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    Multi-Acting Receptor-Targeted Antipsychotics (MARTA)

    BOXED WARNING

    Agranulocytosis, bone marrow suppression, chemotherapy, fever, infection, leukemia, leukopenia, neutropenia

    Because clozapine can cause severe neutropenia, which can lead to infection and death, there is a minimum baseline neutrophil count required to initiate therapy. The mechanism by which clozapine causes neutropenia is not known and it is not dose-dependent. Treatment exclusions occur when the absolute neutrophil count (ANC) falls below the required minimum ANC (e.g., neutropenia, agranulocytosis, granulocytopenia). In general, patients who develop severe neutropenia (ANC less than 500/mm3) with clozapine should not be re-challenged, unless the prescriber determines that the benefit outweighs the risks and has taken into account the ANC thresholds defined by the manufacturer, the patient’s medical and psychiatric history, the severity and characteristics of the neutropenic episode, and has discussed the benefits and risks of clozapine re-challenge with the patient and his/her caregiver. Other conditions that may be associated with neutropenia include, but are not limited to, bone marrow suppression, leukopenia, and leukemia. Because of the risk of severe neutropenia, clozapine is available only through a restricted program called the Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program. The Clozapine REMS Program replaces individual clozapine patient registries and the National Non-Rechallenge Master File (NNRMF). The ANC is the only test result accepted in the Clozapine REMS Program to monitor for neutropenia. The risk of neutropenia appears greatest during the first 18 weeks and then declines. A complete blood count (CBC), including the ANC value, should be obtained prior to initiating treatment with clozapine to ensure a normal baseline neutrophil count (ANC) of at least 1500/mm3 for the general population (i.e., non-Benign Ethnic Neutropenia patients). Patients with documented Benign Ethnic Neutropenia (BEN) must have at least 2 baseline ANC levels of 1000/mm3 or more before treatment can be initiated. Weekly ANC monitoring is required for all patients during the first 6 months of treatment. If the ANC remains at least 1500/mm3 for the first 6 months of treatment in the general population or at least 1000/mm3 for BEN patients, monitoring frequency may be reduced to every 2 weeks for the next 6 months. If the ANC remains at least 1500/mm3 in the general population or at least 1000/mm3 for BEN patients for the second 6 months of continuous therapy, ANC monitoring frequency may be reduced to once every 4 weeks thereafter. When the ANC is within the normal range and treatment is interrupted for less than 30 days, continue monitoring as before; if treatment is interrupted for 30 days or more, monitor as if a new patient. If mild neutropenia (ANC 1000 to 1499/mm3) develops in the general population, continue treatment and obtain an ANC three times weekly until the ANC is at least 1500/mm3, then return to the patient's last "normal range" ANC monitoring interval if clinically appropriate. For moderate neutropenia (ANC 500 to 999/mm3) in the general population, recommend a hematology consult and interrupt treatment for suspected clozapine-induced neutropenia. Obtain ANC values daily until the ANC reaches at least 1000/mm3, then resume treatment and check the ANC three times weekly until the ANC reaches 1500/mm3 or more. Then, the ANC should be checked weekly for 4 weeks, with a subsequent return to the patient's last “normal range” ANC monitoring interval if clinically appropriate. For severe neutropenia (ANC less than 500/mm3) in the general population, recommend a hematology consult and interrupt treatment for suspected clozapine-induced neutropenia. Obtain ANC values daily until the ANC is at least 1000/mm3, then three times weekly until the ANC reaches at least 1500/mm3. If a general population patient is re-challenged after having severe neutropenia, resume treatment as a new patient under “normal range” monitoring when the ANC reaches at least 1500/mm3. For BEN neutropenia (ANC 500 to 999/mm3), recommend a hematology consult and continue treatment. Obtain an ANC three times weekly until the ANC is at least 1000/mm3 or is at least at the patient's baseline. Then, the ANC should be checked weekly for 4 weeks, with a subsequent return to patient’s last “normal BEN range” ANC monitoring interval if clinically appropriate. In BEN severe neutropenia (ANC less than 500/mm3), recommend a hematology consult and interrupt treatment for suspected clozapine-induced neutropenia. The ANC should be checked daily until the ANC is at least 500/mm3, then three times weekly until the ANC is at least to the patient's baseline. If a BEN patient is re-challenged after having severe neutropenia, resume treatment as a new patient under “normal range” monitoring once the ANC is at least 1000/mm3 or at the patient’s baseline. For abrupt treatment discontinuation for a reason unrelated to neutropenia, continuation of the existing ANC monitoring is recommended for general population patients until their ANC is at least 1500/mm3 and for BEN patients until their ANC is at least 1000/mm3 or above their baseline. Interrupt clozapine as a precaution in any patient who develops a fever of 38.5 degrees Celsius or 101.3 degrees Farenheit or higher and obtain an ANC; assess for neutropenia, fever, and other conditions associated with fever (e.g., NMS). If fever occurs in any patient with an ANC less than 1000/mm3, initiate appropriate workup and treatment for infection, refer to the manufacturer's guidelines for ANC monitoring, and consider a hematology consult. Patients should report the appearance of fever, sore throat, lethargy, weakness, or other signs of bone marrow suppression or infection to their health care provider immediately. Risk factors for developing severe neutropenia from clozapine therapy, other than initial bone marrow suppression, are not known. Patients with a Jewish background, those undergoing the first 4 to 10 weeks of drug therapy, female sex, older patients, cachetic patients, or those with serious underlying medical illness may theoretically be at greater risk for severe neutropenia, but definitive data are not available. It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., chemotherapy) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased ANC monitoring and consult the treating oncologist. Clozapine dose or duration of treatment cannot be used as a reliable indicator for severe neutropenia.

    Seizure disorder, seizures

    Use clozapine with caution in patients with a history of seizure disorder or in patients with risk factors that may predispose them to the occurrence of seizures. Clozapine lowers the seizure threshold in a dose-dependent manner, particularly at doses greater than 600 mg/day or following dosage changes greater than 100 mg/day (rapid dose increases). Dosage adjustments in patients with pre-existing epilepsy should be cautious. Clozapine may induce EEG changes, myoclonic jerks or generalized seizures. Patients on clozapine treatment who have seizure disorders should approach activities where sudden loss of consciousness would cause serious risk to themselves or others with caution. Clozapine should be used with caution in patients on certain anticonvulsant therapies due to several possible mechanisms of interaction. If seizures occur, the clozapine dosage should be reduced or discontinued, and, if necessary, anticonvulsant treatment initiated.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, cardiomyopathy, cerebrovascular disease, coronary artery disease, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, hypotension, hypovolemia, long QT syndrome, malnutrition, myocardial infarction, myocarditis, orthostatic hypotension, QT prolongation, syncope, tachycardia, thyroid disease, torsade de pointes, ventricular arrhythmias

    Similar to other antipsychotic agents, ECG repolarization changes and serious cardiac events have been reported with clozapine therapy. Treatment with clozapine has been associated with QT prolongation, ventricular arrhythmias, torsade de pointes (TdP), cardiac arrest, and sudden death. Use clozapine with caution in patients with a history of QT prolongation (including congenital long QT syndrome) or other cardiac disease or conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation. Electrolyte imbalances should be corrected prior to initiating treatment with clozapine. Baseline assessments of serum potassium and magnesium levels should be performed, as well as periodic evaluation during treatment, in patients at risk for electrolyte imbalances. Given the potential for QT prolongation, clozapine should be used cautiously with other drugs that cause QT prolongation. Prescribers should evaluate symptoms of dizziness, syncope, or palpitations. The drug should be discontinued if the QT interval measurement exceeds 500 msec. Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred during clozapine treatment and can be fatal. These symptoms are consistent with neurally mediated reflex bradycardia. The risk is highest during the initial titration period, and particularly with rapid titration. Therefore, the manufacturer's dosing titration guidelines must be followed. Orthostatic hypotension could lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with conditions, diseases, or concurrent medication use that could exacerbate orthostasis. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Clozapine should be used cautiously in patients with cardiac disease (e.g., history of myocardial infarction or ischemia, heart failure, conduction abnormalities), cerebrovascular disease, or other conditions that would predispose patients to hypotension (e.g., concurrent use of antihypertensives, dehydrated state, or hypovolemia). Cardiomyopathy or myocarditis, sometimes fatal, have occurred during clozapine use. Discontinue clozapine and obtain a cardiac evaluation if either of these reactions is suspected. Myocarditis most frequently presents within the first 2 months of treatment and cardiomyopathy symptoms usually occur after 8 weeks of treatment. Cardiomyopathy or myocarditis should be considered in patients receiving clozapine who present with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs or symptoms of heart failure, or ECG findings such as ST-T wave abnormalities or cardiac arrhythmias. It is not known whether eosinophilia is a reliable predictor of myocarditis. In patients who are diagnosed with cardiomyopathy while taking clozapine, mitral valve incompetence has been reported. These cases reported either mild or moderate mitral regurgitation on two-dimensional echocardiography. In patients with suspected cardiomyopathy, consider a 2D-echo Doppler exam to identify mitral valve incompetence. Tachycardia may occur secondary to hypotension, but has also been noted as a presenting sign in patients with myocarditis. Therefore, tachycardia during the first month of therapy warrants close monitoring for other signs of myocarditis. In general, patients with clozapine-related myocarditis or cardiomyopathy should not be re-challenged with clozapine.

    Dementia, geriatric, stroke

    Orthostatic hypotension, tachycardia, and syncope can occur with clozapine treatment. Geriatric patients, especially those with compromised cardiac functioning, may be more susceptible to these effects. Geriatric patients may also be more likely to experience anticholinergic effects, movement disorders, CNS depression, bone marrow suppression, and agranulocytosis. Lower initial doses of clozapine should be considered, with a very gradual titration as tolerated. Antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric patients. In April 2005 the FDA mandated that all manufacturers of atypical antipsychotics include a boxed warning to the labeling noting that increased death rates (1.6 to 1.7 times that of placebo) have been noted in this patient population receiving atypical antipsychotics. A similar warning was subsequently added to product labels for conventional antipsychotics. Death typically occurred due to heart failure, sudden death, or infections (primarily pneumonia). Over a 10-week trial, the rate of death in the elderly was roughly 4.5% compared to 2.6% in the placebo group. In a meta-analysis of 17 placebo controlled trials (n = 5,106) performed with olanzapine, aripiprazole, risperidone, or quetiapine in elderly patients with dementia-related psychosis, 15 showed numerical increases in mortality in the active compared to the placebo-treated patients. Because the increase in mortality was consistent across all three relevant chemical classes, the FDA concluded that the effect was most likely related to the common pharmacologic effects of all atypical antipsychotics, including those that were not included in the meta-analysis. In addition, an increased incidence of cerebrovascular events (stroke, transient ischemia attack), including fatalities, have been reported in elderly patients with dementia-related psychosis taking some atypical antipsychotics. Therefore, caution is advisable when administering clozapine to elderly patients at risk for cerebrovascular events or with compromised cardiac functioning. According to the Beers Criteria, antipsychotics are considered potentially inappropriate medications (PIMs) in elderly patients, and use should be avoided except for treating schizophrenia or bipolar disorder, and for short-term use as antiemetics during chemotherapy. In addition, avoidance of clozapine is recommended in geriatric patients with the following disease states or symptoms due to the potential for exacerbation of the condition or increased risk of adverse effects: lower urinary tract symptoms/benign prostatic hypertrophy in men (decreased urinary flow, urinary retention), delirium (possible new-onset or worsening delirium), and dementia (adverse CNS effects). There is an increased risk of stroke and 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. The Panel recommends avoiding antipsychotics 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 use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. While it is recommended that most dopamine-receptor antagonists be avoided in patients with Parkinson's disease due to the potential to worsen parkinsonian symptoms, clozapine appears less likely to precipitate a worsening of symptoms than most other antipsychotics and is excluded from the recommendation. Although use in elderly patients with chronic seizures/epilepsy should generally be avoided due to a lowering of the seizure threshold by clozapine, the Beers expert panel states that clozapine may be acceptable in those with well-controlled seizures in whom alternative agents have not been effective. 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. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). An antipsychotic should generally be used only for the conditions listed in the guidelines (e.g., schizophrenia, mood disorder, Tourette's disorder) and that meet the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for use. There is an increased risk of morbidity and mortality in elderly patients treated with antipsychotics for dementia-related psychosis. Therefore, identify and address all possible causes of behavioral or psychological symptoms of dementia (BPSD) before considering an antipsychotic. To initiate antipsychotic therapy, behavioral symptoms must be a danger to self or others and are either 1) due to mania or psychosis or 2) the plan of care includes documentation of attempted behavioral interventions (except in an emergency). Limit emergency treatment to 7 days or less with evaluation and documentation within 7 days which identifies and addresses contributors/causes. For acute conditions persisting beyond 7 days, pertinent non-pharmacologic interventions must be attempted, unless clinically contraindicated, and documented. Treatment of non-acute, chronic, or prolonged BPSD must meet all of the OBRA criteria for BPSD treatment, and include monitoring that ensures the behavioral symptoms are not due to a treatable or correctable medical condition, are not due to correctable environmental or treatable psychological stressors alone, and provides clearly documented evidence of persistence. The LTCF must evaluate the appropriateness of the antipsychotic during or within 2 weeks of admission for a newly admitted resident on an antipsychotic. In all cases, the lowest possible dose and shortest duration should be prescribed. OBRA provides general dosing guidance for antipsychotic treatment of BPSD. Monitoring of antipsychotics should include evaluation of ongoing effectiveness, rationale for use, and potential adverse effects (e.g., anticholinergic effects, neurological symptoms, metabolic syndrome, cardiac effects). Antipsychotics are subject to periodic review for effectiveness, necessity, and the potential for gradual dose reduction (GDR) or discontinuation. Refer to the OBRA guidelines for complete information.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral atypical antipsychotic with relatively low potential for extrapyramidal symptoms
    Reserved for refractory schizophrenia in adults due to risk of agranulocytosis and seizures; utility in reducing the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder
    Requires enrollment in the Clozapine REMS Program to ensure appropriate monitoring for neutropenia and proper management of treatment
    As with all antipsychotics, boxed warning for increased mortality risk in elderly patients with dementia-related psychosis

    COMMON BRAND NAMES

    Clozaril, Fazaclo, VERSACLOZ

    HOW SUPPLIED

    Clozapine/Clozaril Oral Tab: 25mg, 50mg, 100mg, 200mg
    Clozapine/Fazaclo Oral Tab Orally Dis: 12.5mg, 25mg, 100mg, 150mg, 200mg
    VERSACLOZ Oral Susp: 1mL, 50mg

    DOSAGE & INDICATIONS

    For the treatment of refractory schizophrenia that has failed to respond adequately to appropriate courses of standard antipsychotic agents; also to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder.
    Oral dosage
    Adults

    12.5 mg PO once or twice daily on the first day. Then, use a gradual titration schedule to minimize the risk of orthostatic hypotension, bradycardia, and syncope. After day 1, the dose may be titrated by 25 to 50 mg every day over a 2 week period, if well tolerated, to a dose of 300 to 450 mg/day, in divided doses. Subsequently titrate no more than once or twice weekly, in increments of no more than 100 mg, to efficacy and tolerability. Doses above 500 mg/day generally require 3 divided doses. Doses above 600 mg/day and rapid dose escalation are associated with an increased risk of seizures. Max: 900 mg/day PO. Debilitated adults, including those who are malnourished or with cardiac disease, should be carefully monitored. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. It may be necessary to reduce the dose in poor metabolizers of CYP2D6 (CYP2D6 PMs). DISCONTINUATION: Gradual reduction is recommended over 1 to 2 weeks unless clinical circumstances (e.g., neutropenia) require abrupt discontinuation. If abruptly discontinued, then monitor for recurrence of psychosis or cholinergic rebound (headache, nausea, vomiting, diarrhea). RE-INITIATION OF HELD TREATMENT: If 2 days or more have elapsed since the last dose, re-initiate with 12.5 mg once or twice daily and follow the usual titration schedule. Some symptoms respond rapidly to antipsychotic treatment; chronic schizophrenia usually improves slowly over many weeks and may continue to improve for months. Early discontinuation of therapy may increase the risk of relapse in some patients. Because of the risk of severe neutropenia and seizures, events which both present a continuing risk over time, extended clozapine treatment of patients failing to show an acceptable level of clinical response should be avoided.

    Children† and Adolescents† 9 years and older

    Initially, 6.25 to 12.5 mg PO per day has been suggested; mean effective dosages after titration during limited trials have been 200 to 300 mg/day PO. Doses should be divided and slowly titrated due to risk for hypotension, bradycardia or syncope. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. It may be necessary to reduce the dose in poor metabolizers of CYP2D6 (CYP2D6 PMs). DISCONTINUATION: If discontinuation of treatment is necessary, a gradual reduction in dose is recommended over 1 to 2 weeks unless clinical circumstances (e.g., neutropenia) require abrupt discontinuation. If abruptly discontinued, monitor for recurrence of psychosis or cholinergic rebound (headache, nausea, vomiting, diarrhea). RE-INITIATION OF HELD TREATMENT: If 2 days or more have elapsed since the last dose, re-initiate with suggested initial doses and follow the recommended dose titration thereafter.

    For the treatment of bipolar disorder†.
    Oral dosage
    Adults

    Limited data are available describing the use of clozapine in the initial management of acute bipolar disorder; data are from studies in non-elderly adults. In one review, the mean dose of clozapine after titration at follow-up was 325.6 +/- 161.9 mg/day in 21 patients with bipolar disorder. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. It may be necessary to reduce the dose in poor metabolizers of CYP2D6 (CYP2D6 PMs). Clozapine has been evaluated as treatment in refractory bipolar I disorder. A small, 3-week, open label trial (n = 27) compared the effectiveness of clozapine (mean dose 166 mg/day) to chlorpromazine (mean dose 310 mg/day); both agents were in combination with lithium for treatment of refractory bipolar mania. At 2 weeks, reduction YMRS scores (Young Mania Rating Scale) were significantly lower in the clozapine group, indicating a more rapid response to clozapine, but at 3 weeks no difference was noted in YMRS. As add-on treatment in a 12-month study, clozapine was effective for mood stabilization at a mean doses of 156 +/- 77 mg/day. Overall, depressive symptoms were not improved. Clozapine has been shown to be effective in a 12-month study as maintenance therapy for patients refractory to combined conventional mood stabilizers (e.g., lithium, divalproex, carbamazepine). Thirty-nine patients were randomly assigned to adjunctive clozapine (mean dose 234 mg/day PO; range 50 to 403 mg/day PO) or treatment as usual. No significant effect was noted on depression scores.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    900 mg/day PO. Debilitated adult patients may require lower total daily dosages.

    Elderly

    900 mg/day PO. Debilitated elderly patients may require lower total daily dosages.

    Adolescents

    Safety and efficacy have not been established; however, doses up to 300 mg/day PO have been reported for the treatment of refractory schizophrenia.

    Children

    >= 9 years: Safety and efficacy have not been established; however, doses up to 300 mg/day PO have been reported for the treatment of refractory schizophrenia.
    < 9 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use clozapine with caution in patients with hepatic disease. Modify dosage depending on clinical response and degree of hepatic impairment. If a patient develops signs or symptoms of liver problems during treatment, liver function tests (LFTs) should be measured. If LFTs are significantly elevated or if jaundice is present, treatment should be discontinued.

    Renal Impairment

    It may be necessary to reduce the dose of clozapine in patients with significant renal impairment; however, quantitative guidelines are not available.
     
    Intermittent hemodialysis
    Hemodialysis, forced diuresis, hemoperfusion, or other methods are unlikely to be of benefit in clozapine removal.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.
     
    Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program
    Healthcare professionals who wish to prescribe clozapine to outpatients or inpatients and pharmacies that dispense clozapine to outpatients or inpatients must be certified in the Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program. Patients receiving clozapine must be registered. All patients registered in any of the existing clozapine registries within the last three years and all patients listed in the National Non-Rechallenge Master File (NNRMF) will be automatically transferred into the Clozapine REMS Program. When the deadlines are established for prescribers and pharmacies to certify in the Clozapine REMS Program, there will be additional communication to all users. For more information or to request materials, call the Clozapine REMS Program at 844-267-8678 or access the REMS website at www.clozapinerems.com.
    Prescriber and Pharmacy enrollment requirements:
    Complete the Enrollment form.
    Review Clozapine and the Risk of Neutropenia: A Guide for Healthcare Providers.
    Successfully complete the Knowledge Assessment.
    Certified prescribers may allow a designee to act on their behalf. Each designee must be certified in the Clozapine REMS Program.
    Pharmacy certification requires the identification of an Authorized Representative for the pharmacy to complete the certification process. The Authorized Representative must ensure all pharmacists with privileges to dispense understand that clozapine is only available to certified pharmacies through the Clozapine REMS Program.
    Additional pharmacy requirements:
    Pharmacies are required to implement the necessary staff training and processes to comply with the Clozapine REMS Program requirements. Education is not required for enrollment but will be available after enrollment is complete through the pharmacy's Authorized Representative.
    OUTPATIENT pharmacies: Following enrollment, pharmacy staff must obtain a pre-dispense authorization (PDA) before dispensing each clozapine prescription. A PDA may be obtained by calling the Clozapine REMS Contact Center or through electronic claim adjudication if available. Pharmacy staff may include pharmacists or other individuals who assist in dispensing medication in a pharmacy.
    INPATIENT pharmacies: Pharmacy staff must enroll to perform eligibility checks through the Clozapine REMS website or the Clozapine REMS Contact Center. Pharmacy staff may include pharmacists or other individuals who assist in dispensing medication in a pharmacy. Inpatient pharmacies do not need to obtain a Pre-Dispense Authorization (PDA) before clozapine can be dispensed.
    Patient Eligibilty Verification:
    As of February 12, 2016, pharmacy staff can perform an eligibility check regardless of the certification status of their associated pharmacy.
    Eligibility check results will include the patient's highest historical lab, lowest historical lab, most recent lab results, and the patient's monitoring frequency.
    Eligibility check results will include an informational warning message if the prescriber or pharmacy has not completed certification in the Clozapine REMS Program. During the transition period, these messages are informational in nature and will not cause a patient to be ineligible to receive the drug.
    Prescribers can modify a patient's monitoring frequency to monthly by performing an attestation in the patient's profile via the website. Alternatively, prescribers/designees can modify a patient's monitoring frequency to monthly by calling the Clozapine REMS Contact Center.
    Prescribers/designees can de-activate patients who they are no longer treating via the website or by calling the Clozapine REMS Contact Center. Prescribers who receive communication regarding a patient they are no longer treating should call the Clozapine REMS Program to re-associate the patient to their current prescriber (if known).

    Oral Administration

    May be administered orally without regard to meals.

    Oral Solid Formulations

    Oral disintegrating tablets (e.g., Fazaclo): Place tablet on the tongue, allow to dissolve, then swallow. Does not need to be administered with water or other liquids. When splitting orally disintegrating tablets in half, immediately dispose of the half-tablet that is not consumed due to stability issues; do not use for a subsequent dose.

    Oral Liquid Formulations

    Oral Suspension (Versacloz) Administration:
    Each box contains one 1 mL oral syringe, one 9 mL oral syringe, and 1 bottle adaptor along with the suspension bottle. For each new bottle, push the provided adaptor into the bottle until the top of the adaptor is lined up with the top of the bottle.
    Prior to each use, shake well for 10 seconds.
    Fill the oral syringe (1 mL or 9 mL depending upon dose) with air and insert into the adaptor, dispelling the air into the bottle.
    If the dose is 1 mL (50 mg) or less, use the 1 mL oral syringe.
    If the dose is greater than 1 mL (50 mg), use the 9 mL oral syringe.
    Fill syringe with the prescribed dose and administer immediately. Do not save the dose in the oral syringe for later administration.
    Administer slowly into 1 side of the mouth with the patient's lips closed tightly around the syringe. The dose should be swallowed slowly.
    After use, the oral syringe may be washed with warm water and air dried in preparation for the patient's next dose.
    Close the bottle with its cap, and without removing the bottle adaptor.
    Storage of opened bottle: The suspension is stable for 100 days after initial opening. Store at or below 25 degrees C (77 degrees F). Do not refrigerate or freeze.

    STORAGE

    Generic:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Clozaril:
    - Store below 86 degrees F
    Fazaclo:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    VERSACLOZ:
    - Do not freeze
    - Do not refrigerate
    - Protect from light
    - Store at or below 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Clozapine is contraindicated for use in patients with a previous hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson Syndrome) or any other component of the product.

    Agranulocytosis, bone marrow suppression, chemotherapy, fever, infection, leukemia, leukopenia, neutropenia

    Because clozapine can cause severe neutropenia, which can lead to infection and death, there is a minimum baseline neutrophil count required to initiate therapy. The mechanism by which clozapine causes neutropenia is not known and it is not dose-dependent. Treatment exclusions occur when the absolute neutrophil count (ANC) falls below the required minimum ANC (e.g., neutropenia, agranulocytosis, granulocytopenia). In general, patients who develop severe neutropenia (ANC less than 500/mm3) with clozapine should not be re-challenged, unless the prescriber determines that the benefit outweighs the risks and has taken into account the ANC thresholds defined by the manufacturer, the patient’s medical and psychiatric history, the severity and characteristics of the neutropenic episode, and has discussed the benefits and risks of clozapine re-challenge with the patient and his/her caregiver. Other conditions that may be associated with neutropenia include, but are not limited to, bone marrow suppression, leukopenia, and leukemia. Because of the risk of severe neutropenia, clozapine is available only through a restricted program called the Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program. The Clozapine REMS Program replaces individual clozapine patient registries and the National Non-Rechallenge Master File (NNRMF). The ANC is the only test result accepted in the Clozapine REMS Program to monitor for neutropenia. The risk of neutropenia appears greatest during the first 18 weeks and then declines. A complete blood count (CBC), including the ANC value, should be obtained prior to initiating treatment with clozapine to ensure a normal baseline neutrophil count (ANC) of at least 1500/mm3 for the general population (i.e., non-Benign Ethnic Neutropenia patients). Patients with documented Benign Ethnic Neutropenia (BEN) must have at least 2 baseline ANC levels of 1000/mm3 or more before treatment can be initiated. Weekly ANC monitoring is required for all patients during the first 6 months of treatment. If the ANC remains at least 1500/mm3 for the first 6 months of treatment in the general population or at least 1000/mm3 for BEN patients, monitoring frequency may be reduced to every 2 weeks for the next 6 months. If the ANC remains at least 1500/mm3 in the general population or at least 1000/mm3 for BEN patients for the second 6 months of continuous therapy, ANC monitoring frequency may be reduced to once every 4 weeks thereafter. When the ANC is within the normal range and treatment is interrupted for less than 30 days, continue monitoring as before; if treatment is interrupted for 30 days or more, monitor as if a new patient. If mild neutropenia (ANC 1000 to 1499/mm3) develops in the general population, continue treatment and obtain an ANC three times weekly until the ANC is at least 1500/mm3, then return to the patient's last "normal range" ANC monitoring interval if clinically appropriate. For moderate neutropenia (ANC 500 to 999/mm3) in the general population, recommend a hematology consult and interrupt treatment for suspected clozapine-induced neutropenia. Obtain ANC values daily until the ANC reaches at least 1000/mm3, then resume treatment and check the ANC three times weekly until the ANC reaches 1500/mm3 or more. Then, the ANC should be checked weekly for 4 weeks, with a subsequent return to the patient's last “normal range” ANC monitoring interval if clinically appropriate. For severe neutropenia (ANC less than 500/mm3) in the general population, recommend a hematology consult and interrupt treatment for suspected clozapine-induced neutropenia. Obtain ANC values daily until the ANC is at least 1000/mm3, then three times weekly until the ANC reaches at least 1500/mm3. If a general population patient is re-challenged after having severe neutropenia, resume treatment as a new patient under “normal range” monitoring when the ANC reaches at least 1500/mm3. For BEN neutropenia (ANC 500 to 999/mm3), recommend a hematology consult and continue treatment. Obtain an ANC three times weekly until the ANC is at least 1000/mm3 or is at least at the patient's baseline. Then, the ANC should be checked weekly for 4 weeks, with a subsequent return to patient’s last “normal BEN range” ANC monitoring interval if clinically appropriate. In BEN severe neutropenia (ANC less than 500/mm3), recommend a hematology consult and interrupt treatment for suspected clozapine-induced neutropenia. The ANC should be checked daily until the ANC is at least 500/mm3, then three times weekly until the ANC is at least to the patient's baseline. If a BEN patient is re-challenged after having severe neutropenia, resume treatment as a new patient under “normal range” monitoring once the ANC is at least 1000/mm3 or at the patient’s baseline. For abrupt treatment discontinuation for a reason unrelated to neutropenia, continuation of the existing ANC monitoring is recommended for general population patients until their ANC is at least 1500/mm3 and for BEN patients until their ANC is at least 1000/mm3 or above their baseline. Interrupt clozapine as a precaution in any patient who develops a fever of 38.5 degrees Celsius or 101.3 degrees Farenheit or higher and obtain an ANC; assess for neutropenia, fever, and other conditions associated with fever (e.g., NMS). If fever occurs in any patient with an ANC less than 1000/mm3, initiate appropriate workup and treatment for infection, refer to the manufacturer's guidelines for ANC monitoring, and consider a hematology consult. Patients should report the appearance of fever, sore throat, lethargy, weakness, or other signs of bone marrow suppression or infection to their health care provider immediately. Risk factors for developing severe neutropenia from clozapine therapy, other than initial bone marrow suppression, are not known. Patients with a Jewish background, those undergoing the first 4 to 10 weeks of drug therapy, female sex, older patients, cachetic patients, or those with serious underlying medical illness may theoretically be at greater risk for severe neutropenia, but definitive data are not available. It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., chemotherapy) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased ANC monitoring and consult the treating oncologist. Clozapine dose or duration of treatment cannot be used as a reliable indicator for severe neutropenia.

    Seizure disorder, seizures

    Use clozapine with caution in patients with a history of seizure disorder or in patients with risk factors that may predispose them to the occurrence of seizures. Clozapine lowers the seizure threshold in a dose-dependent manner, particularly at doses greater than 600 mg/day or following dosage changes greater than 100 mg/day (rapid dose increases). Dosage adjustments in patients with pre-existing epilepsy should be cautious. Clozapine may induce EEG changes, myoclonic jerks or generalized seizures. Patients on clozapine treatment who have seizure disorders should approach activities where sudden loss of consciousness would cause serious risk to themselves or others with caution. Clozapine should be used with caution in patients on certain anticonvulsant therapies due to several possible mechanisms of interaction. If seizures occur, the clozapine dosage should be reduced or discontinued, and, if necessary, anticonvulsant treatment initiated.

    CNS depression, coadministration with other CNS depressants, coma

    Because clozapine may cause CNS depression, it is contraindicated for use in patients with coma or severe CNS depression from any cause. Some cases of collapse, respiratory arrest, and cardiac arrest have occurred during clozapine initiation in patients receiving benzodiazepines or other psychotropic drugs, or in patients receiving clozapine alone. The manufacturer recommends caution during coadministration with other CNS depressants, such as when prescribing clozapine in combination with benzodiazepines or other psychotropic agents.

    Neurological disease, Parkinson's disease, tardive dyskinesia

    Antipsychotics can cause motor and sensory instability, which may lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with diseases (e.g., neurological disease), conditions, or concurrent medication use that could exacerbate motor and sensory instability. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Clozapine is less likely than conventional antipsychotics to cause extrapyramidal side effects. However, all antipsychotics should be used with caution in patients with Parkinson's disease because of possible aggravation of EPS due to dopamine-receptor blockade. Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotics; however, due to the relatively low affinity of clozapine for D-2 receptors, it may be considered as a substitute when patients develop tardive dyskinesia from other antipsychotics. Periodic evaluation for movement disorders is recommended (e.g., AIMS). Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the initiation of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotics differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotics administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief periods at low doses or may even arise after drug discontinuation. The syndrome may remit, partially or completely, if the antipsychotic is withdrawn. Antipsychotics may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, clozapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotics, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic therapy, the smallest dose and the shortest duration producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear, clozapine discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.

    Anticholinergic medications, closed-angle glaucoma, constipation, fecal impaction, GI obstruction, ileus, prostatic hypertrophy, urinary retention

    Clozapine is contraindicated for use in patients with paralytic ileus. Clozapine should be used with caution in adults with closed-angle glaucoma, constipation, fecal impaction, prostatic hypertrophy, or urinary retention because clozapine has strong anticholinergic activity that can exacerbate these conditions. Also use caution in patients with GI obstruction. The anticholinergic effects of clozapine may be additive to other anticholinergic medications.

    Driving or operating machinery

    The sedative effects of clozapine may be most evident in the initial days of treatment; patients should be advised to use caution when driving or operating machinery, or performing other tasks that require mental alertness, until they know how clozapine affects them. Somnolence could lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with conditions, diseases, or concurrent medication use that could exacerbate somnolence. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, cardiomyopathy, cerebrovascular disease, coronary artery disease, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, hypotension, hypovolemia, long QT syndrome, malnutrition, myocardial infarction, myocarditis, orthostatic hypotension, QT prolongation, syncope, tachycardia, thyroid disease, torsade de pointes, ventricular arrhythmias

    Similar to other antipsychotic agents, ECG repolarization changes and serious cardiac events have been reported with clozapine therapy. Treatment with clozapine has been associated with QT prolongation, ventricular arrhythmias, torsade de pointes (TdP), cardiac arrest, and sudden death. Use clozapine with caution in patients with a history of QT prolongation (including congenital long QT syndrome) or other cardiac disease or conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation. Electrolyte imbalances should be corrected prior to initiating treatment with clozapine. Baseline assessments of serum potassium and magnesium levels should be performed, as well as periodic evaluation during treatment, in patients at risk for electrolyte imbalances. Given the potential for QT prolongation, clozapine should be used cautiously with other drugs that cause QT prolongation. Prescribers should evaluate symptoms of dizziness, syncope, or palpitations. The drug should be discontinued if the QT interval measurement exceeds 500 msec. Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred during clozapine treatment and can be fatal. These symptoms are consistent with neurally mediated reflex bradycardia. The risk is highest during the initial titration period, and particularly with rapid titration. Therefore, the manufacturer's dosing titration guidelines must be followed. Orthostatic hypotension could lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with conditions, diseases, or concurrent medication use that could exacerbate orthostasis. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Clozapine should be used cautiously in patients with cardiac disease (e.g., history of myocardial infarction or ischemia, heart failure, conduction abnormalities), cerebrovascular disease, or other conditions that would predispose patients to hypotension (e.g., concurrent use of antihypertensives, dehydrated state, or hypovolemia). Cardiomyopathy or myocarditis, sometimes fatal, have occurred during clozapine use. Discontinue clozapine and obtain a cardiac evaluation if either of these reactions is suspected. Myocarditis most frequently presents within the first 2 months of treatment and cardiomyopathy symptoms usually occur after 8 weeks of treatment. Cardiomyopathy or myocarditis should be considered in patients receiving clozapine who present with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs or symptoms of heart failure, or ECG findings such as ST-T wave abnormalities or cardiac arrhythmias. It is not known whether eosinophilia is a reliable predictor of myocarditis. In patients who are diagnosed with cardiomyopathy while taking clozapine, mitral valve incompetence has been reported. These cases reported either mild or moderate mitral regurgitation on two-dimensional echocardiography. In patients with suspected cardiomyopathy, consider a 2D-echo Doppler exam to identify mitral valve incompetence. Tachycardia may occur secondary to hypotension, but has also been noted as a presenting sign in patients with myocarditis. Therefore, tachycardia during the first month of therapy warrants close monitoring for other signs of myocarditis. In general, patients with clozapine-related myocarditis or cardiomyopathy should not be re-challenged with clozapine.

    Pulmonary disease, thromboembolic disease

    Use clozapine with caution in patients with pulmonary disease. Similar to other antipsychotic agents, serious respiratory events have been reported with clozapine therapy. The possibility of pulmonary embolism should be considered in patients receiving clozapine who present with deep vein thrombosis, acute dyspnea, chest pain or with other respiratory signs and symptoms that might be consistent with thromboembolic disease.

    Dialysis, renal disease, renal failure

    Safety of clozapine in patients with renal disease has not been established. Clozapine treatment is not recommended for patients with clinically significant renal disease, including renal failure. Clozapine is not removed by hemodialysis; patients receiving dialysis should not take clozapine.

    Hepatic disease, hepatitis, hepatotoxicity, jaundice, poor metabolizers

    No specific studies were conducted to investigate the effects of hepatic disease on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with significant hepatic impairment when given usual doses; therefore, a dosage reduction may be necessary in this patient population. Severe, life threatening, and in some cases fatal hepatotoxicity including hepatic failure, hepatic necrosis, and hepatitis have been reported during clozapine administration. Patients should be monitored for the appearance of signs and symptoms of hepatotoxicity such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy. Serum tests for liver injury should be performed and permanent discontinuation of treatment should be considered if hepatitis or transaminase elevations combined with other systemic symptoms of hepatic dysfunction are due to clozapine. Clozapine is a substrate for the hepatic isoenzymes CYP1A2, 2D6, and 3A4. Caution should be exercised in patients receiving concomitant treatment with other drugs that are either inducers or inhibitors of these enzymes. For patients who are poor metabolizers of CYP2D6 (CYP2D6 PMs) it may be necessary to reduce the clozapine dose.

    Dementia, geriatric, stroke

    Orthostatic hypotension, tachycardia, and syncope can occur with clozapine treatment. Geriatric patients, especially those with compromised cardiac functioning, may be more susceptible to these effects. Geriatric patients may also be more likely to experience anticholinergic effects, movement disorders, CNS depression, bone marrow suppression, and agranulocytosis. Lower initial doses of clozapine should be considered, with a very gradual titration as tolerated. Antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric patients. In April 2005 the FDA mandated that all manufacturers of atypical antipsychotics include a boxed warning to the labeling noting that increased death rates (1.6 to 1.7 times that of placebo) have been noted in this patient population receiving atypical antipsychotics. A similar warning was subsequently added to product labels for conventional antipsychotics. Death typically occurred due to heart failure, sudden death, or infections (primarily pneumonia). Over a 10-week trial, the rate of death in the elderly was roughly 4.5% compared to 2.6% in the placebo group. In a meta-analysis of 17 placebo controlled trials (n = 5,106) performed with olanzapine, aripiprazole, risperidone, or quetiapine in elderly patients with dementia-related psychosis, 15 showed numerical increases in mortality in the active compared to the placebo-treated patients. Because the increase in mortality was consistent across all three relevant chemical classes, the FDA concluded that the effect was most likely related to the common pharmacologic effects of all atypical antipsychotics, including those that were not included in the meta-analysis. In addition, an increased incidence of cerebrovascular events (stroke, transient ischemia attack), including fatalities, have been reported in elderly patients with dementia-related psychosis taking some atypical antipsychotics. Therefore, caution is advisable when administering clozapine to elderly patients at risk for cerebrovascular events or with compromised cardiac functioning. According to the Beers Criteria, antipsychotics are considered potentially inappropriate medications (PIMs) in elderly patients, and use should be avoided except for treating schizophrenia or bipolar disorder, and for short-term use as antiemetics during chemotherapy. In addition, avoidance of clozapine is recommended in geriatric patients with the following disease states or symptoms due to the potential for exacerbation of the condition or increased risk of adverse effects: lower urinary tract symptoms/benign prostatic hypertrophy in men (decreased urinary flow, urinary retention), delirium (possible new-onset or worsening delirium), and dementia (adverse CNS effects). There is an increased risk of stroke and 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. The Panel recommends avoiding antipsychotics 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 use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. While it is recommended that most dopamine-receptor antagonists be avoided in patients with Parkinson's disease due to the potential to worsen parkinsonian symptoms, clozapine appears less likely to precipitate a worsening of symptoms than most other antipsychotics and is excluded from the recommendation. Although use in elderly patients with chronic seizures/epilepsy should generally be avoided due to a lowering of the seizure threshold by clozapine, the Beers expert panel states that clozapine may be acceptable in those with well-controlled seizures in whom alternative agents have not been effective. 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. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). An antipsychotic should generally be used only for the conditions listed in the guidelines (e.g., schizophrenia, mood disorder, Tourette's disorder) and that meet the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for use. There is an increased risk of morbidity and mortality in elderly patients treated with antipsychotics for dementia-related psychosis. Therefore, identify and address all possible causes of behavioral or psychological symptoms of dementia (BPSD) before considering an antipsychotic. To initiate antipsychotic therapy, behavioral symptoms must be a danger to self or others and are either 1) due to mania or psychosis or 2) the plan of care includes documentation of attempted behavioral interventions (except in an emergency). Limit emergency treatment to 7 days or less with evaluation and documentation within 7 days which identifies and addresses contributors/causes. For acute conditions persisting beyond 7 days, pertinent non-pharmacologic interventions must be attempted, unless clinically contraindicated, and documented. Treatment of non-acute, chronic, or prolonged BPSD must meet all of the OBRA criteria for BPSD treatment, and include monitoring that ensures the behavioral symptoms are not due to a treatable or correctable medical condition, are not due to correctable environmental or treatable psychological stressors alone, and provides clearly documented evidence of persistence. The LTCF must evaluate the appropriateness of the antipsychotic during or within 2 weeks of admission for a newly admitted resident on an antipsychotic. In all cases, the lowest possible dose and shortest duration should be prescribed. OBRA provides general dosing guidance for antipsychotic treatment of BPSD. Monitoring of antipsychotics should include evaluation of ongoing effectiveness, rationale for use, and potential adverse effects (e.g., anticholinergic effects, neurological symptoms, metabolic syndrome, cardiac effects). Antipsychotics are subject to periodic review for effectiveness, necessity, and the potential for gradual dose reduction (GDR) or discontinuation. Refer to the OBRA guidelines for complete information.

    Neonates, pregnancy, pregnancy testing

    There are no adequate trials of the effect of clozapine in human pregnancy. Animal studies have produced no evidence of adverse fetal effects; however, the use of clozapine during pregnancy should be undertaken only when clearly needed because animal data may not be indicative of human response. Neonates exposed to antipsychotics during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity and have ranged from self-limited to those requiring intensive care unit support and prolonged hospitalization. Neonates exhibiting 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. According to the American Psychiatric Association treatment guidelines for schizophrenia, consider pregnancy testing in women of childbearing potential prior to initiation of an antipsychotic. The National Pregnancy Registry for Psychiatric Medications is dedicated to evaluating the safety of psychiatric medications that may be taken by women during pregnancy to treat a wide range of mood, anxiety, or psychiatric disorders. The primary goal of this Registry is to determine the frequency of major malformations, such as heart defects, cleft lip, or neural tube defects, in babies exposed to various psychiatric drugs during pregnancy. While the research concentrates on atypical antipsychotics and antidepressant use, pregnant women using other psychiatric medications are encouraged to register. For more information, contact the registry at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry or by phone 1-866-961-2388. It is not known if antipsychotics, through their effect on prolactin, would affect labor or obstetric delivery.

    Breast-feeding

    According to the manufacturer, breast-feeding should be avoided in patients receiving clozapine therapy. Animal studies suggest that clozapine may be excreted in breast milk and have an effect on the nursing infant. Anecdotal evidence supports accumulation of clozapine in human breast milk. An antipsychotic agent other than clozapine would be preferred due to the possibility of clozapine-induced agranulocytosis in the nursing infant; guidelines support that women taking clozapine should not breast-feed. Although elevations in prolactin associated with clozapine are minimal relative to many other antipsychotics, interference with proper lactation is possible. Alternate medications for consideration during breast-feeding include atypical agents such as olanzapine or quetiapine. 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 ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Surgery

    Caution is advised for patients on clozapine who will receive general anesthesia, due to the potential for CNS effects. Check with the anesthesiologist regarding the continuation of clozapine in a patient who is scheduled for surgery. Neuroleptic malignant syndrome has been reported in association with antipsychotic medications, including clozapine. In the presence of high fever, the possibility of this complication should be considered.

    Children, infants

    The safety and efficacy of clozapine use in children and adolescents have not been established. Limited data on the use of clozapine for resistant schizophrenia exists for children > 9 years of age. Because of the potential for serious adverse effects from clozapine, it should only be considered for use in children refractory to other antipsychotic medications. In addition to concerns of agranulocytosis and seizures with clozapine, routine cardiovascular monitoring has been suggested for children receiving psychotropic medications due to the potential of these agents to produce adverse cardiac effects. There is no known use of clozapine in infants. Additionally, adverse effects have been reported after delivery in newborns exposed to antipsychotics during the third trimester and some cases have included intensive care unit stays and prolonged hospitalization.

    Diabetes mellitus, diabetic ketoacidosis, hypercholesterolemia, hyperglycemia, hyperlipidemia, hyperosmolar hyperglycemic state (HHS), hypertriglyceridemia, obesity

    Atypical antipsychotics, including clozapine, have been associated with metabolic changes that may increase cardiovascular or cerebrovascular risk over time, including loss of blood glucose control, dyslipidemia and weight gain. Monitoring of weight and evaluation of lipids at baseline and periodically throughout treatment are recommended. Patients with risk factors for diabetes mellitus (e.g., obesity, pre-diabetes, family history) should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Treatment with clozapine should be undertaken with caution in patients with pre-existing conditions such as obesity, pre-diabetes, or hyperlipidemia (e.g., hypercholesterolemia or hypertriglyceridemia). Hyperglycemia and diabetes mellitus, in some cases associated with diabetic ketoacidosis, hyperosmolar hyperglycemic state (HHS) with coma or death, have been reported in patients treated with atypical antipsychotics including clozapine. Epidemiological studies suggest an increased risk of hyperglycemia-related adverse events in patients treated with the atypical antipsychotics, although precise risk estimates are not available. An increased risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in general complicates this concern. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia (polydipsia, polyuria, polyphagia, weakness). Patients with established diabetes mellitus should be monitored regularly for worsening of glucose control. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the antipsychotic was discontinued; however, some patients required continuation of anti-diabetics despite discontinuation of the suspect drug.

    Abrupt discontinuation

    Abrupt discontinuation of clozapine is not recommended, unless required by the patient's medical condition (i.e., leukopenia). Otherwise discontinuation should usually occur via a gradual 1—2 week reduction in dosage. Patients should be carefully observed for the recurrence of psychotic symptoms or cholinergic rebound (headache, nausea, vomiting or diarrhea) during drug discontinuation. Any patient who has previously experienced respiratory or cardiac arrest with initial dosing, but was then able to be successfully titrated to a therapeutic dose, should be re-titrated with extreme caution, even if only 24 hours of discontinuation.

    Tobacco smoking

    Smoking cigarettes (tobacco) increases the clearance of clozapine and may result in a substantial reduction in clozapine plasma concentrations. Tobacco smokers may require higher doses of clozapine. However, tobacco smoking is extremely common in patients who may require clozapine, and the usual doses were established in this population. Tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, sudden smoking cessation may result in a reduced clearance of clozapine, despite the initiation of nicotine replacement. Monitor patients carefully when changes in smoking status occur.

    Phenylketonuria

    Certain clozapine products (i.e., FazaClo) may contain aspartame. Phenylalanine is a component of aspartame and should be used cautiously in patients with phenylketonuria. Each 25 mg, orally-disintegrating tablet of FazaClo contains 3.1 mg of aspartame (1.74 mg of phenylalanine) and each 100 mg, orally-disintegrating tablet of FazaClo contains 12.4 mg of aspartame (6.96 mg of phenylalanine).

    Ambient temperature increase, dehydration, hyperthermia, hypothermia, strenuous exercise

    Antipsychotics have been reported to disrupt the body's ability to reduce core body temperature presumably through effects in the hypothalamus, and they predispose patients to hyperthermia. Patients receiving clozapine should be advised of conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, ambient temperature increase, or dehydration). Transient elevations in temperature above 38 degrees C can occur during initial treatment with clozapine. Because clozapine is associated with agranulocytosis, fever should be promptly assessed to rule out the possibility of an underlying infectious process due to a hematologic abnormality. A less frequently described alteration in thermoregulatory processes reported with both conventional and atypical antipsychotics is hypothermia. Thermoregulation is multi-factorial; however, the dopaminergic system appears to have a primary role, and serotonin may also have modulatory activity (5-HT2a receptors). Most cases of hypothermia associated with antipsychotics have occurred in conjunction with other potential precipitating factors such as hypothyroidism, sepsis, organic brain injury, or environmental temperature. Hypothermia appears to occur more frequently during initiation of antipsychotic therapy or after dose increases.

    Dysphagia

    Antipsychotic drug use has been associated with esophageal dysmotility and aspiration of gastric contents, which may increase the incidence of aspiration pneumonia in certain patient populations, such as patients with advanced Alzheimer's disease. Dysphagia and aspiration have been reported during post-marketing use of clozapine. Patients with dysphagia or who are at risk for aspiration pneumonia should be closely monitored while receiving clozapine.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / 1.0-5.0
    visual impairment / Early / 5.0-5.0
    akinesia / Delayed / 4.0-4.0
    agranulocytosis / Delayed / 1.0-1.0
    cyanosis / Early / 0-1.0
    bradycardia / Rapid / 0-1.0
    peptic ulcer / Delayed / 0-1.0
    hematemesis / Delayed / 0-1.0
    myocarditis / Delayed / 0-0.1
    tardive dyskinesia / Delayed / Incidence not known
    neuroleptic malignant syndrome / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    stroke / Early / Incidence not known
    thrombosis / Delayed / Incidence not known
    pseudopheochromocytoma / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    pericarditis / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    cirrhosis / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    diabetic ketoacidosis / Delayed / Incidence not known
    pleural effusion / Delayed / Incidence not known
    apnea / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    vasculitis / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    ocular hypertension / Delayed / Incidence not known

    Moderate

    sinus tachycardia / Rapid / 25.0-25.0
    constipation / Delayed / 14.0-25.0
    hypotension / Rapid / 9.0-9.0
    orthostatic hypotension / Delayed / 0-6.0
    hypertension / Early / 4.0-4.0
    neutropenia / Delayed / 3.0-3.0
    leukopenia / Delayed / 3.0-3.0
    akathisia / Delayed / 3.0-3.0
    confusion / Early / 3.0-3.0
    anemia / Delayed / 0-1.0
    eosinophilia / Delayed / 1.0-1.0
    dysarthria / Delayed / 0-1.0
    ataxia / Delayed / 1.0-1.0
    pseudoparkinsonism / Delayed / 0-1.0
    phlebitis / Rapid / 0-1.0
    premature ventricular contractions (PVCs) / Early / 0-1.0
    palpitations / Early / 0-1.0
    chest pain (unspecified) / Early / 1.0-1.0
    angina / Early / 1.0-1.0
    edema / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 1.0-1.0
    urinary retention / Early / 1.0-1.0
    urinary incontinence / Early / 1.0-1.0
    impotence (erectile dysfunction) / Delayed / 0-1.0
    ejaculation dysfunction / Delayed / 1.0-1.0
    hyperthermia / Delayed / 0-1.0
    wheezing / Rapid / 0-1.0
    dyspnea / Early / 1.0-1.0
    amnesia / Delayed / 0-1.0
    depression / Delayed / 1.0-1.0
    hallucinations / Early / 0-1.0
    erythema / Early / 0-1.0
    hematoma / Early / 0-1.0
    hot flashes / Early / 0-1.0
    atopic dermatitis / Delayed / 0-1.0
    myasthenia / Delayed / 1.0-1.0
    conjunctival hyperemia / Early / 0-1.0
    nystagmus / Delayed / 0-1.0
    thrombocytosis / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    EEG changes / Delayed / Incidence not known
    myoclonia / Delayed / Incidence not known
    dystonic reaction / Delayed / Incidence not known
    ST-T wave changes / Rapid / Incidence not known
    QT prolongation / Rapid / Incidence not known
    tachypnea / Early / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    dysphagia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    steatosis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    priapism / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    psychosis / Early / Incidence not known
    delirium / Early / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    withdrawal / Early / Incidence not known

    Mild

    hypersalivation / Early / 48.0-48.0
    drowsiness / Early / 39.0-46.0
    dizziness / Early / 19.0-27.0
    insomnia / Early / 2.0-20.0
    vertigo / Early / 19.0-19.0
    vomiting / Early / 3.0-17.0
    nausea / Early / 3.0-17.0
    dyspepsia / Early / 14.0-14.0
    headache / Early / 7.0-7.0
    tremor / Early / 6.0-6.0
    syncope / Early / 6.0-6.0
    xerostomia / Early / 6.0-6.0
    hyperhidrosis / Delayed / 6.0-6.0
    fever / Early / 5.0-5.0
    nightmares / Early / 4.0-4.0
    restlessness / Early / 4.0-4.0
    pyrosis (heartburn) / Early / 4.0-4.0
    agitation / Early / 4.0-4.0
    weight gain / Delayed / 4.0-4.0
    fatigue / Early / 2.0-2.0
    diarrhea / Early / 2.0-2.0
    rash (unspecified) / Early / 2.0-2.0
    epistaxis / Delayed / 0-1.0
    leukocytosis / Delayed / 0-1.0
    asthenia / Delayed / 1.0-1.0
    lethargy / Early / 1.0-1.0
    hyperkinesis / Delayed / 1.0-1.0
    eructation / Early / 0-1.0
    dysgeusia / Early / 0-1.0
    urinary urgency / Early / 1.0-1.0
    dysmenorrhea / Delayed / 0-1.0
    mastalgia / Delayed / 0-1.0
    increased urinary frequency / Early / 1.0-1.0
    polydipsia / Early / 0-1.0
    nasal congestion / Early / 1.0-1.0
    laryngitis / Delayed / 0-1.0
    sneezing / Early / 0-1.0
    malaise / Early / 0-1.0
    infection / Delayed / 0-1.0
    hyperventilation / Early / 0-1.0
    throat irritation / Early / 1.0-1.0
    rhinorrhea / Early / 0-1.0
    chills / Rapid / 0-1.0
    hypothermia / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    anxiety / Delayed / 1.0-1.0
    libido decrease / Delayed / 0-1.0
    paranoia / Early / 0-1.0
    libido increase / Delayed / 0-1.0
    irritability / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    pallor / Early / 0-1.0
    petechiae / Delayed / 0-1.0
    urticaria / Rapid / 0-1.0
    muscle cramps / Delayed / 1.0-1.0
    back pain / Delayed / 1.0-1.0
    myalgia / Early / 1.0-1.0
    mydriasis / Early / 0-1.0
    anorexia / Delayed / 1.0-1.0
    appetite stimulation / Delayed / 0-1.0
    paresthesias / Delayed / Incidence not known
    nocturia / Early / Incidence not known
    polyuria / Early / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Major) Since abarelix can cause QT prolongation, abarelix should be used cautiously, if at all, with other drugs that are associated with QT prolongation. Clozapine may induce QT prolongation.
    Acarbose: (Moderate) Patients taking alpha-glucosidase inhibitors should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Acebutolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Acetaminophen; Aspirin, ASA; Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
    Acetaminophen; Butalbital: (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Acetaminophen; Butalbital; Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention. (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Pain medications such as dihydrocodeine, should be combined cautiously with clozapine due to the potential for additive depressant effects and possible respiratory depression or hypotension. Concurrent use of clozapine and opiates may also lead to reduced intestinal motility or bladder function.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Acetaminophen; Codeine: (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant, and additive anticholinergic effects may be observed during use of other medications with anticholinergic activity such as doxylamine. Clozapine may also cause additive sedation with doxylamine.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Drugs that can cause CNS depression, including dichloralphenazone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness if used concomitantly with atypical antipsychotics.
    Acetaminophen; Diphenhydramine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant, which may be additive with other medications having anticholinergic effects such as diphenhydramine. Clozapine may also cause additive sedation with diphenhydramine.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as clozapine, can lead to additive respiratory depression, hypotension, profound sedation, or coma. In addition, this drug combination may result in additive effects on intestinal motility or bladder function. Prior to concurrent use of oxycodone in patients taking clozapine, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower clozapine dose. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Pentazocine: (Moderate) Coadministration of pentazocine with atypical antipsychotics may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation. Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity.
    Acetaminophen; Propoxyphene: (Moderate) Propoxyphene should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension. Combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Acetaminophen; Tramadol: (Moderate) Concurrent use of tramadol and clozapine should be avoided if possible. Antipsychotics may enhance the seizure risk of tramadol. In addition, in vitro data suggest that clozapine has CYP2D6 inhibitory effects and may increase plasma concentrations of CYP2D6 substrates such as tramadol. Although the full pharmacologic impact of increased tramadol exposure is unknown, close monitoring for serious adverse effects, such as seizures, is advisable. In addition, serotonin syndrome may occur during use of tramadol with medications that impair its metabolism. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, hyperreflexia, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Because the analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), CYP2D6 inhibition by clozapine may alter the analgesic response to tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and clozapine.
    Acetazolamide: (Major) Caution is advisable during concurrent use of clozapine and acetazolamide. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Concurrent use of clozapine and medications known to cause electrolyte imbalance may increase the risk of QT prolongation.
    Ado-Trastuzumab emtansine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Albendazole: (Moderate) Albendazole induces cytochrome P450 1A. and may induce the metabolism of clozapine. Patients receiving this combination should be closely monitored when albendazole is prescribed, as albendazole may increase the clearance of clozapine. Conversely, the discontinuation of albendazole therapy may result in a reduced clearance of the clozapine, leading to an increase in serum concentrations. The patient's clinical status should be monitored carefully when albendazole is prescribed and on discontinuation of albendazole therapy.
    Albiglutide: (Moderate) Patients taking incretin mimetics should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. Changes in lipid profiles and weight may also aggravate diabetes or associated conditions or complications. Temporal associations of atypical antipsychotic therapy with the aggravation or new onset of diabetes mellitus have been reported.
    Albuterol: (Minor) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with clozapine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Albuterol; Ipratropium: (Minor) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with clozapine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Aldesleukin, IL-2: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. In addition, Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psychotropic activity (e.g., antipsychotics). Use with caution. Patients developing mood disturbances, moderate to severe lethargy/somnolence while on aldesleukin should seek evaluation from their health care provider.
    Alemtuzumab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Alfentanil: (Moderate) Concomitant use of alfentanil with other CNS depressants, including clozapine, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. Combining alfentanil with clozapine may also lead to additive effects on intestinal motility or bladder function. A dose reduction of one or both drugs may be warranted.
    Alfuzosin: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), alfuzosin and clozapine should be used together cautiously. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation.
    Aliskiren; Amlodipine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Alkylating agents: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Alogliptin: (Moderate) Patients taking alogliptin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
    Alogliptin; Metformin: (Moderate) Patients taking alogliptin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Patients taking metformin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. Temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Alogliptin; Pioglitazone: (Moderate) Patients taking alogliptin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when clozapine is instituted. Atypical antipsychotics have been associated with causing metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Alosetron: (Moderate) Alosetron, if combined with drugs that possess anticholinergic properties like clozapine, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
    Alpha-glucosidase Inhibitors: (Moderate) Patients taking alpha-glucosidase inhibitors should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Alprazolam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Altretamine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Amantadine: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as clozapine may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects.
    Ambenonium Chloride: (Moderate) The therapeutic benefits of ambenonium may be diminished when co-administered with the antimuscarinics. Drugs known to exhibit anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity include clozapine.
    Amiodarone: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation such as amiodarone. In addition, amiodarone is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP2D6 or CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Amitriptyline; Chlordiazepoxide: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Amlodipine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amlodipine; Atorvastatin: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amlodipine; Benazepril: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amlodipine; Olmesartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amlodipine; Telmisartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amlodipine; Valsartan: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Amobarbital: (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Amoxapine: (Moderate) Use caution during co-administration of amoxapine and antipsychotics. Amoxapine exhibits some antipsychotic activity and may increase the risk of tardive dyskinesia or neuroleptic malignant syndrome (NMS) when antipsychotics are given concurrently. In addition, amoxapine is metabolized by CYP2D6. Clozapine is partially metabolized by CYP2D6, and could compete for the same metabolic pathway.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with clozapine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. In addition, clarithromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with clozapine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. In addition, clarithromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) The addition of omeprazole to clozapine therapy resulted in a roughly 40% reduction in clozapine plasma concentrations in at least 2 patients. Omeprazole is an inducer of CYP1A2, one of the isoenzymes reponsible for the metabolism of clozapine. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
    Amphetamine: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Amphetamine; Dextroamphetamine: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Amphetamines: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Amprenavir: (Moderate) Caution is advisable during concurrent use of amprenavir and clozapine. Amprenavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Anagrelide: (Moderate) Caution is advisable during concurrent use of anagrelide and clozapine. Anagrelide is an inhibitor of CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. When initiating clozapine or adding a mild or moderate CYP1A2 inhibitor to clozapine treatment, monitor for adverse reactions and consider reducing the clozapine dose if necessary. If the inhibitor is discontinued, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Angiotensin II receptor antagonists: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Angiotensin-converting enzyme inhibitors: (Moderate) Lisinopril may decrease the renal elimination of clozapine and metabolites. Clozapine toxicity, including irritability, anger, insomnia, nightmares and sialorrhea may occur. The mechanism of this interaction is unclear; however, as lisinopril does not undergo metabolism, cytochrome P450 enzyme involvement is unlikely. It is speculated that a decrease in renal elimination of clozapine occurs due to a lisinopril-induced reduction in glomerular filtration rate (GFR). Plasma clozapine concentrations should be measured carefully during concomitant lisinopril therapy; another antihypertensive class may need to be selected. In addition, clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Anthracyclines: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. Additionally, treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Antineoplastic agents with a possible risk of QT prolongation and TdP (torsade de pointes) include anthracyclines. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Antimetabolites: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Antitumor antibiotics: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Apomorphine: (Major) Concurrent use of apomorphine and clozapine should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death and apomorphine is associated with a possible risk for QT prolongation and TdP. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Clozapine may block the dopamine agonist properties of apomorphine, thereby compromising apomorphine effectiveness. Apomorphine causes considerable somnolence, and concomitant administration with clozapine could result in additive CNS effects.
    Aprepitant, Fosaprepitant: (Major) Use caution if clozapine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in clozapine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Clozapine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of clozapine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Arformoterol: (Moderate) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with clozapine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Aripiprazole: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Clozapine is an atypical antipsychotic with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with aripiprazole. In addition, caution is advisable when aripiprazole is given in combination with other CNS depressants such as other atypical antipsychotics. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, tardive dyskinesia, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent.
    Armodafinil: (Moderate) Caution is advisable during concurrent use of modafinil or armodafinil with clozapine. Modanil and armodafinil have potential to induce CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Patients receiving clozapine in combination with a CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. An interaction between modafinil and clozapine has been reported in a case report that resulted in clinical side effects. After the addition of modafinil to the drug regimen of a patient stabilized on clozapine, the patient became symptomatic with dizziness, problems with gait, and sinus tachycardia. Clozapine serum concentrations were found to be elevated. All symptoms resolved and the patient's clozapine levels returned to normal on modafinil discontinuation. The mechanism of the interaction is unclear, but may be related to changes in clozapine metabolism by modafinil. Concomitant therapy of modafinil and clozapine should be approached with close monitoring of the patient's clinical status.
    Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide include clozapine. In addition, it is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor and clozapine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased clozapine concentrations. Furthermore, 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. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as clozapine, should be avoided. Consider ECG monitoring if clozapine must be used with or after artemether; lumefantrine treatment.
    Articaine; Epinephrine: (Moderate) Clozapine may induce significant alpha-adrenergic blockade during clozapine overdose, leading to profound hypotension. Epinephrine should generally not be used to treat clozapine-induced hypotension due to the unopposed beta-activity, which potentially could worsen the hypotension.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect, such as clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Coadministration of asenapine with clozapine may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention. (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Moderate) Pain medications such as dihydrocodeine, should be combined cautiously with clozapine due to the potential for additive depressant effects and possible respiratory depression or hypotension. Concurrent use of clozapine and opiates may also lead to reduced intestinal motility or bladder function.
    Aspirin, ASA; Carisoprodol: (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention. (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Aspirin, ASA; Omeprazole: (Moderate) The addition of omeprazole to clozapine therapy resulted in a roughly 40% reduction in clozapine plasma concentrations in at least 2 patients. Omeprazole is an inducer of CYP1A2, one of the isoenzymes reponsible for the metabolism of clozapine. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as clozapine, can lead to additive respiratory depression, hypotension, profound sedation, or coma. In addition, this drug combination may result in additive effects on intestinal motility or bladder function. Prior to concurrent use of oxycodone in patients taking clozapine, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower clozapine dose. Monitor patients for sedation and respiratory depression.
    Atazanavir: (Moderate) Caution is advisable during concurrent use of atazanavir and clozapine. Atazanavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Atazanavir; Cobicistat: (Moderate) Caution is advisable during concurrent use of atazanavir and clozapine. Atazanavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Atenolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Atenolol; Chlorthalidone: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include clozapine.
    Atropine: (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including clozapine.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used with other drugs with moderate to significant anticholinergic effects including clozapine. (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including clozapine.
    Atropine; Difenoxin: (Moderate) Diphenoxylate decreases GI motility. Other drugs that also decrease GI motility, such as clozapine, may produce additive effects with diphenoxylate if used concomitantly. (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including clozapine.
    Atropine; Diphenoxylate: (Moderate) Diphenoxylate decreases GI motility. Other drugs that also decrease GI motility, such as clozapine, may produce additive effects with diphenoxylate if used concomitantly. (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including clozapine.
    Atropine; Edrophonium: (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including clozapine.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as phenobarbital, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Phenobarbital may also increase the metabolism of clozapine through induction of CYP1A2. Close monitoring is recommended when clozapine is administered to patients with a seizure disorder because clozapine lowers the seizure threshold. The effectiveness of phenobarbital in treating seizures may be reduced. Dosage adjustments may be necessary, and close monitoring of clinical and/or adverse effects is warranted when phenobarbital is used with clozapine. Additive sedation may be noted with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent. (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used with other drugs with moderate to significant anticholinergic effects including clozapine. (Moderate) Additive anticholinergic effects may be seen when scopolamine is used concomitantly with other drugs with moderate to significant anticholinergic effects including clozapine. (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including clozapine.
    Azithromycin: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), azithromycin and clozapine should be used together cautiously. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. There have been case reports of QT prolongation and TdP with the use of azithromycin in postmarketing reports. Concurrent use may increase the risk of QT prolongation.
    Bacillus Calmette-Guerin Vaccine, BCG: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Baclofen: (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with clozapine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
    Belinostat: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as phenobarbital, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Phenobarbital may also increase the metabolism of clozapine through induction of CYP1A2. Close monitoring is recommended when clozapine is administered to patients with a seizure disorder because clozapine lowers the seizure threshold. The effectiveness of phenobarbital in treating seizures may be reduced. Dosage adjustments may be necessary, and close monitoring of clinical and/or adverse effects is warranted when phenobarbital is used with clozapine. Additive sedation may be noted with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Belladonna; Opium: (Moderate) Pain medications such as opiate agonists, should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Bendamustine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Bendroflumethiazide; Nadolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Benzodiazepines: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used with other drugs with moderate to significant anticholinergic effects including clozapine.
    Benzphetamine: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Benztropine: (Moderate) Additive anticholinergic effects may be seen when benztropine is used concomitantly with other drugs that possess anticholinergic properties, such as clozapine. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
    Bepridil: (Major) Bepridil is associated with a well-established risk of QT prolongation and torsades de pointes and should be used cautiously in combination with other drugs that may also prolong the QT interval, including clozapine.
    Beta-adrenergic blockers: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Betaxolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Bethanechol: (Moderate) Drugs that possess antimuscarinic properties, such as clozapine, are pharmacologic opposites of bethanechol. These agents should not be used with bethanechol except when the specific intent is to counteract excessive actions of one or the other.
    Bevacizumab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Bexarotene: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include clozapine.
    Bismuth Subsalicylate: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of clozapine may produce additive effects.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include clozapine. (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of clozapine may produce additive effects.
    Bisoprolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Blinatumomab: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Boceprevir: (Moderate) Caution is advisable during concurrent use of boceprevir and clozapine. Boceprevir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Bortezomib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Bosentan: (Moderate) Concomitant use of clozapine and bosentan can increase the risk and severity of hypotension by potentiating the effect of bosentan; monitor for hypotension. In addition, bosentan is an inducer of CYP3A4 and clozapine is partially metabolized by this isoenzyme. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP3A4 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
    Bosutinib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Brentuximab vedotin: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Brexpiprazole: (Major) Caution is advisable during concurrent use of brexpiprazole with other antipsychotics such as clozapine. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary.
    Brigatinib: (Moderate) Monitor for decreased efficacy of clozapine if coadministration with brigatinib is necessary; consider increasing the dose of clozapine if clinically indicated. Clozapine is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of clozapine may decrease.
    Brimonidine; Timolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Bromocriptine: (Moderate) The prolactin-lowering effect of bromocriptine at the anterior pituitary may be antagonized by medications that increase prolactin levels, such as the atypical antipsychotics. The atypical antipsychotics elevate prolactin to various degrees. Like other drugs that antagonize dopamine D2 receptors, the elevation in prolactin from atypical antipsychotics can persist during chronic administration. Monitor the patient for reduced response to bromocriptine.
    Brompheniramine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Brompheniramine; Pseudoephedrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Budesonide; Formoterol: (Moderate) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with clozapine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Bumetanide: (Major) Caution is advisable during concurrent use of clozapine and loop diuretics. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Concurrent use of clozapine and medications known to cause electrolyte imbalance may increase the risk of QT prolongation.
    Buprenorphine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of clozapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clozapine has a possible risk for QT prolongation and 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. If concurrent use of clozapine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of clozapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clozapine has a possible risk for QT prolongation and 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. If concurrent use of clozapine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Buspirone: (Moderate) The combination of buspirone and CNS depressants like the antipsychotics can increase the risk for drowsiness, sedation, and dizziness.
    Butabarbital: (Moderate) Patients on certain anticonvulsant therapies should receive clozapine with caution. Clozapine may interact with anticonvulsants in several ways; concurrent use of clozapine in patients on antiepileptic medications is not recommended in seizures that are not well controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures; dosage adjustments of clozapine should be cautious. CYP1A2, CYP3A4, and CYP2D6 isoenzymes metabolize clozapine; anticonvulsant drugs known to induce one or more of these isoenzymes include barbiturates. Clinicians should monitor for reduced clozapine effectiveness during concurrent use of anticonvulsants that are weak to moderate CYP inducers. Additive sedation may be noted initially with concurrent clozapine and barbiturate use; enzyme induction by barbiturates takes several days to become clinically apparent.
    Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants, such as clozapine, can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation.
    Cabergoline: (Major) The prolactin-lowering effect of cabergoline may be antagonized by medications that increase prolactin levels such as the antipsychotic drugs. In addition, cabergoline is a dopamine agonist and may diminish the effectiveness of dopamine antagonists such as the antipsychotics.
    Cabozantinib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Caffeine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment. (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
    Caffeine; Ergotamine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
    Camptothecin analogs: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Canagliflozin: (Moderate) Patients taking canagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Canagliflozin; Metformin: (Moderate) Patients taking canagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. (Moderate) Patients taking metformin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. Temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Capsaicin; Metaxalone: (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Carbamazepine: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as carbamazepine, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Carbamazepine may also increase the metabolism of clozapine through induction of CYP1A2. Both agents have myelosuppressive properties; patients should be monitored for and instructed about symptoms of infection. Lastly, close monitoring is recommended when clozapine is administered to patients with a seizure disorder because clozapine lowers the seizure threshold. The effectiveness of carbamazepine in treating seizures may be reduced. Dosage adjustments may be necessary and close monitoring is warranted when carbamazepine is used with clozapine.
    Carbetapentane; Chlorpheniramine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant, which may be additive with other medications having anticholinergic effects such as diphenhydramine. Clozapine may also cause additive sedation with diphenhydramine. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.
    Carbidopa; Levodopa: (Major) Antipsychotic agents may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain. In general, however, the 'atypical antipsychotics' are less likely to interfere with these therapies than traditional antipsychotic agents (e.g., phenothiazines). Antipsychotics should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments. In general, experts consider quetiapine the atypical antipsychotic of choice in Parkinson's patients due to a lower incidence of extrapyramidal symptoms, although the choice of antipsychotic medication must always be made on a case-by-case decision.
    Carbidopa; Levodopa; Entacapone: (Major) Antipsychotic agents may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain. In general, however, the 'atypical antipsychotics' are less likely to interfere with these therapies than traditional antipsychotic agents (e.g., phenothiazines). Antipsychotics should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments. In general, experts consider quetiapine the atypical antipsychotic of choice in Parkinson's patients due to a lower incidence of extrapyramidal symptoms, although the choice of antipsychotic medication must always be made on a case-by-case decision. (Major) Atypical antipsychotics are central dopamine antagonists and may inhibit the clinical response to antiparkinsonian agents with dopamine agonist properties by blocking dopamine receptors in the brain. Due to the CNS depressant effects of atypical antipsychotics, additive drowsiness may occur with Parkinson's treatments like entacapone or tolcapone. In general, atypical antipsychotics are less likely to interfere with these therapies than traditional antipsychotic agents.
    Carbinoxamine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Carbinoxamine; Phenylephrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Carbinoxamine; Pseudoephedrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Carboplatin: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Carfilzomib: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Carisoprodol: (Moderate) Skeletal muscle relaxants should be combined cautiously with clozapine because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Carmustine, BCNU: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Carteolol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Carvedilol: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Central-acting adrenergic agents: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Ceritinib: (Major) Monitor for clozapine-related adverse reactions (e.g., life-threatening arrhythmias, sedation, anticholinergic effects, seizures, and orthostasis) if coadministration with ceritinib is necessary; a dosage adjustment may be necessary. Periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. If ceritinib is discontinued after dose adjustments are made, monitor for decreased efficacy of clozapine and consider increasing the dose if necessary. Ceritinib is a CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. Clozapine is metabolized by CYP3A4 and has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Cetrorelix: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers such as dexchlorpheniramine. Clozapine may also cause additive sedation with these drugs.
    Chlorambucil: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Chloramphenicol: (Moderate) Caution is advisable during concurrent use of chloramphenicol and clozapine. Chloramphenicol is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Chlorcyclizine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlordiazepoxide: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Chlordiazepoxide; Clidinium: (Moderate) Clozapine exhibits anticholinergic effects that may be enhanced when combined with other antimuscarinics. (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Chloroquine: (Major) Coadminister chloroquine with other drugs known to prolong the QT interval, such as clozapine, with caution. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
    Chlorpheniramine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Codeine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
    Chlorpheniramine; Dextromethorphan: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Pain medications such as dihydrocodeine, should be combined cautiously with clozapine due to the potential for additive depressant effects and possible respiratory depression or hypotension. Concurrent use of clozapine and opiates may also lead to reduced intestinal motility or bladder function.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Pain medications such as dihydrocodeine, should be combined cautiously with clozapine due to the potential for additive depressant effects and possible respiratory depression or hypotension. Concurrent use of clozapine and opiates may also lead to reduced intestinal motility or bladder function.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Chlorpheniramine; Hydrocodone: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Chlorpheniramine; Phenylephrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpromazine: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). In addition, coadministration of clozapine with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
    Cimetidine: (Moderate) Caution is advisable during concurrent use of cimetidine and clozapine. Cimetidine is an inhibitor of CYP3A4, CYP2D6, and CYP1A2, the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, 2D6, or 3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4, CYP2D6, or CYP1A2 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cinacalcet: (Moderate) Caution is advisable during concurrent use of cinacalcet and clozapine. Cinacalcet is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Ciprofloxacin: (Major) If co-administration of clozapine and a potent inhibitor of CYP1A2 such as ciprofloxacin is necessary, the manufacturer of clozapine recommends using one-third of the usual clozapine dose. If the inhibitor is discontinued, increase the clozapine dose based on clinical response. One study of 7 schizophrenic patients has shown that concurrent therapy with ciprofloxacin (250 mg twice daily) versus placebo resulted in increased clozapine plasma concentrations (29%) and N-desmethylclozapine plasma concentrations (31%). One case study has reported elevated clozapine plasma concentrations (by 80%) during ciprofloxacin coadministration at doses of 500 mg twice daily. In addition, rare cases of QT prolongation and torsade de pointes (TdP) have been reported with both ciprofloxacin and clozapine. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP3A4, or CYP2D6 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. If quinolone administration is indicated during clozapine therapy, an alternative fluoroquinolone with minimal inhibitory effects on CYP1A2, CYP2D6, or CYP3A4 should be considered.
    Cisapride: (Severe) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Because of the potential for TdP, use of cisapride with clozapine is contraindicated.
    Cisplatin: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Citalopram: (Major) Concurrent use of clozapine and citalopram should be avoided if possible. Citalopram causes dose-dependent QT interval prolongation and clozapine is associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. According to the manufacturer of citalopram, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. However, if concurrent therapy is considered essential, ECG monitoring is recommended. In addition, citalopram is a weak inhibitor of CYP2D6, and increased plasma concentrations of antipsychotics partially metabolized via CYP2D6, such as clozapine, may occur. A reduced dosage of clozapine should be considered when clozapine is combined with CYP2D6 inhibitors, due to a decrease in clozapine metabolism and a potential for clozapine-related adverse effects, such as orthostatic hypotension, seizures, or adverse cardiac effects.
    Clarithromycin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with clozapine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. In addition, clarithromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Clemastine: (Moderate) Clozapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using the antimuscarinics or other medications with anticholinergic activity in combination with clozapine. Some medications that exhibit additive anticholinergic effects include sedating H1-blockers. Clozapine may also cause additive sedation with many of these drugs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Clobazam: (Moderate) Clobazam, an inhibitor of CYP2D6, may reduce the metabolism of CYP2D6 substrates, such as aripiprazole, paliperidone, iloperidone, and olanzapine. In addition, benzodiazepines such as clobazam should be combined cautiously with antipsychotics because of the potential for additive CNS depressant effects, and reduced effectiveness of clobazam as an anticonvulsant due to the possible lowering of the seizure threshold by antipsychotics.
    Clofarabine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Clonazepam: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Clorazepate: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Cobicistat: (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Codeine: (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
    Codeine; Guaifenesin: (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
    Codeine; Phenylephrine; Promethazine: (Major) Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Promethazine is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine; elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Coadministration of promethazine and clozapine may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, or other side effects. Monitor for adverse reactions if use together is not avoidable. Consideration should be given to reducing the clozapine dose if necessary. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
    Codeine; Promethazine: (Major) Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Promethazine is an inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of clozapine; elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Coadministration of promethazine and clozapine may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, or other side effects. Monitor for adverse reactions if use together is not avoidable. Consideration should be given to reducing the clozapine dose if necessary. (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
    COMT inhibitors: (Major) Atypical antipsychotics are central dopamine antagonists and may inhibit the clinical response to antiparkinsonian agents with dopamine agonist properties by blocking dopamine receptors in the brain. Due to the CNS depressant effects of atypical antipsychotics, additive drowsiness may occur with Parkinson's treatments like entacapone or tolcapone. In general, atypical antipsychotics are less likely to interfere with these therapies than traditional antipsychotic agents.
    Conivaptan: (Moderate) Caution is advisable during concurrent use of conivaptan and clozapine. Conivaptan is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Crizotinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of clozapine with crizotinib is necessary. An increase in clozapine-related adverse reactions (e.g., life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis) may also occur; consider a dose reduction if necessary. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Clozapine is a CYP3A4 substrate that has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Crizotinib is a moderate CYP3A inhibitor that has also been associated with concentration-dependent QT prolongation.
    Cyclobenzaprine: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation such as cyclobenzaprine. Cyclobenzaprine is associated with a possible risk of QT prolongation and torsades de pointes (TdP), particularly in the event of acute overdose, and should be used cautiously with other drugs with a possible risk of QT prolongation and TdP such as clozapine. In addition, cyclobenzaprine possesses antimuscarinic properties, which can cause dry mouth, urinary difficulties and slowing of gastrointestinal motility. If used with other drugs with antimuscarinic properties, such as clozapine, anticholinergic side effects can be additive. Particular attention should be paid to GI problems because of the possible development of paralytic ileus.
    Cyclophosphamide: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cyproheptadine: (Moderate) Clozapine exhibits anticholinergic effects that may be additive with other medications exhibiting anticholinergic effects, such as cyproheptadine. Clozapine may also cause additive sedation with this sedating H-1 blocker. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Dalfopristin; Quinupristin: (Moderate) Caution is advisable during concurrent use of dalfopristin; quinupristin and clozapine. Dalfopristin; quinupristin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Danazol: (Moderate) Caution is advisable during concurrent use of danazol and clozapine. Danazol is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Dantrolene: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
    Dapagliflozin: (Moderate) Patients taking dapagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Dapagliflozin; Metformin: (Moderate) Patients taking dapagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported. (Moderate) Patients taking metformin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. Temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.
    Dapagliflozin; Saxagliptin: (Moderate) Patients taking dapagliflozin should be closely monitored for worsening glycemic control when an atypical antipsychotic is instituted. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanism