the central alpha-2 autoreceptors, thereby causing a reduction in the synthesis and release of norepinephrine.
    Chlorzoxazone: (Moderate) Skeletal muscle relaxants like chlorzoxazone may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
    Cimetidine: (Moderate) In vitro studies have identified mirtazapine as a substrate for several CYP450 isoenzymes including 2D6, 1A2, and 3A4. Cimetidine is an inhibitor of CYP1A2, CYP2D6, and CYP3A4. In a study of 12 healthy subjects, cimetidine 800 mg twice daily increased the AUC of mirtazapine 30 mg/day by more than 50%. It may be necessary to decrease the mirtazapine dosage during co-administration of mirtazapine and cimetidine. Conversely, if cimetidine is discontinued, the dosage of mirtazapine may need to be increased.
    Ciprofloxacin: (Moderate) Concomitant use of ciprofloxacin and mirtazapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Cisapride: (Contraindicated) Because of the potential for torsade de pointes (TdP), concurrent use of cisapride and mirtazapine is contraindicated. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Citalopram: (Major) Concomitant use of mirtazapine and citalopram may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Citalopram causes dose-dependent QT interval prolongation. The manufacturer of citalopram recommends avoidance of other drugs that prolong the QT interval. If concurrent therapy is required, ECG monitoring is recommended. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and SSRIs such as citalopram have central serotonin-enhancing effects, and case reports suggest that serotonin syndrome is possible. 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 treatment should be implemented.
    Clarithromycin: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and clarithromycin. Coadminister with caution. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Clemastine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as clemastine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with mirtazapine. QT prolongation and torsade de pointes (TdP) have been reported in patients receiving clofazimine in combination with QT prolonging medications. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Clomipramine: (Major) Concomitant use of mirtazapine and tricyclic antidepressants (TCAs) may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose prescription therapy (elevated serum concentrations). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and TCAs have central serotonin-enhancing effects, and case reports with other antidepressants (e.g., SSRIs) suggest that serotonin syndrome is possible. 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 treatment should be implemented. While one small study in healthy subjects (n = 24) reported that the combination of mirtazapine with a TCA may be tolerated and result in only minor alterations in the pharmacokinetics of either agent, the authors still recommended caution and the need for further human data, including safety data and evidence of combined treatment efficacy. Both mirtazapine and TCAs can have significant CNS depressant effects that may be additive. Patients should be advised to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Clonazepam: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Clonidine: (Moderate) Monitor closely for loss of blood pressure control or other loss of effect of clonidine if these agents are used together. Mirtazapine and clonidine have pharmacologic actions that potentially oppose one another. Mirtazapine inhibits central alpha-2 autoreceptors (located presynaptically on noradrenergic neurons) and stimulating norepinephrine and stimulates the serotonergic system through antagonism at alpha-2 heteroreceptors. Clonidine exerts its antihypertensive effect by stimulating the central alpha-2 autoreceptors, thereby causing a reduction in the synthesis and release of norepinephrine.
    Clorazepate: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Clozapine: (Moderate) Use caution when using mirtazapine in combination with clozapine as concurrent use may increase the risk of QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
    Cobicistat: (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor and an inhibitor of CYP2D6, while mirtazapine is a CYP3A4 and CYP2D6 substrate. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%
    Cocaine: (Major) Although unlikely to occur with use of mirtazapine alone, there have been rare case reports of serotonin syndrome with the drug. It is likely that the activation of 5-HT1A receptors by mirtazapine, combined with coadministration of other medications that increase serotonin release, such as cocaine, could result in serotonin syndrome.
    Codeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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.
    Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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.
    Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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. (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and promethazine. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Because both mirtazapine and promethazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of how the combination affects them.
    Codeine; Promethazine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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. (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and promethazine. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Because both mirtazapine and promethazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of how the combination affects them.
    COMT inhibitors: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as mirtazapine, 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.
    Crizotinib: (Major) Avoid coadministration of crizotinib with mirtazapine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported in postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation.
    Cyclizine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as cyclizine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Cyclobenzaprine: (Moderate) Skeletal muscle relaxants like cyclobenzaprine may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances. In addition, anecdotal evidence from case reports suggests that cyclobenzaprine may possess serotonin augmenting effects that may be clinically relevant during administration of the drug with serotonin-enhancing medications. In theory, there is a remote possibility that serotonin syndrome may occur from concurrent administration of cyclobenzaprine and mirtazapine since mirtazapine increases central serotonin activity. In addition, cyclobenzaprine is closely related to the tricyclic antidepressants, which are known to decrease serotonin reuptake. Caution is advisable during concurrent use with mirtazapine until more information about cyclobenzaprine's effects on serotonin becomes available.
    Cyproheptadine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as cyproheptadine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Dantrolene: (Moderate) Skeletal muscle relaxants like dantrolene may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
    Darunavir: (Moderate) Concurrent administration of mirtazapine and darunavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
    Darunavir; Cobicistat: (Moderate) Concurrent administration of mirtazapine and darunavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4. (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor and an inhibitor of CYP2D6, while mirtazapine is a CYP3A4 and CYP2D6 substrate. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Concurrent administration of mirtazapine and darunavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4. (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor and an inhibitor of CYP2D6, while mirtazapine is a CYP3A4 and CYP2D6 substrate. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor, while mirtazapine is a CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%.
    Dasatinib: (Moderate) Use caution when using mirtazapine in combination with dasatinib as concurrent use may increase the risk of QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
    Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving mirtazapine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Delavirdine: (Moderate) In vitro studies have identified mirtazapine as a substrate for several CYP450 isoenzymes including 2D6, 1A2, and 3A4. Pharmacokinetic studies with some CYP3A4 inhibitors have shown that elevations in mirtazapine concentrations are possible during co-administration.Therefore, caution is advised during concurrent use of mirtazapine and potent inhibitors of CYP3A4 such as delavirdine.
    Desflurane: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Reports of QT prolongation, associated with TdP (in exceptional cases, fatal), have been received. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Desipramine: (Major) Concomitant use of mirtazapine and tricyclic antidepressants (TCAs) may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose prescription therapy (elevated serum concentrations). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and TCAs have central serotonin-enhancing effects, and case reports with other antidepressants (e.g., SSRIs) suggest that serotonin syndrome is possible. 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 treatment should be implemented. While one small study in healthy subjects (n = 24) reported that the combination of mirtazapine with a TCA may be tolerated and result in only minor alterations in the pharmacokinetics of either agent, the authors still recommended caution and the need for further human data, including safety data and evidence of combined treatment efficacy. Both mirtazapine and TCAs can have significant CNS depressant effects that may be additive. Patients should be advised to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as mirtazapine and desvenlafaxine. Cases of serotonin syndrome have been reported between mirtazapine and other antidepressants such as selective serotonin reuptake inhibitors (SSRIs). 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.
    Deutetrabenazine: (Moderate) Use caution when using mirtazipine in combination with deutetrabenazine. Mirtazipine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing with mirtazipine, primarily in overdose or in patients with other risk factors for QT prolongation. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. Monitor for excessive sedation and somnolence during coadministration of mirtazapine and deutetrabenazine. Concurrent use may result in additive CNS depression.
    Dexbrompheniramine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as dexbrompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Dexbrompheniramine; Pseudoephedrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as dexbrompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Dexchlorpheniramine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as dexchlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as dexchlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as diphenhydramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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 mirtazapine. 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 mirtazapine. 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 mirtazapine. 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: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and quinidine. Coadminister with caution. Quinidine administration is associated with QT prolongation and TdP. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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.
    Diazepam: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Dicyclomine: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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.
    Dihydroergotamine: (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
    Dimenhydrinate: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as dimenhydrindate. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Diphenhydramine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as diphenhydramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as diphenhydramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Diphenhydramine; Ibuprofen: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as diphenhydramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Diphenhydramine; Naproxen: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as diphenhydramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Diphenhydramine; Phenylephrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as diphenhydramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Diphenoxylate; Atropine: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including diphenoxylate/difenoxin. (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Disopyramide: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and disopyramide. Coadminister with caution. Disopyramide is associated with QT prolongation and TdP. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Dofetilide: (Major) Coadministration of dofetilide and mirtazapine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Dolasetron: (Moderate) Administer dolasetron with caution in combination with mirtazapine as concurrent use may increase the risk of QT prolongation; the risk of serotonin syndrome may also increase. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. If serotonin syndrome occurs, discontinue all serotonergic agents and initiate appropriate medical treatment.
    Dolutegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with mirtazapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Donepezil: (Moderate) Use donepezil with caution in combination with mirtazapine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Donepezil; Memantine: (Moderate) Use donepezil with caution in combination with mirtazapine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Doxepin: (Major) Concomitant use of mirtazapine and tricyclic antidepressants (TCAs) may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose prescription therapy (elevated serum concentrations). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and TCAs have central serotonin-enhancing effects, and case reports with other antidepressants (e.g., SSRIs) suggest that serotonin syndrome is possible. 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 treatment should be implemented. While one small study in healthy subjects (n = 24) reported that the combination of mirtazapine with a TCA may be tolerated and result in only minor alterations in the pharmacokinetics of either agent, the authors still recommended caution and the need for further human data, including safety data and evidence of combined treatment efficacy. Both mirtazapine and TCAs can have significant CNS depressant effects that may be additive. Patients should be advised to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Doxylamine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as doxylamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Doxylamine; Pyridoxine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as doxylamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Dronabinol: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, such as dronabinol.
    Dronedarone: (Contraindicated) Because of the potential for torsade de pointes (TdP), concurrent use of dronedarone and mirtazapine is contraindicated. Dronedarone is associated with a dose-related increase in the QTc interval. The increase in QTc is about 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Droperidol: (Major) Droperidol should not be used in combination with any drug known to have potential to prolong the QT interval, such as mirtazapine. If coadministration cannot be avoided, use extreme caution. Initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Droperidol is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, particularly in the setting of overdose or when other risk factors for QT prolongation are present, including concomitant use of other medications associated with QT prolongation. Central nervous system depressants, including mirtazapine and droperidol, may have additive CNS effects. Lower doses of either agent may be required.
    Duloxetine: (Moderate) Coadministration of duloxetine and mirtazapine may increase the risk for serotonin syndrome. Cases of serotonin syndrome have been reported when mirtazapine has been administered with other serotonergic antidepressants. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with mirtazapine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. QTc prolongation have been reported with the use of efavirenz. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Consider alternatives to efavirenz when coadministering with mirtazapine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. QTc prolongation have been reported with the use of efavirenz. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with mirtazapine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. QTc prolongation have been reported with the use of efavirenz. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Elbasvir; Grazoprevir: (Moderate) Administering mirtazapine with elbasvir; grazoprevir may result in elevated mirtazapine plasma concentrations. Mirtazapine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eletriptan: (Major) Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when mirtazapine is coadministered with other drugs that may affect these neurotransmitter systems, including the serotonin-receptor agonists ("triptans"). The co-use of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
    Eliglustat: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and eliglustat. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor and an inhibitor of CYP2D6, while mirtazapine is a CYP3A4 and CYP2D6 substrate. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor and an inhibitor of CYP2D6, while mirtazapine is a CYP3A4 and CYP2D6 substrate. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Caution is advised when administering rilpivirine with mirtazapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering rilpivirine with mirtazapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Encorafenib: (Major) Avoid coadministration of encorafenib and mirtazapine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Enflurane: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Reports of QT prolongation, associated with TdP (in exceptional cases, fatal), have been received. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Entacapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as mirtazapine, 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 mirtazapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Enzalutamide: (Moderate) Monitor for decreased efficacy of mirtazapine if coadministration with enzalutamide is necessary; a dosage adjustment of mirtazapine may be necessary. Mirtazapine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers increased mirtazapine clearance by approximately 2-fold, decreasing the average mirtazapine plasma concentrations by 45% to 60%.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Ergoloid Mesylates: (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
    Ergonovine: (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
    Ergot alkaloids: (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
    Ergotamine: (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
    Ergotamine; Caffeine: (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
    Eribulin: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and eribulin. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Eribulin has been associated with QT prolongation. If eribulin and mirtazapine must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Erythromycin: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and erythromycin. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other QT prolonging medications. Erythromycin is associated with QT prolongation and TdP; fatalities have been reported. Pharmacokinetic studies with some CYP3A4 inhibitors have shown that elevations in concentrations of mirtazapine, a CYP3A4 substrate, are possible. Therefore, caution is advised during concurrent use of mirtazapine and macrolide antibiotics that are CYP3A4 inhibitors such as erythromycin.
    Erythromycin; Sulfisoxazole: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and erythromycin. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other QT prolonging medications. Erythromycin is associated with QT prolongation and TdP; fatalities have been reported. Pharmacokinetic studies with some CYP3A4 inhibitors have shown that elevations in concentrations of mirtazapine, a CYP3A4 substrate, are possible. Therefore, caution is advised during concurrent use of mirtazapine and macrolide antibiotics that are CYP3A4 inhibitors such as erythromycin.
    Escitalopram: (Moderate) Concomitant use of mirtazapine and escitalopram may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Escitalopram has been associated with a risk of QT prolongation and TdP. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and SSRIs such as escitalopram have central serotonin-enhancing effects, and case reports suggest that serotonin syndrome is possible. 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 mirtazapine 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.
    Estazolam: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Ethacrynic Acid: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
    Etomidate: (Moderate) Consistent with the pharmacology of mirtazapine and the CNS depression that may occur, additive effects may occur with other CNS depressants, including etomidate. Close monitoring is recommended in patients receiving mirtazapine and requiring an anesthetic.
    Ezogabine: (Moderate) Use caution when using mirtazapine in combination with ezogabine as concurrent use may increase the risk of QT prolongation. Ezogabine has been associated with QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Fenfluramine: (Moderate) Use fenfluramine and mirtazapine 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 mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with mirtazapine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Flavoxate: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Flecainide: (Major) Concomitant use of flecainide and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Flibanserin: (Moderate) The concomitant use of flibanserin with CNS depressants, such as mirtazapine, may increase the risk of CNS depression (e.g., dizziness, somnolence) compared to the use of flibanserin alone. Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how flibanserin affects them.
    Fluconazole: (Moderate) Use fluconazole with caution in combination with mirtazapine. Concurrent use may increase the risk of QT prolongation and increased mirtazapine exposure. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Mirtazapine has been associated with dose-dependent prolongation of the QT interval, primarily in overdose or in patients with other risk factors for QT prolongation. Fluconazole is a moderate CYP3A4 inhibitor and may increase mirtazapine serum concentrations. Mirtazapine is a substrate of CYP3A4, and coadministration of a potent CYP3A4 inhibitor azole antifungal increased the Cmax and the AUC of a single 30-mg dose of mirtazapine by approximately 40% and 50%, respectively.
    Fluoxetine: (Moderate) Use fluoxetine with caution in combination with mirtazapine. Coadministration may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. Case reports of serotonin syndrome have been reported with this combination. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. Both drugs have been reported to cause QT prolongation and TdP.
    Fluphenazine: (Moderate) Coadministration may increase the risk of QT prolongation, torsade de pointes, and CNS depression. Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of mirtazapine and fluphenazine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Because both mirtazapine and fluphenazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of the effects of the combination.
    Flurazepam: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Fluvoxamine: (Moderate) There may be an increased risk for QT prolongation, torsade de pointes (TdP), or serotonin syndrome during concurrent use of mirtazapine and fluvoxamine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. QT prolongation and torsade de pointes have been reported during postmarketing use of 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. Case reports suggest that serotonin syndrome is possible during concurrent use of mirtazapine and SSRIs. In addition, mirtazapine is a substrate for CYP2D6, CYP1A2, and CYP3A4. Increased mirtazapine serum concentrations (3 to 4 fold) have been reported following the addition of fluvoxamine, an inhibitor of CYP3A4, CYP1A2, and CYP2D6, to stable mirtazapine regimens. Patients receiving mirtazapine with fluvoxamine should be monitored for the emergence of serotonin syndrome, QT prolongation, or other adverse effects.
    Fosamprenavir: (Moderate) Concurrent administration of mirtazapine and fosamprenavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
    Foscarnet: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and foscarnet. Both QT prolongation and TdP have been reported during postmarketing use of foscarnet. Because of these reports, avoid the use of foscarnet with other drugs known to prolong the QT interval. If coadministration is necessary, monitor ECG and serum electrolytes. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Fospropofol: (Moderate) Consistent with the pharmacology of mirtazapine and the CNS depression that may occur, additive effects may occur with other CNS depressants, including fospropofol. Close monitoring is recommended in patients receiving mirtazapine and requiring an anesthetic.
    Fostemsavir: (Moderate) Use caution when using mirtazapine in combination with fostemsavir due to the potential for QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Frovatriptan: (Major) Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when mirtazapine is coadministered with other drugs that may affect these neurotransmitter systems, including the serotonin-receptor agonists ("triptans"). The co-use of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
    Furosemide: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Gabapentin: (Major) Initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of gabapentin and mirtazapine. Concomitant use of gabapentin with mirtazapine may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
    Gemifloxacin: (Moderate) Use caution when using mirtazapine in combination with gemifloxacin as concurrent use may increase the risk of QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. Gemifloxacin may prolong the QT interval in some patients. The maximal change in QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and mirtazapine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP has also been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Gilteritinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and mirtazapine is necessary. Gilteritinib has been associated with QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Glasdegib: (Major) Avoid coadministration of glasdegib with mirtazapine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Glycopyrrolate: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Glycopyrrolate; Formoterol: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving mirtazapine. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported in postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Granisetron: (Moderate) Use caution when using mirtazapine in combination with granistetron as concurrent use may increase the risk of QT prolongation and serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. Granisetron has been associated with QT prolongation.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine.
    Halogenated Anesthetics: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Reports of QT prolongation, associated with TdP (in exceptional cases, fatal), have been received. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Haloperidol: (Moderate) Use caution when using mirtazapine in combination with haloperidol as concurrent use may increase the risk of QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. QT prolongation and TdP have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Halothane: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Reports of QT prolongation, associated with TdP (in exceptional cases, fatal), have been received. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving mirtazapine. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported in postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Homatropine; Hydrocodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Hydantoins: (Moderate) Mirtazapine plasma concentrations and pharmacologic action may be decreased in patients taking hydantoins. The mechanism appears to be induction of cytochrome P450 enzymes CYP3A3 and CYP3A4 by the hydantoin, leading to increased metabolism of mirtazapine. Closely monitor mirtazapine response if hydantoin therapy is started, stopped or if the dose is adjusted; alter mirtazapine doses as needed.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Hydrocodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine.
    Hydromorphone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Hydroxyzine: (Moderate) Concomitant use of hydroxyzine and mirtazapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Hyoscyamine: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Contraindicated) According to the manufacturer of mirtazapine, treatment initiation with mirtazapine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than mirtazapine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving mirtazapine and requiring urgent treatment with intravenous methylene blue, mirtazapine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Mirtazapine may be re-initiated 24 hours after the last dose of methylene blue Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and mirtazapine increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. 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. (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Ibuprofen; Oxycodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Ibutilide: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and ibutilide. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Ibutilide can cause QT prolongation and TdP; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with mirtazapine, a CYP3A substrate, as mirtazapine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and iloperidone. According to the manufacturer of iloperidone, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Imipramine: (Major) Concomitant use of mirtazapine and tricyclic antidepressants (TCAs) may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose prescription therapy (elevated serum concentrations). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and TCAs have central serotonin-enhancing effects, and case reports with other antidepressants (e.g., SSRIs) suggest that serotonin syndrome is possible. 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 treatment should be implemented. While one small study in healthy subjects (n = 24) reported that the combination of mirtazapine with a TCA may be tolerated and result in only minor alterations in the pharmacokinetics of either agent, the authors still recommended caution and the need for further human data, including safety data and evidence of combined treatment efficacy. Both mirtazapine and TCAs can have significant CNS depressant effects that may be additive. Patients should be advised to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Indacaterol; Glycopyrrolate: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Indinavir: (Moderate) Concurrent administration of mirtazapine and indinavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with mirtazapine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP has also been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Iobenguane I 131: (Major) Discontinue mirtazapine for at least 5 half-lives before the administration of the dosimetry dose or a therapeutic dose of iobenguane I-131. Do not restart mirtazapine until at least 7 days after each iobenguane I-131 dose. Drugs that reduce catecholamine uptake or deplete catecholamine stores, such as mirtazapine, may interfere with iobenguane I-131 uptake into cells and interfere with dosimetry calculations resulting in altered iobenguane I-131 efficacy.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Isocarboxazid: (Contraindicated) Use of mirtazapine concurrently with the monoamine oxidase inhibitors (MAOIs) is contraindicated. If combined, there is a possibility of developing serious reactions such as serotonin syndrome. In patients receiving nonselective MAOIs in combination with serotoninergic agents there have been reports of serious, sometimes fatal, reactions. At least 2 weeks should elapse between stopping one agent and beginning the other. Monitor for serotonin-related side effects during therapy transitions.
    Isoflurane: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Reports of QT prolongation, associated with TdP (in exceptional cases, fatal), have been received. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Isoniazid, INH: (Major) Due to the risk of serotonin syndrome, concurrent use of mirtazapine and medications with MAO-like activity, such as isoniazid, INH, should be avoided if possible. 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 treatment should be implemented. In addition, mirtazapine is a substrate for 2D6, 1A2, and 3A4. Pharmacokinetic studies with some CYP3A4 inhibitors have shown that elevations in mirtazapine concentrations are possible during coadministration. Therefore, caution is advised during concurrent use of mirtazapine and inhibitors of CYP3A4 such as isoniazid, INH.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Due to the risk of serotonin syndrome, concurrent use of mirtazapine and medications with MAO-like activity, such as isoniazid, INH, should be avoided if possible. 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 treatment should be implemented. In addition, mirtazapine is a substrate for 2D6, 1A2, and 3A4. Pharmacokinetic studies with some CYP3A4 inhibitors have shown that elevations in mirtazapine concentrations are possible during coadministration. Therefore, caution is advised during concurrent use of mirtazapine and inhibitors of CYP3A4 such as isoniazid, INH. (Moderate) Mirtazapine plasma concentrations and pharmacologic action may be decreased in patients taking rifampin. Rifampin is a potent inducer of CYP3A4, and may be a modest inducer of CYP2D6. Rifampin is also a relatively weak inducer of CYP1A2. In vitro studies have identified mirtazapine as a substrate for several CYP450 isoenzymes including 2D6, 1A2, and 3A4. Monitor for reduced effectiveness of mirtazapine during co-administration of rifampin. It may be necessary to increase the mirtazapine dosage during concurrent therapy. Conversely, if rifampin is discontinued, the dosage of mirtazapine may need to be reduced.
    Isoniazid, INH; Rifampin: (Major) Due to the risk of serotonin syndrome, concurrent use of mirtazapine and medications with MAO-like activity, such as isoniazid, INH, should be avoided if possible. 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 treatment should be implemented. In addition, mirtazapine is a substrate for 2D6, 1A2, and 3A4. Pharmacokinetic studies with some CYP3A4 inhibitors have shown that elevations in mirtazapine concentrations are possible during coadministration. Therefore, caution is advised during concurrent use of mirtazapine and inhibitors of CYP3A4 such as isoniazid, INH. (Moderate) Mirtazapine plasma concentrations and pharmacologic action may be decreased in patients taking rifampin. Rifampin is a potent inducer of CYP3A4, and may be a modest inducer of CYP2D6. Rifampin is also a relatively weak inducer of CYP1A2. In vitro studies have identified mirtazapine as a substrate for several CYP450 isoenzymes including 2D6, 1A2, and 3A4. Monitor for reduced effectiveness of mirtazapine during co-administration of rifampin. It may be necessary to increase the mirtazapine dosage during concurrent therapy. Conversely, if rifampin is discontinued, the dosage of mirtazapine may need to be reduced.
    Itraconazole: (Moderate) Use itraconazole with caution in combination with mirtazapine as concurrent use may increase the risk of QT prolongation; mirtazapine exposure may also increase. Itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Mirtazapine is a CYP3A4 substrate that has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with mirtazapine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Ketamine: (Moderate) Consistent with the pharmacology of mirtazapine and the CNS depression that may occur, additive effects may occur with other CNS depressants, including ketamine. Close monitoring is recommended in patients receiving mirtazapine and requiring an anesthetic.
    Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and mirtazapine if possible due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Decrease the dose of mirtazapine if needed with concomitant strong CYP3A inhibitor use. Conversely, an increase in dosage of mirtazapine may be needed if the CYP3A inhibitor is discontinued. Mirtazapine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the AUC of mirtazapine by approximately 50%.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and clarithromycin. Coadminister with caution. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Lapatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with mirtazapine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Mirtazapine has also been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Lasmiditan: (Moderate) Monitor for excessive sedation, somnolence, and serotonin syndrome during coadministration of lasmiditan and mirtazapine. 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 lefamulin with mirtazapine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and mirtazapine. Dosage adjustments of lemborexant and mirtazapine may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with mirtazapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has also been reported in postmarketing experience with mirtazapine, primarily in overdose or in patients with other risk factors for QT prolongation.
    Letermovir: (Moderate) Monitor for mirtazapine-related adverse events if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Mirtazapine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration with another strong CYP3A4 inhibitor increased the maximum plasma concentration and exposure of mirtazapine by approximately 40% and 50%, respectively.
    Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving mirtazapine. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported in postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving mirtazapine. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported in postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Levocetirizine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with cetirizine, a low-sedating antihistamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Levofloxacin: (Moderate) Concomitant use of levofloxacin and mirtazapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and mirtazapine if possible due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Decrease the dose of mirtazapine if needed with concomitant strong CYP3A inhibitor use. Conversely, an increase in dosage of mirtazapine may be needed if the CYP3A inhibitor is discontinued. Mirtazapine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the AUC of mirtazapine by approximately 50%.
    Levomethadyl: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents including levomethadyl. Mirtazapine should be administered with caution with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as mirtazapine and levomilnacipran. Cases of serotonin syndrome have been reported between mirtazapine and other antidepressants such as selective serotonin reuptake inhibitors (SSRIs). 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.
    Levorphanol: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Linezolid: (Contraindicated) Concurrent use of linezolid and mirtazapine is contraindicated due to an increased risk of serotonin syndrome. Mirtazapine is a serotonergic antidepressant and linezolid is a nonselective inhibitor of monoamine oxidase which increases central serotonin levels. If urgent psychiatric treatment is required, interventions other than mirtazapine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving mirtazapine and requiring urgent treatment with linezolid, mirtazapine should be discontinued immediately and linezolid therapy initiated only if acceptable alternatives are not available and the potential benefits of linezolid outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first. Mirtazapine may be resumed 24 hours after the last dose of linezolid.
    Lisdexamfetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and mirtazapine. At high doses, amphetamines can increase serotonin release and 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; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Lithium: (Major) Concomitant use of mirtazapine and lithium may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP), and mirtazapine may increase the likelihood of precipitating a mixed/manic episode in susceptible patients receiving lithium. Lithium and mirtazapine have been associated with QT prolongation. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Lithium has been reported to increase 5-hydroxytryptamine metabolites in the cerebrospinal fluid and may interact pharmacodynamically with serotonergic agents such as mirtazapine to cause 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, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Lofexidine: (Moderate) Monitor ECG if lofexidine is coadministered with mirtazapine due to the potential for additive QT prolongation and torsade de pointes (TdP). Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Lonafarnib: (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with lonafarnib is necessary. Mirtazapine is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
    Loop diuretics: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Loperamide: (Moderate) Concomitant use of loperamide and mirtazapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Loperamide; Simethicone: (Moderate) Concomitant use of loperamide and mirtazapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with mirtazapine due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor, while mirtazapine is a CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%.
    Lorazepam: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of mirtazapine by decreasing its systemic exposure; if used together, it may be necessary to increase the mirtazapine dose to achieve clinical efficacy. If lumacaftor; ivacaftor is subsequently discontinued, consider mirtazapine dosage reduction. Mirtazapine is a substrate of CYP3A. Lumacaftor is a strong CYP3A inducer. At steady state, carbamazepine and phenytoin, both strong inducers of CYP3A, increased mirtazapine clearance approximately 2-fold, resulting in respective decreases of 60% and 45% in average plasma mirtazapine concentrations.
    Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and mirtazapine. Concurrent use may result in additive CNS depression.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as mirtazapine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Maprotiline: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and maprotiline. In addition, these medications may be duplicate treatment for some conditions. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in commonly prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Meclizine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as meclizine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving mirtazapine. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mepenzolate: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Meperidine: (Moderate) Because of the potential risk and severity of excessive sedation, somnolence, and serotonin syndrome, caution should be observed when administering meperidine with mirtazapine. Limit the use of opiod pain medications with mirtazapine 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. Inform patients taking this combination of the possible increased risks and monitor for the emergence of excessive CNS depression and serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Meperidine; Promethazine: (Moderate) Because of the potential risk and severity of excessive sedation, somnolence, and serotonin syndrome, caution should be observed when administering meperidine with mirtazapine. Limit the use of opiod pain medications with mirtazapine 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. Inform patients taking this combination of the possible increased risks and monitor for the emergence of excessive CNS depression and serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and promethazine. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Because both mirtazapine and promethazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of how the combination affects them.
    Mephobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Mesoridazine: (Major) Coadministration may increase the risk of QT prolongation, torsade de pointes, and CNS depression. Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of mesoridazine and mirtazapine. Mesoridazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Both drugs also have CNS depressant properties, and patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of the effects of the combination.
    Metaxalone: (Moderate) Coadministration of mirtazapine with metaxalone may result in additive CNS-depressant effects, such as sedation, and may increase the risk for serotonin syndrome. Use with caution and monitor for the emergence of excessive sedation or serotonin syndrome. If serotonin syndrome is suspected, serotonergic agents should be discontinued and appropriate medical treatment instituted.
    Methadone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Methamphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as methamphetamine and mirtazapine. 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: (Contraindicated) According to the manufacturer of mirtazapine, treatment initiation with mirtazapine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than mirtazapine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving mirtazapine and requiring urgent treatment with intravenous methylene blue, mirtazapine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Mirtazapine may be re-initiated 24 hours after the last dose of methylene blue Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and mirtazapine increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. 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. (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Methohexital: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Methscopolamine: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Methyclothiazide: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Methylene Blue: (Contraindicated) According to the manufacturer of mirtazapine, treatment initiation with mirtazapine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than mirtazapine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving mirtazapine and requiring urgent treatment with intravenous methylene blue, mirtazapine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Mirtazapine may be re-initiated 24 hours after the last dose of methylene blue Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and mirtazapine increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. 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.
    Methylergonovine: (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
    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 mirtazapine.
    Methysergide: (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
    Metolazone: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Metronidazole: (Moderate) Concomitant use of metronidazole and mirtazapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Midazolam: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Midostaurin: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and midostaurin. QT prolongation was reported in patients who received midostaurin in clinical trials. Consider obtaining electrocardiograms to monitor the QT interval if it is used with other drugs that prolong the QT interval. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Mifepristone: (Major) Concomitant use of mifepristone and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as mirtazapine and milnacipran. Cases of serotonin syndrome have been reported between mirtazapine and other antidepressants such as selective serotonin reuptake inhibitors (SSRIs). 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.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs partially metabolized by CYP2D6 such as mirtazapine may be increased when co-administered with mirabegron. Mirtazapine as a substrate for several CYP450 isoenzymes including 2D6, 1A2, and 3A4 in vitro. Appropriate monitoring and dose adjustment may be necessary.
    Mitotane: (Major) Use caution if mitotane and mirtazapine are used concomitantly, and monitor for decreased efficacy of mirtazapine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and mirtazapine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of mirtazapine.
    Mobocertinib: (Major) Concomitant use of mobocertinib and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Molindone: (Moderate) Molindone may cause central nervous system (CNS) depression thereby having additive effects with other drugs that can cause CNS depression such as mirtazapine. Caution is advisable during concurrent use.
    Monoamine oxidase inhibitors: (Contraindicated) Use of mirtazapine concurrently with the monoamine oxidase inhibitors (MAOIs) is contraindicated. If combined, there is a possibility of developing serious reactions such as serotonin syndrome. In patients receiving nonselective MAOIs in combination with serotoninergic agents there have been reports of serious, sometimes fatal, reactions. At least 2 weeks should elapse between stopping one agent and beginning the other. Monitor for serotonin-related side effects during therapy transitions.
    Morphine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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 mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Moxifloxacin: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and moxifloxacin. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nabilone: (Moderate) Nabilone should be combined cautiously with mirtazapine because of additive sedation or other CNS effects.
    Nalbuphine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Naratriptan: (Major) Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when mirtazapine is coadministered with other drugs that may affect these neurotransmitter systems, including the serotonin-receptor agonists ("triptans"). The co-use of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
    Nefazodone: (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.
    Nelfinavir: (Moderate) Concurrent administration of mirtazapine and nelfinavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as mirtazapine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. 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.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and mirtazapine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Cases of QT prolongation, torsade de pointes, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Nirmatrelvir; Ritonavir: (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor, while mirtazapine is a CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%.
    Norfloxacin: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and norfloxacin. Coadminister with caution. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Nortriptyline: (Major) Concomitant use of mirtazapine and tricyclic antidepressants (TCAs) may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose prescription therapy (elevated serum concentrations). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and TCAs have central serotonin-enhancing effects, and case reports with other antidepressants (e.g., SSRIs) suggest that serotonin syndrome is possible. 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 treatment should be implemented. While one small study in healthy subjects (n = 24) reported that the combination of mirtazapine with a TCA may be tolerated and result in only minor alterations in the pharmacokinetics of either agent, the authors still recommended caution and the need for further human data, including safety data and evidence of combined treatment efficacy. Both mirtazapine and TCAs can have significant CNS depressant effects that may be additive. Patients should be advised to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Octreotide: (Moderate) Use octreotide with caution in combination with mirtazapine. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Moderate) Concomitant use of ofloxacin and mirtazapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Olanzapine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and TdP. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Olanzapine; Fluoxetine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and TdP. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. (Moderate) Use fluoxetine with caution in combination with mirtazapine. Coadministration may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. Case reports of serotonin syndrome have been reported with this combination. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. Both drugs have been reported to cause QT prolongation and TdP.
    Olanzapine; Samidorphan: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and TdP. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Oliceridine: (Major) Concomitant use of oliceridine with mirtazapine may cause excessive sedation and somnolence. Limit the use of oliceridine with mirtazapine 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.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor, while mirtazapine is a CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%.
    Ondansetron: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of mirtazapine and ondansetron is necessary. Both medications may cause QT interval prolongation and a risk for torsade de pointes (TdP). ECG monitoring has been recommended for at-risk patients. In addition, concurrent use of ondansetron with other drugs that modulate serotonergic function, such as mirtazapine, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
    Opicapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as mirtazapine, 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.
    Orphenadrine: (Moderate) Skeletal muscle relaxants like orphenadrine may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
    Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with mirtazapine. Osilodrostat is associated with dose-dependent QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Osimertinib: (Major) Avoid coadministration of mirtazapine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Mirtazapine has also been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing surveillance with mirtazapine, primarily in overdose or in patients with other risk factors for QT prolongation.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of mirtazapine with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported in postmarketing experience with mirtazapine, primarily in overdose or in patients with other risk factors for QT prolongation. QT prolongation and ventricular arrhythmias including fatal TdP have also been reported with oxaliplatin use in postmarketing experience.
    Oxazepam: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Oxybutynin: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Oxycodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Oxymorphone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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) In general, do not initiate ozanimod in patients taking mirtazapine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). Additionally, there is a potential for hypertensive crisis. If treatment initiation is considered, seek advice from a cardiologist and monitor for hypertension. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis. Ozanimod may also result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Mirtazapine is a serotonergic drug that has been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Pacritinib: (Major) Concomitant use of pacritinib and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Paliperidone: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and paliperidone. According to the manufacturer of paliperidone, use of the drug should be avoided with agents known to prolong the QT interval since paliperidone also has this effect; TdP and ventricular fibrillation have been reported in the setting of paliperidone overdose. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. If concurrent use is necessary and the patient has risk factors for cardiac disease or arrhythmias, close monitoring is essential.
    Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as mirtazapine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. 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.
    Panobinostat: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and panobinostat. QT prolongation has been reported with panobinostat and concurrent use with other agents that prolong the QT interval is not recommended. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Paroxetine: (Moderate) Coadministration of paroxetine and mirtazapine may increase the risk for serotonin syndrome. Cases of serotonin syndrome have been reported when mirtazapine has been administered with other selective serotonin reuptake inhibitors (SSRIs). Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Pasireotide: (Moderate) Use caution when using pasireotide in combination with mirtazapine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Pazopanib: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and pazopanib. Coadministration of pazopanib and other drugs that prolong the QT interval is not advised. If pazopanib and mirtazapine must be coadministered, closely monitor for QT prolongation. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to mirtazapine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP1A2 and CYP2D6 inhibitor, while mirtazapine is a CYP1A2 and CYP2D6 substrate.
    Pentamidine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and pentamidine. Coadminister with caution. Systemic pentamidine has been associated with QT prolongation. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Pentazocine: (Major) Concomitant use of pentazocine with other CNS depressants can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously in any patient receiving mirtazapine.
    Pentazocine; Naloxone: (Major) Concomitant use of pentazocine with other CNS depressants can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously in any patient receiving mirtazapine.
    Pentobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as mirtazapine.
    Pergolide: (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
    Perphenazine: (Moderate) Coadministration may increase the risk of QT prolongation, torsade de pointes, and CNS depression. Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of mirtazapine and perphenazine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Perphenazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Because both mirtazapine and perphenazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of the effects of the combination.
    Perphenazine; Amitriptyline: (Major) Concomitant use of mirtazapine and tricyclic antidepressants (TCAs) may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose prescription therapy (elevated serum concentrations). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and TCAs have central serotonin-enhancing effects, and case reports with other antidepressants (e.g., SSRIs) suggest that serotonin syndrome is possible. 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 treatment should be implemented. While one small study in healthy subjects (n = 24) reported that the combination of mirtazapine with a TCA may be tolerated and result in only minor alterations in the pharmacokinetics of either agent, the authors still recommended caution and the need for further human data, including safety data and evidence of combined treatment efficacy. Both mirtazapine and TCAs can have significant CNS depressant effects that may be additive. Patients should be advised to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Coadministration may increase the risk of QT prolongation, torsade de pointes, and CNS depression. Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of mirtazapine and perphenazine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Perphenazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Because both mirtazapine and perphenazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of the effects of the combination.
    Phenelzine: (Contraindicated) Use of mirtazapine concurrently with the monoamine oxidase inhibitors (MAOIs) is contraindicated. If combined, there is a possibility of developing serious reactions such as serotonin syndrome. In patients receiving nonselective MAOIs in combination with serotoninergic agents there have been reports of serious, sometimes fatal, reactions. At least 2 weeks should elapse between stopping one agent and beginning the other. Monitor for serotonin-related side effects during therapy transitions.
    Phenobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression. (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Phentermine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed during co-administration of mirtazapine with other drugs that have serotonergic properties. As a drug related to the amphetamines, phentermine has the potential to cause serotonin syndrome when combined with serotonergic agents. Patients receiving this combination should be monitored for the emergence of serotonin syndrome.
    Phentermine; Topiramate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed during co-administration of mirtazapine with other drugs that have serotonergic properties. As a drug related to the amphetamines, phentermine has the potential to cause serotonin syndrome when combined with serotonergic agents. Patients receiving this combination should be monitored for the emergence of serotonin syndrome.
    Pimavanserin: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and pimavanserin. Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Pimozide: (Contraindicated) Because of the potential for torsade de pointes (TdP), concurrent use of pimozide and mirtazapine is contraindicated. Pimozide is associated with a well established risk of QT prolongation and TdP. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Pitolisant: (Major) Avoid coadministration of pitolisant with mirtazapine as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like mirtazapine, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Ponesimod: (Major) In general, do not initiate ponesimod in patients taking mirtazapine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Mirtazapine has been associated with dose-dependent prolongation of the QT interval; TdP has been reported postmarketing primarily in overdose or in patients with other risk factors for QT prolongation.
    Posaconazole: (Contraindicated) The concurrent use of posaconazole, a potent CYP3A4 inhibitor, with drugs that are associated with QT prolongation and are CYP3A4 substrates, such as mirtazapine, is contraindicated. Posaconazole has been associated with QT prolongation and torsade de pointes (TdP). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation.
    Potassium-sparing diuretics: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Pramipexole: (Moderate) Some medicines used for treatment of Parkinson's disease, like pramipexole, could potentially cause additive drowsiness when coadministered with mirtazapine.
    Pregabalin: (Major) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and mirtazapine. Concomitant use of pregabalin with mirtazapine may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
    Primaquine: (Moderate) Exercise caution when administering primaquine in combination with mirtazapine as concurrent use may increase the risk of QT prolongation. Primaquine is associated with QT prolongation. Primaquine has the potential for QT interval prolongation. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Primidone: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Procainamide: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and procainamide. Procainamide is associated with a well-established risk of QT prolongation and TdP. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Procarbazine: (Contraindicated) Use of mirtazapine concurrently with drugs that exhibit MAO-inhibition, such as procarbazine, is contraindicated. If combined, there is a possibility of developing serious reactions such as hyperpyrexia, hypertension, or seizures. An interval of 14 days is recommended between cessation of MAOI therapy and initiation of mirtazapine therapy and vice versa.
    Prochlorperazine: (Moderate) Coadministration may increase the risk of QT prolongation, torsade de pointes, and CNS depression. Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of mirtazapine and prochlorperazine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Prochlorperazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Because both mirtazapine and prochlorperazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of the effects of the combination.
    Promethazine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and promethazine. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Because both mirtazapine and promethazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of how the combination affects them.
    Promethazine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and promethazine. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Because both mirtazapine and promethazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of how the combination affects them.
    Promethazine; Phenylephrine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and promethazine. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Because both mirtazapine and promethazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of how the combination affects them.
    Propafenone: (Major) Concomitant use of propafenone and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Propantheline: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Propofol: (Moderate) Consistent with the pharmacology of mirtazapine and the CNS depression that may occur, additive effects may occur with other CNS depressants, including propofol. Close monitoring is recommended in patients receiving mirtazapine and requiring an anesthetic.
    Propoxyphene: (Moderate) Concomitant use of propoxyphene with other CNS depressants, such as mirtazapine, can potentiate the effects of propoxyphene on respiratory depression and/or sedation. Use together with caution.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Protriptyline: (Major) Concomitant use of mirtazapine and tricyclic antidepressants (TCAs) may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose prescription therapy (elevated serum concentrations). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and TCAs have central serotonin-enhancing effects, and case reports with other antidepressants (e.g., SSRIs) suggest that serotonin syndrome is possible. 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 treatment should be implemented. While one small study in healthy subjects (n = 24) reported that the combination of mirtazapine with a TCA may be tolerated and result in only minor alterations in the pharmacokinetics of either agent, the authors still recommended caution and the need for further human data, including safety data and evidence of combined treatment efficacy. Both mirtazapine and TCAs can have significant CNS depressant effects that may be additive. Patients should be advised to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Pseudoephedrine; Triprolidine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as triprolidine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Pyrilamine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as pyrilamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Quazepam: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Quetiapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and quetiapine. The manufacturer of quetiapine recommends avoiding combined use of quetiapine with drugs known to increase the QT interval. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Because both mirtazapine and quetiapine can cause somnolence, monitoring for additive CNS depressant effects is recommended.
    Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Quinidine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and quinidine. Coadminister with caution. Quinidine administration is associated with QT prolongation and TdP. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Quinine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and quinine. Avoid concurrent use of quinine with other drugs that may cause QT prolongation and TdP. Quinine has been associated with QT prolongation and rare cases of torsade de pointes. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Ranolazine: (Moderate) Use ranolazine with caution in combination with mirtazapine as concurrent use may increase the risk of QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Rasagiline: (Major) It is recommended to avoid concurrent use of rasagiline and antidepressants, including mirtazapine. 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 mirtazapine. Conversely, when discontinuing mirtazapine, it is advisable to wait the length of 4 to 5 half-lives of the drug prior to initiation with rasagiline.
    Relugolix: (Moderate) Use caution when using mirtazapine in combination with relugolix. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
    Relugolix; Estradiol; Norethindrone acetate: (Moderate) Use caution when using mirtazapine in combination with relugolix. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
    Remifentanil: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Remimazolam: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Ribociclib: (Major) Avoid coadministration of mirtazapine with ribociclib due to the risk of QT prolongation; mirtazapine plasma concentrations may also increase. Mirtazapine is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; torsade de pointes (TdP) has also been reported in postmarketing experience, primarily in overdose cases or in patients with other risk factors. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Additive QT prolongation may occur. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%.
    Ribociclib; Letrozole: (Major) Avoid coadministration of mirtazapine with ribociclib due to the risk of QT prolongation; mirtazapine plasma concentrations may also increase. Mirtazapine is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; torsade de pointes (TdP) has also been reported in postmarketing experience, primarily in overdose cases or in patients with other risk factors. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Additive QT prolongation may occur. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%.
    Rifampin: (Moderate) Mirtazapine plasma concentrations and pharmacologic action may be decreased in patients taking rifampin. Rifampin is a potent inducer of CYP3A4, and may be a modest inducer of CYP2D6. Rifampin is also a relatively weak inducer of CYP1A2. In vitro studies have identified mirtazapine as a substrate for several CYP450 isoenzymes including 2D6, 1A2, and 3A4. Monitor for reduced effectiveness of mirtazapine during co-administration of rifampin. It may be necessary to increase the mirtazapine dosage during concurrent therapy. Conversely, if rifampin is discontinued, the dosage of mirtazapine may need to be reduced.
    Rifapentine: (Moderate) Monitor for decreased efficacy of mirtazapine if coadministration with rifapentine is necessary; an increased mirtazapine dose may be necessary. If rifapentine is discontinued, a decrease in mirtazapine dose may be needed. Concomitant use may decrease mirtazapine exposure. Mirtazapine is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers increased mirtazapine clearance by approximately 2-fold, decreasing the average mirtazapine plasma concentrations by 45% to 60%.
    Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with mirtazapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Risperidone: (Moderate) Use risperidone and mirtazapine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Ritonavir: (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor, while mirtazapine is a CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%.
    Rizatriptan: (Major) Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when mirtazapine is coadministered with other drugs that may affect these neurotransmitter systems, including the serotonin-receptor agonists ("triptans"). The co-use of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
    Rolapitant: (Major) Use caution if mirtazapine and rolapitant are used concurrently, and monitor for mirtazapine-related adverse effects. Mirtazapine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with mirtazapine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Ropinirole: (Moderate) Some medicines used for treatment of Parkinson's disease, like ropinirole, could potentially cause additive drowsiness when coadministered with mirtazapine.
    Saquinavir: (Moderate) Concurrent administration of mirtazapine and saquinavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
    Scopolamine: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Secobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Selegiline: (Contraindicated) Mirtazapine 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 mirtazapine. After stopping treatment with mirtazapine, a time period equal to 4 to 5 half-lives of mirtazapine or any active metabolite should elapse before starting therapy with selegiline. Serotonin syndrome has occurred in patients receiving selective MAO-B inhibitors and serotonergic antidepressants simultaneously.
    Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with mirtazapine is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Serotonin-Receptor Agonists: (Major) Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when mirtazapine is coadministered with other drugs that may affect these neurotransmitter systems, including the serotonin-receptor agonists ("triptans"). The co-use of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
    Sertraline: (Moderate) Use sertraline with caution in combination with mirtazapine. Coadministration may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. Both drugs have been reported to cause QT prolongation. However, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease.
    Sevoflurane: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Reports of QT prolongation, associated with TdP (in exceptional cases, fatal), have been received. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Sibutramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as mirtazapine and sibutramine. Avoid use and consider alternatives if possible. Additive CNS effects may be possible, such as sedation. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving mirtazapine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Solifenacin: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and solifenacin. Solifenacin has been associated with dose-dependent prolongation of the QT interval. TdP has been reported with postmarketing use, although causality was not determined. This should be taken into consideration when prescribing solifenacin to patients taking other drugs that are associated with QT prolongation. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Mirtazapine exhibits weak anticholinergic activity that may be additive with the anticholinergic effects of solifenacin.
    Sorafenib: (Major) Avoid coadministration of sorafenib with mirtazapine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation. Sorafenib is also associated with QTc prolongation.
    Sotalol: (Major) Concomitant use of sotalol and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Spironolactone: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    St. John's Wort, Hypericum perforatum: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering mirtazapine with St. John's Wort. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Sufentanil: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Sumatriptan: (Major) Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when mirtazapine is coadministered with other drugs that may affect these neurotransmitter systems, including the serotonin-receptor agonists ("triptans"). The co-use of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
    Sumatriptan; Naproxen: (Major) Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when mirtazapine is coadministered with other drugs that may affect these neurotransmitter systems, including the serotonin-receptor agonists ("triptans"). The co-use of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
    Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with mirtazapine. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. Sunitinib can prolong the QT interval.
    Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with mirtazapine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Tamoxifen: (Moderate) Concomitant use of tamoxifen and mirtazapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Tapentadol: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and mirtazapine. Tedizolid is an antibiotic that is also a weak reversible, non-selective inhibitor of MAO. Since monoamine oxidase type A deaminates serotonin, administration of a non-selective MAO inhibitor concurrently with mirtazapine can potentially lead to serious reactions including serotonin syndrome. 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.
    Telavancin: (Moderate) Coadminister mirtazapine and telavancin with caution as concurrent use may lead to increased risks for QT prolongation and torsade de pointes (TdP). Telavancin has been associated with QT prolongation. Mirtazapine has ben associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Telithromycin: (Moderate) Use caution when using mirtazapine in combination with telithromycin as concurrent use may increase the risk of QT prolongation and mirtazapine-related adverse effects. Telithromycin is a strong CYP3A4 inhibitor that is associated with QT prolongation and TdP. Mirtazapine is a CYP3A4 substrate that has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Temazepam: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Tetrabenazine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and tetrabenazine. Because tetrabenazine causes a small increase in the corrected QT interval (QTc), the manufacturer recommends avoiding use of tetrabenazine with other drugs known to prolong QTc. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Thiazide diuretics: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Thiopental: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
    Thioridazine: (Contraindicated) Because of the potential for torsade de pointes (TdP), concurrent use of thioridazine and mirtazapine is contraindicated. Thioridazine has a well established risk of QT prolongation and TdP. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Tipranavir: (Moderate) Concurrent administration of mirtazapine and tipranavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
    Tolcapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as mirtazapine, 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: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and tolterodine. Coadminister with caution. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Mirtazapine exhibits weak anticholinergic activity that may be additive with the anticholinergic effects of tolterodine.
    Toremifene: (Major) Avoid coadministration of mirtazapine with toremifene if possible due to the risk of additive 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. Both drugs have been shown to prolong the QTc interval in a dose- and concentration-related manner. Torsade de pointes (TdP) has also been reported during postmarketing use of mirtazapine, primarily in overdose or in patients with other risk factors for QT prolongation.
    Torsemide: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Tramadol: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Tramadol; Acetaminophen: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
    Tranylcypromine: (Contraindicated) Use of mirtazapine concurrently with the monoamine oxidase inhibitors (MAOIs) is contraindicated. If combined, there is a possibility of developing serious reactions such as serotonin syndrome. In patients receiving nonselective MAOIs in combination with serotoninergic agents there have been reports of serious, sometimes fatal, reactions. At least 2 weeks should elapse between stopping one agent and beginning the other. Monitor for serotonin-related side effects during therapy transitions.
    Trazodone: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of trazodone and mirtazapine is necessary.Both drugs may cause QT interval prolongation and a risk for torsade de pointes (TdP). In addition, concurrent use of trazodone with other drugs that modulate serotonergic function, such as mirtazapine, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
    Triamterene: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Triazolam: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Triclabendazole: (Moderate) Monitor ECGs in patients receiving triclabendazole with mirtazapine. Transient prolongation of the mean QTc interval was noted on the ECG recordings in dogs administered triclabendazole. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Tricyclic antidepressants: (Major) Concomitant use of mirtazapine and tricyclic antidepressants (TCAs) may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose prescription therapy (elevated serum concentrations). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and TCAs have central serotonin-enhancing effects, and case reports with other antidepressants (e.g., SSRIs) suggest that serotonin syndrome is possible. 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 treatment should be implemented. While one small study in healthy subjects (n = 24) reported that the combination of mirtazapine with a TCA may be tolerated and result in only minor alterations in the pharmacokinetics of either agent, the authors still recommended caution and the need for further human data, including safety data and evidence of combined treatment efficacy. Both mirtazapine and TCAs can have significant CNS depressant effects that may be additive. Patients should be advised to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Trifluoperazine: (Moderate) Coadministration is contraindicated due to the potential for QT prolongation and torsade de pointes. Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of mirtazapine and trifluoperazine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Trifluoperazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Because both mirtazapine and trifluoperazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of the effects of the combination.
    Trihexyphenidyl: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Trimipramine: (Major) Concomitant use of mirtazapine and tricyclic antidepressants (TCAs) may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose prescription therapy (elevated serum concentrations). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and TCAs have central serotonin-enhancing effects, and case reports with other antidepressants (e.g., SSRIs) suggest that serotonin syndrome is possible. 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 treatment should be implemented. While one small study in healthy subjects (n = 24) reported that the combination of mirtazapine with a TCA may be tolerated and result in only minor alterations in the pharmacokinetics of either agent, the authors still recommended caution and the need for further human data, including safety data and evidence of combined treatment efficacy. Both mirtazapine and TCAs can have significant CNS depressant effects that may be additive. Patients should be advised to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Triprolidine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as triprolidine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
    Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving mirtazapine. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported in postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Trospium: (Moderate) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
    Tryptophan, 5-Hydroxytryptophan: (Major) Concurrent use of tryptophan and mirtazapine is not recommended. Since tryptophan is converted to serotonin, the use of tryptophan in patients receiving mirtazapine could lead to serotonin excess, and potentially, 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. Because tryptophan is found in some herbal supplements, patients receiving mirtazapine should be instructed to talk to their doctor or pharmacist before taking any non-prescription products.
    Tucatinib: (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with tucatinib is necessary. Mirtazapine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
    Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Hyponatremia has been reported very rarely during mirtazapine administration. Caution is advisable in patients receiving medications known to cause hyponatremia, such as diuretics. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of mirtazapine, as well as implementation of the appropriate medical interventions.
    Vandetanib: (Major) Avoid coadministration of vandetanib with mirtazapine due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Mirtazapine has also been associated with dose-dependent prolongation of the QT interval; TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Vardenafil: (Moderate) Concomitant use of vardenafil and mirtazapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Vemurafenib: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and vemurafenib. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and TdP must be coadministered, ECG monitoring is recommended. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Venlafaxine: (Major) Concomitant use of mirtazapine and venlafaxine may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Both medications are associated with a possible risk of QT prolongation and torsade de pointes (TdP). Cases of serotonin syndrome have been reported between mirtazapine and other serotonin-enhancing antidepressants. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given with mirtazapine.
    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 mirtazapine. 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 toxicity. Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as mirtazapine.
    Voclosporin: (Moderate) Concomitant use of voclosporin and mirtazapine may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Voclosporin has been associated with QT prolongation at supratherapeutic doses. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP in patients receiving mirtazapine has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Voriconazole: (Contraindicated) The concurrent use of voriconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as mirtazapine, is contraindicated. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Vorinostat: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and vorinostat. Coadminister with caution. Vorinostat therapy is associated with a risk of QT prolongation. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    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 mirtazapine. 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. If serotonin syndrome is suspected, vortioxetine and concurrent serotonergic agents should be discontinued.
    Warfarin: (Moderate) In a study of 16 healthy subjects, concurrent use of mirtazapine (30 mg/day) and warfarin resulted in a small (0.20) but statistically significant increase in INR. The mechanism of this interaction has not been described. Until further information becomes available, it is advisable to carefully monitor the INR during concurrent use of mirtazapine and warfarin.
    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 mirtazipine. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
    Ziprasidone: (Major) Concomitant use of ziprasidone and mirtazapine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Zolmitriptan: (Major) Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when mirtazapine is coadministered with other drugs that may affect these neurotransmitter systems, including the serotonin-receptor agonists ("triptans"). The co-use of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.

    PREGNANCY AND LACTATION

    Pregnancy

    Mirtazapine should be used during pregnancy only after careful consideration of the possible fetal risks from drug exposure and potential harm to the mother from untreated depression (e.g., relapse). Available data from prolonged experience with mirtazapine have not established an increased risk of major birth defects, miscarriage, or adverse maternal and fetal outcomes. Postnatal adaptation syndrome (PNAS) has been reported in neonates with third-trimester exposure to some serotonergic antidepressants (e.g., SSRIs, SNRIs); however, there is no clear evidence of an association between mirtazapine and PNAS. The effects of mirtazapine during labor and delivery are unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to mirtazapine; information about the registry can be obtained at womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants or by calling 1-866-961-2388 or 1-844-405-6185.

    MECHANISM OF ACTION

    Mirtazapine inhibits presynaptic serotonin (5-HT)-2 and alpha-2 adrenergic auto- and hetero-receptors, thereby increasing serotonergic and noradrenergic neurotransmission. The increased amount of 5-HT released interacts with postsynaptic 5-HT1 receptors, which may be relevant to the antidepressant effects of the drug. The affinity of mirtazapine for central alpha-2 adrenoreceptors is 10 times higher than for peripheral receptors, resulting in fewer peripheral effects related to increased blood pressure. Mirtazapine is an antagonist at postsynaptic 5-HT2A, 5-HT2C, and 5-HT3 receptors. The blockade of these receptors may result in a lower incidence of certain adverse effects (e.g., anxiety, insomnia, nausea) than occurs with antidepressants that do not antagonize these receptors. Mirtazapine significantly antagonizes histamine H1 receptors at low doses, and this activity is associated with sedation and appetite stimulation. Higher doses have a greater effect on norepinephrine release relative to antihistamine effects, which may offset the sedative potential and appetite stimulation observed at low doses. Mirtazapine has muscarinic antagonist properties, which may be associated with xerostomia, constipation, and other anticholinergic effects. Orthostatic hypotension is the result of the peripheral alpha-1 adrenergic antagonism of the drug. Mirtazapine does not have clinically significant receptor affinity for dopamine, 5-HT1A, or 5-HT1B, and has no effects on the central reuptake of either norepinephrine or serotonin.

    PHARMACOKINETICS

    Mirtazapine is administered orally. Plasma protein binding is approximately 85%. Mirtazapine is extensively metabolized in the liver, primarily by demethylation and hydroxylation followed by glucuronide conjugation. The isoenzymes CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine and CYP3A is responsible for the formation of the N-desmethyl and N-oxide metabolite. Several unconjugated metabolites possess pharmacological activity but levels are very low in the plasma. The half-life of mirtazapine ranges from 20 to 40 hours. Elimination occurs primarily in the urine (75%) and to a lesser extent in the feces (15%).
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, CYP2D6, CYP1A2
    In vitro data indicate that CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite and that CYP3A is responsible for the formation of the N-desmethyl and N-oxide metabolites. Strong CYP3A4 inhibitors and inducers altered the pharmacokinetics of mirtazapine during drug interaction studies. Dosage adjustments may be needed during coadministration of strong CYP3A4 inhibitors or inducers. During the administration of a strong CYP2D6 inhibitor to healthy subjects that were CYP2D6 extensive metabolizers, no relevant changes to the pharmacokinetics of steady-state mirtazapine were noted.

    Oral Route

    Following oral administration, peak plasma concentrations are reached within about 2 hours. The absolute bioavailability is about 50%. Food has minimal effects on both the rate and extent of absorption; therefore, mirtazapine can be taken without regard to meals. Steady-state plasma concentrations are reached within 5 days. The (-) enantiomer has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about 3 times as high as the (+) enantiomer.