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  • CLASSES

    Inverse Serotonin Agonist and Antagonist Antipsychotics

    BOXED WARNING

    Dementia, geriatric

    Pimavanserin, an atypical antipsychotic, is not approved for the treatment of patients with dementia-related psychosis unrelated to hallucinations and delusions associated with Parkinson's disease psychosis. Atypical antipsychotic labels include a boxed warning indicating that geriatric patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death. Of 17 placebo-controlled trials performed in elderly patients with dementia-related psychosis receiving primarily atypical antipsychotics, the risk of death in the drug-treated patients was 1.6 to 1.7 times that of patients receiving placebo. Death typically occurred due to heart failure, sudden death, or infections (e.g., pneumonia).[60748] Geriatric patients may be at increased risk for developing a prolonged QT interval when using pimavanserin.   According to the Beers Criteria, antipsychotics are considered potentially inappropriate medications (PIMs) in elderly patients; avoid use in geriatric patients with the following conditions due to the potential for symptom exacerbation or adverse effects: delirium (new-onset or worsening delirium) and dementia (adverse CNS effects). There is an increased risk of stroke and a greater rate of cognitive decline and mortality in persons with dementia receiving antipsychotics, and the Beers expert panel recommends avoiding antipsychotics to treat delirium- or dementia-related behavioral problems unless non-pharmacological options have failed or are not possible and the patient is a substantial threat to self or others. Avoid use in elderly patients with a history of falls or fractures unless safer alternatives are not available since antipsychotics can cause ataxia, impaired psychomotor function, syncope, and additional falls. If an antipsychotic must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures, and implement other strategies to reduce fall risk. While most dopamine-receptor antagonists should be avoided in patients with Parkinson's disease due to the potential to worsen parkinsonian symptoms, pimavanserin appears less likely to precipitate a worsening of symptoms than other antipsychotics and is excluded from the Beers recommendation to avoid use in these patients, consistent with the drug's FDA-approved indication. Because antipsychotics 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 of antipsychotics in older adults.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of psychotropic medications, including antipsychotics, in residents of long-term care facilities. The OBRA guidelines provide criteria for the use of psychotropic medications and requirements for medical record documentation, monitoring, and dosage guidance. Pimavanserin is considered less likely than other antipsychotics to induce extrapyramidal symptoms. However, patients in skilled nursing facilities receiving any antipsychotic should have regular assessments for movement disorders and other antipsychotic side effects. Under OBRA guidelines, when antipsychotics are used without monitoring and appropriate documentation of use, they may be considered unnecessary medications.[60742]

    DEA CLASS

    Rx

    DESCRIPTION

    Atypical antipsychotic with serotonin modulator activity
    Used for hallucinations and delusions associated with Parkinson's disease psychosis; not approved for patients with dementia-related behavioral problems unrelated to Parkinson's disease psychosis
    May cause QT prolongation; avoid use with other drugs that prolong the QT interval and avoid in patients with risk factors for QT prolongation

    COMMON BRAND NAMES

    NUPLAZID

    HOW SUPPLIED

    NUPLAZID/Pimavanserin Oral Tab: 10mg, 17mg
    Pimavanserin Oral Cap: 34mg

    DOSAGE & INDICATIONS

    For the treatment of hallucinations and delusions associated with Parkinson's disease psychosis.
    Oral dosage
    Adults

    The recommended dose is 34 mg PO once daily, without titration. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    MAXIMUM DOSAGE

    Adults

    34 mg/day PO.

    Geriatric

    34 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

    Dosage adjustments are not necessary in patients with hepatic impairment.

    Renal Impairment

    CrCl 30 mL/minute or more: No dosage adjustment is required.
    CrCl less than 30 mL/minute: No dosage adjustment is required. Due to increased exposure to pimavanserin in these patients and those with end stage renal disease, caution is advisable.
     
    Intermittent Hemodialysis
    No dosage adjustment is required. Caution is recommended in patients with ESRD due to increased systemic exposure to pimavanserin. In a renal impairment study, dialysis did not appear to significantly affect the concentrations of pimavanserin.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    May be administered with or without food.
    Administer the capsules whole. Alternatively, the capsule may be opened and the entire contents sprinkled over a tablespoon (15 mL) of cool applesauce, yogurt, pudding, or a liquid nutritional supplement. Have the patient consume the drug/food mixture immediately without chewing; do not store for future use.

    STORAGE

    NUPLAZID :
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Pimavanserin is contraindicated in patients with a history of a hypersensitivity reaction to pimavanserin or any of its components. Reactions have included rash, urticaria, tongue swelling, circumoral edema, and throat tightness.

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

    Pimavanserin prolongs the QT interval. Avoid the use of pimavanserin in patients with known QT prolongation, receiving medications known to prolong the QT interval (i.e., Class 1A antiarrhythmics, Class 3 antiarrhythmics, certain antipsychotic medications, and certain antibiotics), with a history of cardiac arrhythmias, or with other conditions that may increase the risk of the occurrence of torsade de pointes and/or sudden death (including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval such as congenital long QT syndrome). Use pimavanserin with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypocalcemia, or in patients receiving medications known to 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.

    Renal failure, renal impairment

    No dosage adjustment is required in patients with mild to severe renal impairment or end stage renal disease (ESRD). Due to increased exposure to pimavanserin in patients with severe renal impairment (CrCl less than 30 mL/minute), caution is advisable in patients with severe renal impairment, renal failure, or ESRD. In a renal impairment study, dialysis did not appear to significantly affect the concentrations of pimavanserin.

    Dementia, geriatric

    Pimavanserin, an atypical antipsychotic, is not approved for the treatment of patients with dementia-related psychosis unrelated to hallucinations and delusions associated with Parkinson's disease psychosis. Atypical antipsychotic labels include a boxed warning indicating that geriatric patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death. Of 17 placebo-controlled trials performed in elderly patients with dementia-related psychosis receiving primarily atypical antipsychotics, the risk of death in the drug-treated patients was 1.6 to 1.7 times that of patients receiving placebo. Death typically occurred due to heart failure, sudden death, or infections (e.g., pneumonia).[60748] Geriatric patients may be at increased risk for developing a prolonged QT interval when using pimavanserin.   According to the Beers Criteria, antipsychotics are considered potentially inappropriate medications (PIMs) in elderly patients; avoid use in geriatric patients with the following conditions due to the potential for symptom exacerbation or adverse effects: delirium (new-onset or worsening delirium) and dementia (adverse CNS effects). There is an increased risk of stroke and a greater rate of cognitive decline and mortality in persons with dementia receiving antipsychotics, and the Beers expert panel recommends avoiding antipsychotics to treat delirium- or dementia-related behavioral problems unless non-pharmacological options have failed or are not possible and the patient is a substantial threat to self or others. Avoid use in elderly patients with a history of falls or fractures unless safer alternatives are not available since antipsychotics can cause ataxia, impaired psychomotor function, syncope, and additional falls. If an antipsychotic must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures, and implement other strategies to reduce fall risk. While most dopamine-receptor antagonists should be avoided in patients with Parkinson's disease due to the potential to worsen parkinsonian symptoms, pimavanserin appears less likely to precipitate a worsening of symptoms than other antipsychotics and is excluded from the Beers recommendation to avoid use in these patients, consistent with the drug's FDA-approved indication. Because antipsychotics 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 of antipsychotics in older adults.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of psychotropic medications, including antipsychotics, in residents of long-term care facilities. The OBRA guidelines provide criteria for the use of psychotropic medications and requirements for medical record documentation, monitoring, and dosage guidance. Pimavanserin is considered less likely than other antipsychotics to induce extrapyramidal symptoms. However, patients in skilled nursing facilities receiving any antipsychotic should have regular assessments for movement disorders and other antipsychotic side effects. Under OBRA guidelines, when antipsychotics are used without monitoring and appropriate documentation of use, they may be considered unnecessary medications.[60742]

    Neonates, pregnancy

    There are no data on pimavanserin use in pregnant women which would assist in determining drug-associated risks of major congenital malformations or miscarriage. Data obtained during the use of other antipsychotics during human pregnancy indicate that neonates exposed to antipsychotics during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms after delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder. Symptoms have ranged from self-limiting to those requiring hospitalization. Because pimavanserin has no appreciable affinity for dopaminergic receptors, the potential effects on newborns from in utero exposure, if any, are unknown. Nevertheless, neonates exhibiting possible signs or symptoms of extrapyramidal effects or withdrawal should be carefully monitored. The knowledge about long-term neurobehavioral effects in offspring is limited for all antipsychotic agents and requires further investigation. No adverse developmental effects were seen in animal reproduction studies during organogenesis at doses of pimavanserin up to 10- or 12-times the maximum recommended human dose (MRHD). Administration of pimavanserin to pregnant and lactating rats resulted in maternal toxicity and lower pup survival and body weight at doses that were 2 times the MRHD. The effects of pimavanserin during labor and delivery are unknown.

    Breast-feeding

    There is no information regarding the presence of pimavanserin in human breast milk. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for pimavanserin and any possible adverse effects on the infant from pimavanserin or from the underlying maternal condition. The American Academy of Pediatrics has previously considered some other antipsychotics (haloperidol, clozapine, etc.) to be drugs for which the effects on the nursing infant are not known but may be of concern, particularly with prolonged exposure. Use of antipsychotics during breast-feeding has been associated with drowsiness or lethargy in the infant and a decline in developmental scores. In addition, antipsychotics may cause hyperprolactinemia and galactorrhea to varying degrees, and thus may interfere with proper lactation. It should be noted that data related to the safety of antipsychotics during breast-feeding are limited and chronic administration of any antipsychotic during breast-feeding should be avoided if possible. Regardless of the antipsychotic used, the nursing infant should be closely monitored for excessive drowsiness, lethargy, and developmental delays. Combination treatment with antipsychotics may increase the risk of these adverse events. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants

    The safety and efficacy of pimavanserin in pediatric patients have not been established. Pimavanserin is not indicated for use in children or adolescents. There is no known use of this drug in infants.

    ADVERSE REACTIONS

    Severe

    stroke / Early / Incidence not known

    Moderate

    peripheral edema / Delayed / 7.0-7.0
    confusion / Early / 6.0-6.0
    hallucinations / Early / 5.0-5.0
    constipation / Delayed / 4.0-4.0
    edema / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known

    Mild

    nausea / Early / 7.0-7.0
    infection / Delayed / 0-1.0
    drowsiness / Early / Incidence not known
    agitation / Early / Incidence not known
    rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    fatigue / Early / Incidence not known

    DRUG INTERACTIONS

    Alfuzosin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as alfuzosin. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. Coadministration may increase the risk for QT prolongation.
    Amiodarone: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as amiodarone. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Coadministration may increase the risk for QT prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amisulpride: (Major) Avoid coadministration of amisulpride and pimavanserin due to the potential for additive QT prolongation. Amisulpride causes dose- and concentration- dependent QT prolongation. Pimavanserin may cause QT prolongation.
    Amobarbital: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Coadministration of pimavanserin and clarithromycin should be avoided if possible. Clarithromycin is associated with a risk for QT prolongation and torsade de pointes (TdP); pimavanserin may also cause QT prolongation. In addition, pimavanserin is primarily metabolized by CYP3A4 and CYP3A5. Concurrent use of a strong inhibitor of CYP3A4, such as clarithromycin, is expected to increase pimavanserin exposure. If coadministration cannot be avoided, reduce the pimavanserin dose to 10 mg/day PO and closely monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Amprenavir: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as amprenavir. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Anagrelide: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as anagrelide. Torsades de pointes (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. Coadministration may increase the risk for QT prolongation. If coadministration cannot be avoided, 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.
    Apalutamide: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as apalutamide. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Apomorphine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as apomorphine. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    Aripiprazole: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as aripiprazole. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Coadministration may increase the risk for QT prolongation.
    Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with other drugs that may cause QT interval prolongation, such as pimavanserin. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms.
    Artemether; Lumefantrine: (Major) Pimavanserin should be avoided in combination with artemether; lumefantrine. Pimavanserin may cause QT prolongation. The administration of artemether; lumefantrine is also associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment.
    Asenapine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as asenapine. Coadministration may increase the risk for QT prolongation.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Atazanavir: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as atazanavir. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Atazanavir; Cobicistat: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as atazanavir. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation. (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with cobcistat is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Atomoxetine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as atomoxetine. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Coadministration may increase the risk for QT prolongation.
    Azithromycin: (Major) Avoid coadministration of azithromycin with pimavanserin 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. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Pimavanserin prolongs the QT interval.
    Barbiturates: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Bedaquiline: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as bedaquiline. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. If coadministration cannot be avoided, obtain serum electrolyte concentrations and a baseline ECG prior to initiating bedaquiline. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with pimavanserin may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with pimavanserin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking pimavanserin, reduce initial dosage and titrate to clinical response. If pimavanserin is initiated a patient taking an opioid agonist, use a lower initial dose of pimavanserin and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bexarotene: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as bexarotene. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and pimavanserin 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.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and pimavanserin 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.
    Boceprevir: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as boceprevir. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Bosentan: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as bosentan. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Brigatinib: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as brigatinib. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Buprenorphine: (Major) Pimavanserin should be avoided in combination with buprenorphine. Pimavanserin may cause QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as pimavanserin. Coadministration may further increase the risk of QT prolongation and TdP.
    Buprenorphine; Naloxone: (Major) Pimavanserin should be avoided in combination with buprenorphine. Pimavanserin may cause QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as pimavanserin. Coadministration may further increase the risk of QT prolongation and TdP.
    Butabarbital: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Butalbital; Acetaminophen: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Butalbital; Acetaminophen; Caffeine: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Cabotegravir; Rilpivirine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Coadministration may increase the risk for QT prolongation.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and pimavanserin. CNS depressants can potentiate the effects of cannabidiol.
    Carbamazepine: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as carbamazepine. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Cenobamate: (Major) Avoid coadministration of pimavanserin with cenobamate as concurrent use may decrease pimavanserin exposure which may lead to decreased efficacy. Pimavanserin is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Additionally, monitor for excessive sedation and somnolence during coadministration of cenobamate and pimavanserin. Concurrent use may result in additive CNS depression.
    Ceritinib: (Major) Pimavanserin should generally be avoided in patients receiving ceritinib due to the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, and loss of balance or coordination. Monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Pimavanserin is a CYP3A4 substrate that may cause QT prolongation. Ceritinib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with pimavanserin should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with pimavanserin should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Chloramphenicol: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as chloramphenicol. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Chloroquine: (Major) Avoid coadministration of chloroquine with pimavanserin 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. Pimavanserin also prolongs the QT interval.
    Chlorpromazine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as chlorpromazine. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). Coadministration may increase the risk for QT prolongation.
    Ciprofloxacin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as ciprofloxacin. Rare cases of QT prolongation and torsade de pointe (TdP) have been reported with ciprofloxacin during post-marketing surveillance. Coadministration may increase the risk for QT prolongation.
    Cisapride: (Contraindicated) QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Because pimavanserin causes QT prolonging effects that may be additive to those of cisapride, coadministration is contraindicated.
    Citalopram: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as citalopram. Citalopram causes dose-dependent QT interval prolongation. Coadministration may increase the risk for QT prolongation. If concurrent therapy is considered essential, ECG monitoring is recommended.
    Clarithromycin: (Major) Coadministration of pimavanserin and clarithromycin should be avoided if possible. Clarithromycin is associated with a risk for QT prolongation and torsade de pointes (TdP); pimavanserin may also cause QT prolongation. In addition, pimavanserin is primarily metabolized by CYP3A4 and CYP3A5. Concurrent use of a strong inhibitor of CYP3A4, such as clarithromycin, is expected to increase pimavanserin exposure. If coadministration cannot be avoided, reduce the pimavanserin dose to 10 mg/day PO and closely monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Clofazimine: (Major) Avoid coadministration of clofazimine and pimavanserin due to the potential for additive QT prolongation. QT prolongation and torsade de pointes have been reported in patients receiving clofazimine in combination with QT prolonging medications. Pimavanserin may cause QT prolongation.
    Clozapine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Cobicistat: (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with cobcistat is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Codeine; Phenylephrine; Promethazine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as promethazine.
    Codeine; Promethazine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as promethazine.
    Crizotinib: (Major) Avoid coadministration of crizotinib with pimavanserin 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. Pimavanserin may also cause QT prolongation.
    Dabrafenib: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as dabrafenib. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Darunavir: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as darunavir. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Darunavir; Cobicistat: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as darunavir. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation. (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with cobcistat is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as darunavir. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation. (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with cobcistat is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with ritonavir is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Dasatinib: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as dasatinib. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Coadministration may increase the risk for QT prolongation.
    Degarelix: (Major) Avoid coadminsitration of pimavanserin with degarelix due to additive QT effects and increased risk of cardiac arrhythmia. Pimavanserin prolongs the QT interval. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
    Delavirdine: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as delavirdine. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Desflurane: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as halogenated anesthetics. Coadministration may increase the risk for QT prolongation. Patients should discuss their medication regimen with their surgeon or anesthesiologist prior to any surgical or other procedures with these anesthetics.
    Deutetrabenazine: (Major) Avoid coadministration of pimavanserin with deutetrabenazine due to additive QT effects and increased risk of cardiac arrhythmia. Pimavanserin prolongs the QT interval. 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 pimavanserin and deutetrabenazine. Concurrent use may result in additive CNS depression.
    Dexamethasone: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as dexamethasone. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Dextromethorphan; Quinidine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as quinidine. Quinidine administration is associated with QT prolongation and torsades de pointes (TdP).
    Disopyramide: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as disopyramide. Disopyramide administration is associated with QT prolongation and torsades de pointes (TdP).
    Dofetilide: (Major) Coadministration of dofetilide and pimavanserin 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 Pimavanserin prolongs the QT interval.
    Dolasetron: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as dolasetron. Dolasetron has been associated with a dose-dependant prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Use of dolasetron injection for the prevention of chemotherapy-induced nausea and vomiting is contraindicated because the risk of QT prolongation is higher with the doses required for this indication; when the injection is used at lower doses (i.e., those approved for post-operative nausea and vomiting) or when the oral formulation is used, the risk of QT prolongation is lower. Coadministration may increase the risk for QT prolongation.
    Dolutegravir; Rilpivirine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Coadministration may increase the risk for QT prolongation.
    Donepezil: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Donepezil; Memantine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Dronedarone: (Contraindicated) Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 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. Because pimavanserin causes QT prolonging effects that may be additive to those of dronedarone, coadministration is contraindicated.
    Droperidol: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as droperidol. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). In December 2001, the FDA issued a black box warning regarding the use of droperidol and its association with QT prolongation and potential for cardiac arrhythmias based on post-marketing surveillance data. Coadministration may increase the risk for QT prolongation.
    Efavirenz: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as efavirenz. In addition, pimavanserin is primarily metabolized by CYP3A4 and CYP3A5 and the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as efavirenz. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as efavirenz. In addition, pimavanserin is primarily metabolized by CYP3A4 and CYP3A5 and the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as efavirenz. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as efavirenz. In addition, pimavanserin is primarily metabolized by CYP3A4 and CYP3A5 and the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as efavirenz. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Elagolix: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as elagolix. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as elagolix. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Eliglustat: (Major) Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Because pimavanserin may also cause QT prolongation, coadministration should generally be avoided.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with cobcistat is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with cobcistat is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Coadministration may increase the risk for QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Coadministration may increase the risk for QT prolongation.
    Encorafenib: (Major) Avoid coadministration of encorafenib and pimavanserin due to the potential for additive QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Pimavanserin may also cause QT prolongation.
    Enflurane: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as halogenated anesthetics. Coadministration may increase the risk for QT prolongation. Patients should discuss their medication regimen with their surgeon or anesthesiologist prior to any surgical or other procedures with these anesthetics.
    Entrectinib: (Major) Avoid coadministration of entrectinib with pimavanserin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Pimavanserin also prolongs the QT interval.
    Enzalutamide: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as enzalutamide. Strong inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Eribulin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as eribulin. If coadministration is necessary, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Erythromycin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as erythromycin. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Coadministration may increase the risk for QT prolongation.
    Erythromycin; Sulfisoxazole: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as erythromycin. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Coadministration may increase the risk for QT prolongation.
    Escitalopram: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as escitalopram. Coadministration may increase the risk for QT prolongation.
    Esketamine: (Moderate) Closely monitor patients receiving esketamine and pimavanserin 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.
    Eslicarbazepine: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as eslicarbazepine. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Etravirine: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as etravirine. Moderate inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Ezogabine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as ezogabine. Coadministration may increase the risk for QT prolongation.
    Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and pimavanserin. Concurrent use may result in additive CNS depression.
    Fingolimod: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. If coadministration cannot be avoided, after the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). 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.
    Flecainide: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as flecainide. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsades de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Coadministration may increase the risk for QT prolongation.
    Fluconazole: (Contraindicated) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are CYP3A4 substrates is contraindicated. Fluconazole has been associated with QT prolongation; pimavanserin has been associated with QT prolongation and is primarily metabolized by CYP3A4/3A5.
    Fluoxetine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as fluoxetine. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration may increase the risk for QT prolongation.
    Fluphenazine: (Minor) Pimavanserin may cause QT prolongation and should be avoided in patients receiving other medications known to prolong the QT interval. Fluphenazine, perphenazine, prochlorperazine, and trifluoperazine are associated with a possible risk for QT prolongation. Theoretically, these phenothiazines may increase the risk of QT prolongation if coadministered with drugs with a risk of QT prolongation.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and pimavanserin. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval.
    Food: (Major) It is recommended that patients avoid the use of marijuana, by any route, if they are treated for a psychiatric history, including psychosis and bipolar disorder, as the cannabinoids (the psychoactive ingredients, such as THC) in marijuana can produce psychotoxic effects and may exacerbate psychiatric disorders. A high frequency of use and use of products with high-potency of THC are potential risk factors for psychiatric effects. Additionally, additive CNS effects, such as sedation or CNS depression are possible. Clinical studies suggest that cannabis use may reduce the efficacy of some antipsychotic drugs. In addition, several cannabinoids in marijuana appear to influence the activity of CYP enzymes and P-glycoprotein, which may alter the concentrations of antipsychotics and influence either safety or efficacy.
    Fosamprenavir: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4. Further, pimavanserin should be avoided in combination with moderate CYP3A4 inducers, Because fosamprenavir has both strong CYP3A4 inhibitory and moderate CYP3A4 inducer properties, the outcome of this potential interaction is unpredictable.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as pimavanserin. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Pimavanserin may also cause QT prolongation. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosphenytoin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as fosphenytoin. Strong inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Fostemsavir: (Major) Avoid coadministration of pimavanserin with fostemsavir due to additive QT effects and increased risk of cardiac arrhythmia. Pimavanserin prolongs the QT interval. 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.
    Gabapentin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of pimavanserin and gabapentin. Concurrent use may result in additive CNS depression.
    Gemifloxacin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as gemifloxacin. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the 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. Coadministration may increase the risk for QT prolongation.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of gemtuzumab ozogamicin with pimavanserin due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin. Pimavanserin may cause QT prolongation.
    Gilteritinib: (Major) Avoid concomitant use of pimavanserin with gilteritinib due to the potential for additive QT prolongation. Both drugs have been associated with QT prolongation.
    Glasdegib: (Major) Avoid coadministration of glasdegib with pimavanserin due to the potential for additive QT prolongation. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Pimavanserin may also cause QT prolongation.
    Goserelin: (Major) Avoid coadministration of pimavanserin with goserelin due to additive QT effects and increased risk of cardiac arrhythmia. Pimavanserin prolongs the QT interval. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
    Granisetron: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as granisetron. Use of granisetron in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic, may result in clinical consequences.
    Halogenated Anesthetics: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as halogenated anesthetics. Coadministration may increase the risk for QT prolongation. Patients should discuss their medication regimen with their surgeon or anesthesiologist prior to any surgical or other procedures with these anesthetics.
    Haloperidol: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as haloperidol. QT prolongation and torsade de pointes (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. Coadministration may increase the risk for QT prolongation.
    Halothane: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as halogenated anesthetics. Coadministration may increase the risk for QT prolongation. Patients should discuss their medication regimen with their surgeon or anesthesiologist prior to any surgical or other procedures with these anesthetics.
    Histrelin: (Major) Coadministration of pimavanserin with histrelin should generally be avoided due to the risk of QT prolongation. Pimavanserin may cause QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Hydroxychloroquine: (Major) Avoid coadministration of pimavanserin and hydroxychloroquine due to an 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. Hydroxychloroquine and pimavanserin both prolong the QT interval.
    Hydroxyzine: (Major) Avoid coadministration of hydroxyzine and pimavanserin due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Pimavanserin may cause QT prolongation.
    Ibutilide: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as ibutilide. Ibutilide administration can cause QT prolongation and torsades de pointes (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) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as idelalisib. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Iloperidone: (Major) Coadministration of pimavanserin and iloperidone should be avoided. Pimavanserin may cause QT prolongation. Iloperidone has also been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. Coadministration may increase the risk for QT prolongation.
    Indinavir: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as indinavir. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with pimavanserin 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. Pimavanserin may also cause QT prolongation.
    Isoflurane: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as halogenated anesthetics. Coadministration may increase the risk for QT prolongation. Patients should discuss their medication regimen with their surgeon or anesthesiologist prior to any surgical or other procedures with these anesthetics.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid use of rifampin with pimavanserin due to decreased pimavanserin exposure. Rifampin is a strong CYP3A4 inducer; pimavanserin is a CYP3A4 substrate. Monitor for reduced pimavanserin efficacy if concurrent use is required. Rifampin decreased the AUC by 91% when it was coadministered with pimavanserin during drug interaction studies.
    Isoniazid, INH; Rifampin: (Major) Avoid use of rifampin with pimavanserin due to decreased pimavanserin exposure. Rifampin is a strong CYP3A4 inducer; pimavanserin is a CYP3A4 substrate. Monitor for reduced pimavanserin efficacy if concurrent use is required. Rifampin decreased the AUC by 91% when it was coadministered with pimavanserin during drug interaction studies.
    Itraconazole: (Major) Avoid concurrent administration of itraconazole and pimavanserin if possible due to the potential for additive effects on the QT interval and increased exposure to pimavanserin. If an alternative to itraconazole is not available and coadministration is unavoidable, the manufacturer recommends reducing the pimavanserin dose to 10 mg once daily. In addition, coadministration of itraconazole (a CYP3A4 inhibitor) with pimavanserin (a CYP3A4 substrate) may result in elevated pimavanserin plasma concentrations and an increased risk for adverse events, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks while itraconazole plasma concentrations decrease. The decline in itraconazole plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with pimavanserin 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. Pimavanserin may also cause QT prolongation.
    Ketoconazole: (Major) Avoid concurrent administration of ketoconazole and pimavanserin if possible due to the potential for additive effects on the QT interval and increased exposure to pimavanserin. If an alternative to ketoconazole is not available and coadministration is unavoidable, the manufacturer recommends reducing the pimavanserin dose to 10 mg once daily. In addition, coadministration of ketoconazole (a CYP3A4 inhibitor) with pimavanserin (a CYP3A4 substrate) may result in elevated pimavanserin plasma concentrations and an increased risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for pimavanserin-related adverse effects including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Coadministration of pimavanserin and clarithromycin should be avoided if possible. Clarithromycin is associated with a risk for QT prolongation and torsade de pointes (TdP); pimavanserin may also cause QT prolongation. In addition, pimavanserin is primarily metabolized by CYP3A4 and CYP3A5. Concurrent use of a strong inhibitor of CYP3A4, such as clarithromycin, is expected to increase pimavanserin exposure. If coadministration cannot be avoided, reduce the pimavanserin dose to 10 mg/day PO and closely monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Lapatinib: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval such as lapatinib. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct electrolyte abnormalities prior to treatment. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and pimavanserin. Concurrent use may result in additive CNS depression.
    Lefamulin: (Major) Avoid coadministration of lefamulin with pimavanserin 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. Pimavanserin also prolongs the QT interval.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with pimavanserin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Pimavanserin may also cause QT prolongation.
    Letermovir: (Moderate) An increase in the plasma concentration of pimavanserin, a primary CYP3A4 substrate, may occur if given with letermovir, a moderate CYP3A4 inhibitor. Reduce the dose of pimavanserin to 10 mg PO once daily in patients who are also receiving treatment with cyclosporine because the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to use of a strong CYP3A4 inhibitor alone. In a drug interaction study, administration with another strong CYP3A4 inhibitor increased pimavanserin maximum plasma concentration and exposure by 1.5- and 3-fold, respectively.
    Leuprolide: (Major) Coadministration of pimavanserin with leuprolide should generally be avoided due to the risk of QT prolongation. Pimavanserin may cause QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Major) Coadministration of pimavanserin with leuprolide should generally be avoided due to the risk of QT prolongation. Pimavanserin may cause QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with pimavanserin should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Levofloxacin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as levofloxacin. Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Rare cases of torsade de pointes (TdP) have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. Coadministration may increase the risk for QT prolongation.
    Levoketoconazole: (Major) Avoid concurrent administration of ketoconazole and pimavanserin if possible due to the potential for additive effects on the QT interval and increased exposure to pimavanserin. If an alternative to ketoconazole is not available and coadministration is unavoidable, the manufacturer recommends reducing the pimavanserin dose to 10 mg once daily. In addition, coadministration of ketoconazole (a CYP3A4 inhibitor) with pimavanserin (a CYP3A4 substrate) may result in elevated pimavanserin plasma concentrations and an increased risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for pimavanserin-related adverse effects including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Lithium: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as lithium. Coadministration may increase the risk for QT prolongation.
    Lofexidine: (Major) Avoid coadministration of lofexidine and pimavanserin due to the potential for additive QT prolongation. Monitor ECG if coadministration cannot be avoided. 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 torsade de pointes. Pimavanserin may cause QT prolongation.
    Lonafarnib: (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with lonafarnib is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Loperamide: (Major) Pimavanserin should be avoided in combination with loperamide. Pimavanserin may cause QT prolongation; high doses of loperamide have been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Coadministration may further increase the risk of QT prolongation and TdP.
    Loperamide; Simethicone: (Major) Pimavanserin should be avoided in combination with loperamide. Pimavanserin may cause QT prolongation; high doses of loperamide have been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Coadministration may further increase the risk of QT prolongation and TdP.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with pimavanserin 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. Both drugs are associated with QT prolongation. (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with ritonavir is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Lorlatinib: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as lorlatinib. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Lumacaftor; Ivacaftor: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as lumacaftor; ivacaftor. Strong inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Lumacaftor; Ivacaftor: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as lumacaftor; ivacaftor. Strong inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and pimavanserin. Concurrent use may result in additive CNS depression.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as pimavanserin. 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. Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval.
    Maprotiline: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as maprotiline. 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 torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal 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, but coadministration may increase the risk for QT prolongation.
    Mefloquine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as mefloquine. 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.
    Meperidine; Promethazine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as promethazine.
    Mephobarbital: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Methadone: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as methadone. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Coadministration may increase the risk for QT prolongation.
    Methohexital: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Metronidazole: (Major) Concomitant use of metronidazole and pimavanserin 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.
    Midostaurin: (Major) Avoid the concomitant use of midostaurin and pimavanserin; both drugs have been reported to increase the QT interval. If coadministration cannot be avoided, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Pimavanserin may cause QT prolongation; one pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation in the therapeutic range.
    Mifepristone: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as mifepristone, due to a potential increased risk of QT prolongation. In addition, because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as mifepristone. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Mirtazapine: (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.
    Mitotane: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as mitotane. Strong inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Mobocertinib: (Major) Concomitant use of mobocertinib and pimavanserin 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.
    Modafinil: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as modafinil. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Moxifloxacin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as moxifloxacin. Prolongation of the QT interval has been reported with administration of moxifloxacin. Post-marketing surveillance has identified very rare cases of ventricular arrhythmias including torsade de pointes (TdP), usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
    Nabilone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of nabilone and pimavanserin. Concurrent use may result in additive CNS depression.
    Nafcillin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as nafcillin. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Nefazodone: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as nefazodone. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Nelfinavir: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as nelfinavir. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Nevirapine: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as nevirapine. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and pimavanserin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Pimavanserin may also cause QT prolongation.
    Nirmatrelvir; Ritonavir: (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with ritonavir is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Norfloxacin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as norfloxacin. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, torsade de pointes has been reported during post-marketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory. Coadministration may increase the risk for QT prolongation.
    Octreotide: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as octreotide. 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: (Major) Pimavanserin should be avoided in combination with ofloxacin. Some quinolones, including ofloxacin, have been associated with QT prolongation and infrequent cases of arrhythmia. Post-marketing surveillance for ofloxacin has identified very rare cases of torsades de pointes (TdP). Pimavanserin may also cause QT prolongation. Coadministration may increase the risk for QT prolongation.
    Olanzapine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Coadministration may increase the risk for QT prolongation.
    Olanzapine; Fluoxetine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as fluoxetine. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration may increase the risk for QT prolongation. (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Coadministration may increase the risk for QT prolongation.
    Olanzapine; Samidorphan: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Coadministration may increase the risk for QT prolongation.
    Oliceridine: (Moderate) Concomitant use of oliceridine with pimavanserin may cause excessive sedation and somnolence. Limit the use of oliceridine with pimavanserin 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.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with ritonavir is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as rifabutin. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Ondansetron: (Major) Pimavanserin should be avoided in combination with ondansetron. Pimavanserin may cause QT prolongation. Ondansetron has also been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If coadministration is necessary, ECG monitoring is recommended.
    Osilodrostat: (Major) Avoid coadministration of osilodrostat and pimavanserin due to the potential for additive QT prolongation. Pimavanserin may cause QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation.
    Osimertinib: (Major) Avoid coadministration of pimavanserin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is necessary, periodically monitor ECGs and electrolytes; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Pimavanserin may also cause QT prolongation.
    Oxaliplatin: (Major) Avoid coadministration of pimavanserin with oxaliplatin due to additive QT effects and increased risk of cardiac arrhythmia. Pimavanserin prolongs the QT interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking pimavanserin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may 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. Pimavanserin prolongs the QT interval.
    Pacritinib: (Major) Concomitant use of pacritinib and pimavanserin 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) Coadministration of pimavanserin and paliperidone should be avoided if possible. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Pimavanserin may also cause QT prolongation. If coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
    Panobinostat: (Major) Coadministration of pimavanserin and panobinostat is not recommended. Pimavanserin may cause QT prolongation. QT prolongation has also been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial. If coadministration cannot be avoided, obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
    Pasireotide: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as pasireotide. Coadministration may increase the risk for QT prolongation.
    Pazopanib: (Major) Co-administration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and pimavanserin have been reported to prolong the QT interval. If pazopanib and pimavanserin must be continued, closely monitor the patient for QT interval prolongation. In addition, pazopanib is a weak inhibitor of CYP3A4 and pimavanserin is a substrate for CYP3A4. Concurrent administration of pimavanserin and pazopanib may result in increased pazopanib and/or pimavanserin concentrations. Use caution when concurrent administration is necessary.
    Pentamidine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval. Systemic pentamidine has been associated with QT prolongation. Coadministration may increase the risk for QT prolongation.
    Pentobarbital: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Perphenazine: (Minor) Pimavanserin may cause QT prolongation and should be avoided in patients receiving other medications known to prolong the QT interval. Fluphenazine, perphenazine, prochlorperazine, and trifluoperazine are associated with a possible risk for QT prolongation. Theoretically, these phenothiazines may increase the risk of QT prolongation if coadministered with drugs with a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Pimavanserin may cause QT prolongation and should be avoided in patients receiving other medications known to prolong the QT interval. Fluphenazine, perphenazine, prochlorperazine, and trifluoperazine are associated with a possible risk for QT prolongation. Theoretically, these phenothiazines may increase the risk of QT prolongation if coadministered with drugs with a risk of QT prolongation.
    Pexidartinib: (Major) Avoid coadministration of pimavanserin with pexidartinib as concurrent use may decrease pimavanserin exposure which may lead to decreased efficacy. Pimavanserin is a CYP3A4 substrate; pexidartinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the exposure of pimavanserin by approximately 70%.
    Phenobarbital: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Phenytoin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as phenytoin. Strong inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because pimavanserin causes QT prolonging effects that may be additive to those of pimozide, coadministration is contraindicated.
    Pitolisant: (Major) Avoid coadministration of pimavanserin with pitolisant due to additive QT effects and increased risk of cardiac arrhythmia. Both pimavanserin and pitolisant prolong the QT interval.
    Ponesimod: (Major) In general, do not initiate ponesimod in patients taking pimavanserin 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. Pimavanserin prolongs the QT interval.
    Posaconazole: (Contraindicated) Coadministration of posaconazole and pimavanserin is contraindicated. The manufacturer of posaconazole contraindicates concurrent use with drugs that are CYP3A4 substrates and prolong the QT interval. Pimavanserin is primarily metabolized by CYP3A4/3A5 and has been associated with QT prolongation.
    Pregabalin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of pimavanserin and pregabalin. Concurrent use may result in additive CNS depression.
    Primaquine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as primaquine. Coadministration may increase the risk for QT prolongation.
    Primidone: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Procainamide: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as procainamide. Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP).
    Prochlorperazine: (Minor) Pimavanserin may cause QT prolongation and should be avoided in patients receiving other medications known to prolong the QT interval. Fluphenazine, perphenazine, prochlorperazine, and trifluoperazine are associated with a possible risk for QT prolongation. Theoretically, these phenothiazines may increase the risk of QT prolongation if coadministered with drugs with a risk of QT prolongation.
    Promethazine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as promethazine.
    Promethazine; Dextromethorphan: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as promethazine.
    Promethazine; Phenylephrine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as promethazine.
    Propafenone: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Coadministration may increase the risk for QT prolongation.
    Quetiapine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as quetiapine. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. Coadministration may increase the risk for QT prolongation.
    Quinidine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as quinidine. Quinidine administration is associated with QT prolongation and torsades de pointes (TdP).
    Quinine: (Major) Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP). In addition, quinine is an inhibitor of CYP3A4. Avoid concurrent use of quinine with other drugs that prolong the QT and are CYP3A4 substrates, such as pimavanserin. Co-administration may result in an elevated plasma concentration of the interacting drug, causing an increased risk for adverse events, such as QT prolongation.
    Ranolazine: (Major) Pimavanserin should be avoided in combination with ranolazine. Pimavanserin may cause QT prolongation and ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. 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.
    Relugolix: (Major) Avoid coadministration of pimavanserin with relugolix due to additive QT effects and increased risk of cardiac arrhythmia. Pimavanserin prolongs the QT interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of pimavanserin with relugolix due to additive QT effects and increased risk of cardiac arrhythmia. Pimavanserin prolongs the QT interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
    Ribociclib: (Major) Avoid coadministration of pimavanserin with ribociclib due to the risk of QT prolongation. Plasma concentrations of pimavanserin may also increase, resulting in treatment-related adverse reactions. Pimavanserin is a CYP3A4 substrate that may cause QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Additive QT prolongation may occur.
    Ribociclib; Letrozole: (Major) Avoid coadministration of pimavanserin with ribociclib due to the risk of QT prolongation. Plasma concentrations of pimavanserin may also increase, resulting in treatment-related adverse reactions. Pimavanserin is a CYP3A4 substrate that may cause QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Additive QT prolongation may occur.
    Rifabutin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as rifabutin. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Rifampin: (Major) Avoid use of rifampin with pimavanserin due to decreased pimavanserin exposure. Rifampin is a strong CYP3A4 inducer; pimavanserin is a CYP3A4 substrate. Monitor for reduced pimavanserin efficacy if concurrent use is required. Rifampin decreased the AUC by 91% when it was coadministered with pimavanserin during drug interaction studies.
    Rifapentine: (Major) Avoid coadministration of pimavanserin with rifapentine as concurrent use may decrease pimavanserin exposure which may lead to decreased efficacy. Pimavanserin is a CYP3A4 substrate; rifapentine is a strong CYP3A4 inducer. Coadministration with another strong inducer decreased pimavanserin exposure by 91%.
    Rilpivirine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Coadministration may increase the risk for QT prolongation.
    Risperidone: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval. Risperidone has been associated with a possible risk for QT prolongation and/or torsade de pointes; however, data are currently lacking to establish causality in association with torsades de pointes (TdP). Reports of QT prolongation and torsades de pointes during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting. Consider the patient's underlying disease state(s) and additional potential risk factors if pimavanserin and risperidone coadministration cannot be avoided. If coadministration is chosen, and the patient has known risk factors for cardiac disease or arrhythmia, then the patient should be closely monitored clinically.
    Ritonavir: (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with ritonavir is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Romidepsin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as romidepsin. Romidepsin has been reported to prolong the QT interval. Coadministration may increase the risk for QT prolongation. If romidepsin must be coadministered with another drug that prolongs the QT interval, the manufacturer recommends appropriate cardiovascular monitoring precautions, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Saquinavir: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as saquinavir. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    Secobarbital: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Selpercatinib: (Major) Avoid coadministration of pimavanserin with selpercatinib due to additive QT effects and increased risk of cardiac arrhythmia. Monitor ECGs more frequently for QT prolongation if coadministration is necessary. Pimavanserin prolongs the QT interval. Concentration-dependent QT prolongation has been observed with selpercatinib therapy.
    Sertraline: (Major) Avoid coadminsitration of pimavanserin with sertraline due to additive QT effects and increased risk of cardiac arrhythmia. Pimavanserin prolongs the QT interval. QTc prolongation and torsade de pointes (TdP) have been reported during postmarketing use of sertraline; most cases had confounding risk factors. 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 (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Sevoflurane: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as halogenated anesthetics. Coadministration may increase the risk for QT prolongation. Patients should discuss their medication regimen with their surgeon or anesthesiologist prior to any surgical or other procedures with these anesthetics.
    Siponimod: (Major) Avoid coadministration of siponimod and pimavanserin due to the potential for additive 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. Pimavanserin may also cause QT prolongation.
    Solifenacin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as solifenacin. Solifenacin has been associated dose-dependent prolongation of the QT interval. Torsades de pointes (TdP) has been reported with post-marketing use, although causality was not determined. Coadministration may increase the risk for QT prolongation.
    Sorafenib: (Major) Avoid coadministration of sorafenib with pimavanserin due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Pimavanserin also prolongs the QT interval.
    Sotalol: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as sotalol. Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    Sotorasib: (Major) Avoid coadministration of pimavanserin with sotorasib as concurrent use may decrease pimavanserin exposure which may lead to decreased efficacy. Pimavanserin is a CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease the exposure of pimavanserin by approximately 70%.
    St. John's Wort, Hypericum perforatum: (Major) The use of St. John's Wort with pimavanserin should be avoided. Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding use of strong CYP3A4 inducers, such as St. John's Wort. Strong inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Sunitinib: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as sunitinib. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP).
    Tacrolimus: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as tacrolimus. Coadministration may increase the risk for QT prolongation.
    Tamoxifen: (Major) Avoid coadministration of tamoxifen with pimvanserin due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Pimvanserin has also been associated with QT prolongation.
    Telaprevir: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as telaprevir. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Telavancin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as telavancin. Coadministration may increase the risk for QT prolongation.
    Telithromycin: (Major) Coadministration of pimavanserin and telithromycin should be avoided if possible. Telithromycin is associated with a possible risk for QT prolongation and torsade de pointes (TdP); pimavanserin may also cause QT prolongation. In addition, pimavanserin is primarily metabolized by CYP3A4 and CYP3A5. Concurrent use of a strong inhibitor of CYP3A4, such as telithromycin, is expected to increase pimavanserin exposure. If coadministration cannot be avoided, reduce the pimavanserin dose to 10 mg/day PO and closely monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Tetrabenazine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as tetrabenazine. Tetrabenazine causes a small increase in the corrected QT interval (QTc). Coadministration may increase the risk for QT prolongation.
    Thiopental: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as barbiturates. Strong inducers of CYP3A4 reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Because pimavanserin causes QT prolonging effects that may be additive to those of thioridazine, coadministration is contraindicated. Also, the manufacturer of pimavanserin recommends avoiding use of moderate inducers of CYP3A4, such as thioridazine, with pimavanserin because of a reduction in pimavanserin exposure, which has the potential to reduce the effectiveness of the drug.
    Tipranavir: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as tipranavir. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Tolterodine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Coadministration may increase the risk for QT prolongation. This should be taken into consideration when prescribing tolterodine to patients taking other drugs that are associated with QT prolongation.
    Toremifene: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Coadministration may increase the risk for QT prolongation.
    Trazodone: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Coadministration may increase the risk for QT prolongation.
    Triclabendazole: (Major) Avoid coadministration of triclabendazole and pimavanserin due to the potential for additive QT prolongation. Pimavanserin may cause QT prolongation. Transient prolongation of the mean QTc interval was noted on the ECG recordings in dogs administered triclabendazole.
    Trifluoperazine: (Minor) Pimavanserin may cause QT prolongation and should be avoided in patients receiving other medications known to prolong the QT interval. Fluphenazine, perphenazine, prochlorperazine, and trifluoperazine are associated with a possible risk for QT prolongation. Theoretically, these phenothiazines may increase the risk of QT prolongation if coadministered with drugs with a risk of QT prolongation.
    Triptorelin: (Major) Coadministration of pimavanserin with triptorelin should generally be avoided due to the risk of QT prolongation. Pimavanserin may cause QT prolongation. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
    Tucatinib: (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with tucatinib is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
    Vandetanib: (Major) Coadministration of vandetanib with pimavanserin should generally be avoided 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. Pimavanserin may also cause QT prolongation.
    Vardenafil: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval. Vardenafil is associated with QT prolongation. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed. The effect of vardenafil on the QT interval should be considered when prescribing the drug. Coadministration may increase the risk for QT prolongation.
    Vemurafenib: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval. Vemurafenib has been associated with QT prolongation. Coadministration may increase the risk for QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Venlafaxine: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use. Coadministration may increase the risk for QT prolongation.
    Voclosporin: (Major) Avoid concomitant use of pimavanserin and voclosporin due to the risk of additive QT prolongation. Pimavanserin prolongs the QT interval. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
    Voriconazole: (Major) Avoid concurrent administration of voriconazole and pimavanserin if possible due to the potential for additive effects on the QT interval and increased exposure to pimavanserin. If an alternative to voriconazole is not available and coadministration is unavoidable, the manufacturer recommends reducing the pimavanserin dose to 10 mg once daily. Both drugs have been associated with prolongation of the QT interval and voriconazole has also been associated with rare cases of torsade de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with pimavanserin (a CYP3A4 substrate) may result in elevated pimavanserin plasma concentrations and an increased risk for adverse events, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation. Correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) before initiating concurrent therapy.
    Vorinostat: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval. Vorinostat therapy is also associated with a risk of QT prolongation. Coadministration may increase the risk for QT prolongation.
    Ziprasidone: (Major) Concomitant use of ziprasidone and pimavanserin 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. Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval. In addition, both drugs are dopamine antagonists and additive effects are possible; however, an interaction has not been confirmed.

    PREGNANCY AND LACTATION

    Pregnancy

    There is no information regarding the presence of pimavanserin in human breast milk. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for pimavanserin and any possible adverse effects on the infant from pimavanserin or from the underlying maternal condition. The American Academy of Pediatrics has previously considered some other antipsychotics (haloperidol, clozapine, etc.) to be drugs for which the effects on the nursing infant are not known but may be of concern, particularly with prolonged exposure. Use of antipsychotics during breast-feeding has been associated with drowsiness or lethargy in the infant and a decline in developmental scores. In addition, antipsychotics may cause hyperprolactinemia and galactorrhea to varying degrees, and thus may interfere with proper lactation. It should be noted that data related to the safety of antipsychotics during breast-feeding are limited and chronic administration of any antipsychotic during breast-feeding should be avoided if possible. Regardless of the antipsychotic used, the nursing infant should be closely monitored for excessive drowsiness, lethargy, and developmental delays. Combination treatment with antipsychotics may increase the risk of these adverse events. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    The exact mechanism of action of pimavanserin in treating hallucinations and delusions associated with Parkinson's disease psychosis is unknown. However, the effect could be mediated through a combination of inverse agonist and antagonist activity at serotonin 5-HT2A receptors, and to a lesser extent at 5-HT2C receptors. In vitro, pimavanserin demonstrates a high binding affinity at serotonin 5-HT2A receptors and a lower binding affinity at 5-HT2C receptors. Pimavanserin demonstrates low binding to sigma-1 receptors, and has no appreciable affinity to serotonin 5-HT2B, dopaminergic (including D-2), muscarinic, histaminic, or adrenergic receptors; the drug has no affinity for calcium channels.

    PHARMACOKINETICS

    Pimavanserin is administered orally. The drug is highly protein bound (about 95%). Hepatic metabolism of pimavanserin occurs mainly through CYP3A4 and CYP3A5. Formation of AC-279, the major active metabolite, occurs primarily by CYP3A4. The median Tmax of AC-279 is 6 hours. The mean plasma half-lives of pimavanserin and AC-279 are about 57 hours and 200 hours, respectively. During premarketing analysis, about 0.55% of a dose was eliminated unchanged in the urine and 1.53% was eliminated in feces after 10 days. Less than 1% of the administered dose of pimavanserin and AC-279 were recovered in urine.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, CYP3A5
    Pimavanserin metabolism occurs mainly through CYP3A4 and CYP3A5, and to a lesser extent by CYP2J2, CYP2D6, and various other CYP and FMO enzymes. The CYP3A4 enzyme is primarily responsible for the formation of the pimavanserin major active metabolite (AC-279). The recommended dose of pimavanserin during concurrent use of strong CYP3A4 inhibitors is 10 mg/day. Monitor for reduced efficacy if pimavanserin is used concurrently with strong CYP3A4 inducers. Inhibitors or inducers of other CYP enzymes do not produce clinically significant metabolic drug-drug interactions with pimavanserin. Based on in vitro studies, drug transporters are not significantly involved in the disposition of pimavanserin.
     
    In vitro data indicate that pimavanserin is not an irreversible inhibitor of any of the major hepatic and intestinal human CYP enzymes involved in drug metabolism (e.g., CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4). AC-279 is neither a reversible or irreversible inhibitor of any of the major hepatic and intestinal human CYP enzymes involved in drug metabolism. AC-279 is not a clinically significant CYP3A inducer and is not expected to cause induction of other isoenzymes.

    Oral Route

    After single oral doses, the drug demonstrates dose-proportional pharmacokinetics. The median time to maximal concentration (Tmax) is 6 hours (range: 4 to 24 hours) and is generally unaffected by dose. A high-fat meal does not have a significant effect on the maximum concentration (Cmax) or AUC of pimavanserin exposure; therefore, pimavanserin may be taken without regard to meals.