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Clozapine: Drug information

Clozapine: Drug information
(For additional information see "Clozapine: Patient drug information" and see "Clozapine: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Special Alerts
FDA Temporarily Suspends Certain Clozapine REMS November 2021

The FDA has temporarily suspended certain clozapine Risk Evaluation and Mitigation Strategy (REMS) program requirements because of problems with implementation and the potential impact to patient care. Pharmacists may dispense clozapine without a REMS dispense authorization, and wholesalers may continue to ship clozapine to pharmacies and health care settings without confirming enrollment in the REMS. Abrupt discontinuation of clozapine can result in significant complications for patient treatment. Health care providers should use their clinical judgement with regard to prescribing and dispensing clozapine to patients with an absolute neutrophil count within the acceptable range.

Further information may be found at https://www.fda.gov/drugs/drug-safety-and-availability/fda-temporarily-suspending-certain-clozapine-rems-program-requirements-ensure-continuity-care.

Clozapine REMS Requirements Updated July 2021

The FDA has approved a modification to the Clozapine Risk Evaluation and Mitigation Strategy (REMS). Beginning November 15, 2021, new requirements will go into effect. Key changes including the following:

  • Pharmacies will no longer be able to use the telecommunication verification (the switch system) to verify safe use conditions for clozapine. The authorization to dispense clozapine can be obtained either through the contact center or online via the REMS website.

  • Pharmacists will have to go to www.clozapineREMS.com or call the Clozapine Call Center (888-586-0758) to verify information and obtain a REMS dispense authorization to dispense clozapine.

  • New Patient Status Form to document monitoring for all outpatients. This form must be submitted monthly.

  • Patient monitoring must still continue per the prescribing information.

  • All prescribers and pharmacies must be recertified by November 15, 2021, or they will no longer be able to prescribe/dispense clozapine.

  • Prescribers must re-enroll their patients who will continue clozapine by November 15, 2021. Patients who are not re-enrolled by that date will no longer be able to receive clozapine. Recertification and re-enrollment can begin on August 16, 2021.

  • To recertify and re-enroll in the Clozapine REMS, please see the Important Program Update at www.clozapineREMS.com.

For more information on the changes to the clozapine REMS that take effect on November 15, 2021, please see the updated CDER Statement, CDER Questions and Answers, and the Clozapine REMS website.

REMS Drugs COVID-19 Safety Alert March 2020

Due to challenges with completion of required laboratory testing or imaging studies for REMS drugs because of self-isolation or quarantine during the COVID-19 public health emergency, the FDA is recommending health care providers prescribing and/or dispensing REMS drugs consider whether there are compelling reasons or not to complete these requirements during this public health emergency and weigh with the patient the benefits and risks of continuing treatment in the absence of the laboratory testing and imaging studies. The FDA will not take action against sponsors and others during the public health emergency for failing to adhere to REMS requirements.

Further information may be found at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-provides-update-patient-access-certain-rems-drugs-during-covid-19.

ALERT: US Boxed Warning
Severe neutropenia:

Clozapine treatment has caused severe neutropenia, defined as an absolute neutrophil count (ANC) less than 500/mm3. Severe neutropenia can lead to serious infection and death. Prior to initiating treatment, a baseline ANC must be at least 1,500/mm3 for the general population and must be at least 1,000/mm3 for patients with documented Benign Ethnic Neutropenia. During treatment, patients must have regular ANC monitoring. Advise patients to immediately report symptoms consistent with severe neutropenia or infection (eg, fever, weakness, lethargy, sore throat).

Because of the risk of severe neutropenia, clozapine is available only through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program.

Orthostatic hypotension, bradycardia, syncope:

Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with treatment. The risk is highest during the initial titration period, particularly with rapid dose escalation. These reactions can occur with the first dose, with dosages as low as 12.5 mg/day. Initiate treatment at 12.5 mg once or twice daily, titrate slowly, and use divided dosages. Use cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (eg, dehydration, use of antihypertensive medications).

Seizures:

Seizures have occurred with treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering to patients with a history of seizures or other predisposing risk factors for seizure (CNS pathology, medications that lower the seizure threshold, alcohol abuse). Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others.

Myocarditis, cardiomyopathy and mitral valve incompetence:

Fatal myocarditis and cardiomyopathy have occurred with treatment. Discontinue clozapine and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with clozapine-related myocarditis or cardiomyopathy should not be rechallenged with clozapine. Consider the possibility of myocarditis or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or electrocardiogram (ECG) changes occur.

Increased mortality in elderly patients with dementia-related psychosis:

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Clozapine is not approved for use in patients with dementia-related psychosis.

Brand Names: US
  • Clozaril;
  • FazaClo [DSC];
  • Versacloz
Brand Names: Canada
  • AA-Clozapine;
  • Clozaril;
  • GEN-Clozapine
Pharmacologic Category
  • Second Generation (Atypical) Antipsychotic
Dosing: Adult

Note: Prior to initiating treatment, obtain a baseline ANC; the ANC must be ≥1,500/mm3 for the general population and ≥1,000/mm3 for patients with documented benign ethnic neutropenia in order to initiate treatment. To continue treatment, the ANC must be monitored regularly. Laboratory hematology results may be presented in different units; 1 mcL equals 1 mm3. Due to risks for GI hypomotility, consider concomitant use of preventative treatments (high-fiber diet, exercise, fluids, laxatives) for constipation (Cohen 2017; Every-Palmer 2016). The manufacturer recommends twice-daily dosing to minimize the risk of adverse effects, and in some efficacy studies, total daily dosage was administered in 3 divided doses; however, once the dose is stabilized, once-daily dosing may be tolerated in some patients and is generally given at bedtime to avoid daytime sedation (Takeuchi 2016).

Agitation/aggression and psychosis associated with dementia, severe or refractory (alternative agent) (off-label use):

Note: For short-term use while addressing underlying causes of severe symptoms. Patients with dementia with Lewy bodies are at increased risk for severe adverse reactions; caution is required even with low doses (APA [Reus 2016]).

Oral: Initial: 6.5 to 12.5 mg at bedtime; increase by 12.5 mg every 3 to 5 days as needed based on response and tolerability (given as divided doses in the morning and at bedtime); mean doses of 60 mg/day have been studied (Lee 2007; Teodorescu 2018). In patients without a clinically significant response after 4 weeks, taper and withdraw therapy. In patients with an adequate response, attempt to taper and withdraw therapy within 4 months, unless symptoms recurred with a previous taper attempt. Assess symptoms at least monthly during taper and for at least 4 months after withdrawal of therapy (APA [Reus 2016]).

Bipolar disorder, treatment resistant (off-label use):

Acute mania (monotherapy or adjunctive therapy): Oral: Initial: 25 mg daily; increase daily dose based on response and tolerability in 25 mg increments at intervals ≥1 day to a maximum dose of 550 mg/day. Usual daily dose ~100 to 300 mg/day (CANMAT/ISBD [Yatham 2018]; Green 2000; Li 2015; WFSBP [Grunze 2009]).

Maintenance treatment (monotherapy or adjunctive therapy): Continue dose and combination regimen that was used to achieve control of the acute episode (CANMAT [Yatham 2018]; WFSBP [Grunze 2009]).

Psychosis in Parkinson disease (off-label use): Oral: Initial: 6.25 mg/day, in 1 or 2 divided doses; increase daily dose based on response and tolerability in 6.25 or 12.5 mg increments at intervals of 3 to 7 days to a maximum dose of 50 mg/day (Morgante 2004; Parkinson Study Group 1999; Pollack 2004).

Schizophrenia: Oral: Initial: 12.5 mg once or twice daily; increase daily dose, as tolerated, in increments of 25 to 50 mg at intervals ≥1 day to a target dose of 300 to 450 mg/day by the end of 2 weeks; may further titrate in increments not exceeding 100 mg and no more frequently than once or twice weekly. Maximum total daily dose: 900 mg (manufacturer's labeling).

Suicidal behavior in schizophrenia or schizoaffective disorder: Oral: Initial: 12.5 mg once or twice daily; increase daily dose, as tolerated, in increments of 25 to 50 mg daily to a target dose of 300 to 450 mg daily (administered in divided doses) by the end of 2 weeks; may further titrate in increments not exceeding 100 mg and no more frequently than once or twice weekly. Mean dose is ~300 mg daily; maximum total daily dose: 900 mg.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Reinitiation of therapy: If dosing is interrupted for ≥48 hours, therapy must be reinitiated at 12.5 mg once or twice daily to minimize the risk of hypotension, bradycardia, and syncope; if dose is well tolerated, may be increased more rapidly than with initial titration, unless cardiopulmonary arrest occurred during initial titration, then retitrate with extreme caution.

Discontinuation of therapy: In the treatment of chronic psychiatric disease, switching therapy rather than discontinuation is generally advised if side effects are intolerable or treatment is not effective. If patient insists on stopping treatment, in general, gradual dose reduction (ie, over several weeks to months) is advised to detect a re-emergence of symptoms and to avoid withdrawal reactions (eg, agitation, alternating feelings of warmth and chill, anxiety, diaphoresis, dyskinesias, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, vertigo) unless discontinuation is due to significant adverse effects; the manufacturer recommends reducing the clozapine dose gradually over a period of 1 to 2 weeks if termination of therapy is not related to neutropenia. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (APA [Keepers 2020]; Lambert 2007; Moncrieff 2020; Post 2020).

Switching antipsychotics: An optimal universal strategy for switching antipsychotic drugs has not been established. Strategies include: cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). In patients with schizophrenia at high risk of relapse, the current medication may be maintained at full dose as the new medication is increased (ie, overlap); once the new medication is at therapeutic dose, the first medication is gradually decreased and discontinued over 1 to 2 weeks (Cerovecki 2013; Remington 2005; Takeuchi 2017). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Stroup 2020).

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; however, labeling suggests that dose reductions may be necessary with significant impairment but does not provide specific dosing recommendations. Alternatively, an initial dose of 12.5 mg once daily has been recommended for patients with mild to moderate impairment (Clozaril Canadian product labeling).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; however, labeling suggests that dose reductions may be necessary with significant impairment.

Dosing: Pediatric

(For additional information see "Clozapine: Pediatric drug information")

Note: Obtain a baseline CBC, including the ANC. In order to initiate treatment, minimum baseline ANC values must be met; for the general population, the ANC must be ≥1,500/mm3 and for patients with documented benign ethnic neutropenia, the ANC must be ≥1,000/mm3. Laboratory hematology results may be presented in different units; 1 mcL equals 1 mm3. The ANC must be monitored regularly with continued treatment. Due to risks for gastrointestinal hypomotility, consider concomitant use of preventative treatments (high fiber diet, exercise, fluids, laxatives) for constipation (Cohen 2017; Every-Palmer 2016). Titration to the lowest effective dose should be used to minimize potential adverse effects (see "Adverse Reactions [Significant]: Considerations") including seizures (clozapine may decrease seizure threshold) (Findling 2005; Findling 2007).

Schizophrenia; treatment resistant: Limited data available: Note: Dose should be individualized based on tolerability, concomitant antipsychotic therapy, and clinical response.

Initial dose:

Children ≥6 years: Oral: 6.25 or 12.5 mg once daily.

Adolescents: Oral: 12.5 mg once or twice daily.

Titration and maintenance dosing: Increase daily dose by ≤25 mg increments (lower initial doses should use smaller increments [1 to 2 times the starting dose]), as tolerated, every 3 to 5 days, to a target dose of 200 to 400 mg/day in divided doses. Dose may be divided, with a higher dose at bedtime; if excessive daytime sedation, entire dose may be at bedtime (Findling 2007; Kumar 2013; Kumra 1996; Kumra 2008; Schneider 2014). Mean effective dose range in most pediatric studies: 220 to 431 mg/day (Schneider 2014).

Reinitiation of therapy: Based on experience in adult patients, if dosing is interrupted for ≥48 hours, therapy must be reinitiated at initial doses to minimize the risk of hypotension, bradycardia, and syncope; if dose is well tolerated, may be increased more rapidly than with initial titration, unless cardiopulmonary arrest occurred during initial titration, then retitrate with extreme caution.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Discontinuation of therapy: Children and Adolescents: In adults, the manufacturer recommends reducing the dose gradually over a period of 1 to 2 weeks if termination of therapy is not related to neutropenia. The American Academy of Child and Adolescent Psychiatry (AACAP), American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), National Institute for Health and Care Excellence (NICE), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (AACAP [McClellan 2007]; APA [Lehman 2004]; Cerovecki 2013; CPA 2005; NICE 2013; WFSBP [Hasan 2012]); risk for withdrawal symptoms may be highest with highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). When stopping antipsychotic therapy in patients with schizophrenia, the CPA guidelines recommend a gradual taper over 6 to 24 months and the APA guidelines recommend reducing the dose by 10% each month (APA [Lehman 2004]; CPA 2005). Continuing antiparkinsonism agents for a brief period after discontinuation may prevent withdrawal symptoms (Cerovecki 2013). When switching antipsychotics, three strategies have been suggested: Cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic), overlap and taper (maintaining the dose of the first antipsychotic while gradually increasing the new antipsychotic, then tapering the first antipsychotic), and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). Evidence supporting ideal switch strategies and taper rates is limited and results are conflicting (Cerovecki 2013; Remington 2005).

Dosing: Kidney Impairment: Pediatric

All patients: There are no dosage adjustments provided in the manufacturer's labeling; however, labeling suggests that dose reductions may be necessary with significant impairment but does not provide specific dosing recommendations.

Dosing: Hepatic Impairment: Pediatric

All patients: There are no dosage adjustments provided in the manufacturer's labeling; however, labeling suggests that dose reductions may be necessary with significant impairment.

Dosing: Older Adult

Note: Prior to initiating treatment, obtain a baseline ANC; the ANC must be ≥1,500/mm3 for the general population and ≥1,000/mm3 for patients with documented Benign Ethnic Neutropenia (BEN) in order to initiate treatment. To continue treatment, the ANC must be monitored regularly. Laboratory hematology results may be presented in different units; 1 mcL equals 1 mm3. Due to risks for GI hypomotility, consider concomitant use of preventative treatments (high-fiber diet, exercise, fluids, laxatives) for constipation (Cohen 2017; Every-Palmer 2016).

Schizophrenia: Oral: Experience in the elderly is limited; may initiate with 12.5 mg once daily for 3 days, then increase to 25 mg once daily for 3 days as tolerated; may further increase, as tolerated, in increments of 12.5 to 25 mg daily every 3 days to desired response, up to 700 mg/day (mean dose: 300 mg/day) (Howanitz 1999; Pridan 2015). Dosages in the lower range of recommended adult dosing are generally sufficient for patient with late-onset schizophrenia or psychosis (Howard 2000).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Suspension, Oral:

Versacloz: 50 mg/mL (100 mL) [contains methylparaben sodium, propylparaben sodium]

Tablet, Oral:

Clozaril: 25 mg [contains corn starch]

Clozaril: 50 mg [scored; contains corn starch]

Clozaril: 100 mg, 200 mg [contains corn starch]

Generic: 25 mg, 50 mg, 100 mg, 200 mg

Tablet Disintegrating, Oral:

FazaClo: 12.5 mg [DSC], 25 mg [DSC], 100 mg [DSC], 150 mg [DSC], 200 mg [DSC] [contains aspartame]

Generic: 12.5 mg, 25 mg, 100 mg, 150 mg, 200 mg

Generic Equivalent Available: US

May be product dependent

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Clozaril: 25 mg, 50 mg, 100 mg, 200 mg

Generic: 25 mg, 50 mg, 100 mg, 200 mg

Prescribing and Access Restrictions

Canada: Currently, there are multiple manufacturers that distribute clozapine and each manufacturer has its own registry and distribution system. Patients must be registered in a database that includes their location, prescribing physician, testing laboratory, and dispensing pharmacist before using clozapine. Patients may not be switched from one brand of clozapine to another without completion of a new registry-specific patient registration form by signed by the prescribing physician. Information specific to each monitoring program is available from the individual manufacturers.

Administration: Adult

Oral: Administer without regard to food. Total daily dose may be divided into uneven doses with larger dose administered at bedtime.

Orally disintegrating tablet: Remove from foil blister by peeling apart (do not push tablet through the foil). Remove immediately prior to use. Place tablet in mouth and chew or allow to dissolve; swallow with saliva. If dosing requires splitting tablet, throw unused portion away.

Suspension: Shake bottle prior to use. Using syringe adaptor and oral syringe provided withdrawal dose from bottle. Administer immediately after preparation using the oral syringe provided.

Administration: Pediatric

Oral: May be administered without regard to food. Total daily dose may be divided into uneven doses with larger dose administered at bedtime.

Orally-disintegrating tablet: Immediately prior to use, gently remove the tablet from the bottle or blister package by peeling the foil from the blister (do not push tablet through the foil). Upon removing, place tablet in mouth; it may be allowed to dissolve, chewed, or swallowed with saliva (no water is needed). If dosing requires splitting tablet, throw unused portion away.

Oral suspension: Oral syringes, a bottle neck adaptor should be provided. Appropriate syringe size dependent upon dose: Use the 1-mL syringe for doses ≤50 mg and the 9-mL syringe for doses >50 mg.

Shake the bottle for 10 seconds, then remove the cap. For the first use of the bottle, after removing the cap, push the adaptor into the top of the bottle. Once dose is withdrawn from the bottle, it should be administered immediately and not stored for later use. After use, re-cap the bottle and rinse the syringe with water.

Use: Labeled Indications

Schizophrenia, treatment resistant: Treatment of severely ill patients with schizophrenia who fail to respond adequately to antipsychotic treatment.

Suicidal behavior in schizophrenia or schizoaffective disorder: To reduce the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for reexperiencing suicidal behavior, based on history and recent clinical state.

Use: Off-Label: Adult

Agitation/aggression and psychosis associated with dementia, severe or refractory; Bipolar disorder (treatment resistant); Psychosis in Parkinson disease

Medication Safety Issues
Sound-alike/look-alike issues:

CloZAPine may be confused with clonazePAM, cloNIDine, KlonoPIN

Clozaril may be confused with Clinoril, Colazal

Geriatric Patients: High-Risk Medication:

Beers Criteria: Antipsychotics are identified in the Beers Criteria as potentially inappropriate medications to be avoided in patients 65 years and older due to an increased risk of cerebrovascular accidents (stroke) and a greater rate of cognitive decline and mortality in patients with dementia. Antipsychotics may be appropriate for schizophrenia, bipolar disorder, other mental health conditions or short-term use as antiemetic during chemotherapy but should be given in the lowest effective dose for the shortest duration possible. In addition, antipsychotics should be used with caution in older adults due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults (Beers Criteria [AGS 2019]).

Adverse Reactions (Significant): Considerations
Anticholinergic effects

Anticholinergic activity of clozapine at usual therapeutic doses is considered to be high, relative to other second-generation antipsychotics and may lead to nonadherence (Ref). Peripheral anticholinergic effects include blurred vision, xerostomia, urinary retention, tachycardia, and constipation (potentially resulting in severe and potentially fatal complications such as intestinal obstruction and ileus). Central anticholinergic effects may result in cognitive dysfunction, including confusion, new-onset delirium, and an increased risk of falling, particularly in older adults. However, there are conflicting data on the cognitive effects of clozapine with some studies showing a beneficial effect (Ref).

Mechanism: Dose-related; believed to be mediated primarily through antagonism at muscarinic receptors (Ref). In addition, some anticholinergic effects are also potentiated by other pathways, such as clozapine's antiadrenergic effects contributing to urinary retention potential and clozapine’s antagonism of serotonin receptors in GI smooth muscle contributing to constipation potential (Ref). Cognitive effects may also be further mediated by clozapine-induced D2 blockade and by differences in plasma concentration ratios of clozapine and its major metabolite, N-desmethylclozapine (NDMC), with some evidence suggesting that NDMC may be associated with cognitive improvement (Ref).

Risk factors:

Variable and dependent upon:

• Total cumulative anticholinergic burden (Ref)

• Baseline cognitive function (Ref)

• Comorbidities (Ref)

• Older adults (Ref)

• Interindividual variability of the pharmacokinetic and pharmacodynamic parameters (Ref)

Dyslipidemia

Clozapine is strongly associated with dyslipidemia, which is a component of the metabolic syndrome observed with this pharmacologic class. Dyslipidemia observed with clozapine primarily manifests as hypercholesterolemia and/or hypertriglyceridemia (Ref). A 10-year naturalistic study of clozapine-treated adult patients suggested an increased risk of mortality from cardiovascular disease (CVD) secondary to disorders such as obesity, diabetes, hypertension, and hyperlipidemia; however, patients with schizophrenia have a higher risk of CVD than the general population due to lifestyle habits (eg, smoking, physical inactivity, unhealthy diet), regardless of medication use (Ref).

Mechanism: The mechanism is not entirely understood and is likely multifactorial (Ref).

Onset: Varied; metabolic alterations from antipsychotics can develop in as short as 3 months after initiation (Ref).

Risk factors:

• Family history of hyperlipidemia (Ref)

• Schizophrenia (regardless of medication use) is associated with a higher rate of morbidity/mortality compared to the general population primarily due to CVD (Ref)

• Higher doses (potential risk factor). Note: Conflicting data exist on a correlation between clozapine levels and triglycerides or cholesterol; however, higher clozapine levels have been associated with an increased risk for metabolic syndrome in general (clozapine levels 1.5 times higher in patients with metabolic syndrome compared to those without) (Ref)

• Specific antipsychotic: Risk of dyslipidemia and overall metabolic disturbances appears to be high with clozapine (Ref)

Extrapyramidal symptoms

Clozapine may cause extrapyramidal symptoms (EPS), also known as drug-induced movement disorders, but EPS is typically rare or uncommon in adults treated with therapeutic doses of clozapine compared to first-generation (conventional) antipsychotics, and in some studies, has been equal to or less than the control group. Incidence may be higher in children and adolescents, particularly with akathisia (Ref); however, some limited evidence is conflicting (Ref). Antipsychotics can cause four main extrapyramidal reactions: Acute dystonia, drug-induced parkinsonism, akathisia, and tardive dyskinesia. Of these, clozapine is very rarely associated with acute dystonia or dyskinesia (acute or tardive) and some clinicians use a switch to clozapine to mitigate tardive dyskinesia induced by other antipsychotics (Ref). EPS presenting as dysphagia, esophageal dysmotility, or pulmonary aspiration have also been reported with antipsychotics which may not be recognized as EPS. Clozapine has been the sole antipsychotic in several of these case reports, although it is unknown the role and to what degree clozapine-induced EPS, -sialorrhea, and/or -anticholinergic properties may have contributed (Ref).

Mechanism: EPS: Dose-related; due to antagonism of dopaminergic D2 receptors in nigrostriatal pathways (Ref); however, compared to other antipsychotics, clozapine has a much lower affinity for D2 receptors and displays rapid dissociation from D2 receptors (‘fast off’ phenomenon), which may contribute to the lower propensity of clozapine for EPS development (Ref).

Onset:

Antipsychotics in general:

Acute dystonia: Rapid; in the majority of cases, dystonia usually occurs within the first 5 days after initiating antipsychotic therapy (even with the first dose, particularly in patients receiving parenteral antipsychotics) or a dosage increase (Ref).

Drug-induced parkinsonism: Varied; onset may be delayed from days to weeks, with 50% to 75% of cases occurring within 1 month and 90% within 3 months of antipsychotic initiation, a dosage increase, or a change in the medication regimen (such as adding another antipsychotic agent or discontinuing an anticholinergic medication) (Ref).

Akathisia: Varied; may begin within several days after antipsychotic initiation but usually increases with treatment duration, occurring within 1 month in up to 50% of cases, and within 3 months in 90% of cases (Ref).

Tardive dyskinesia: Delayed; symptoms usually appear after 1 to 2 years of continuous exposure to a dopamine 2 receptor antagonist and almost never before 3 months, with an insidious onset, evolving into a full syndrome over days and weeks, followed by symptom stabilization, and then a chronic waxing and waning of symptoms (Ref).

Esophageal dysfunction (associated with extrapyramidal symptoms): Varied; ranges from weeks to months following initiation (Ref).

Risk factors:

EPS (in general):

• Prior history of EPS (Ref)

• Higher doses (Ref)

• Younger age (in general, children and adolescents are usually at higher risk for EPS compared to adults) (Ref); however, some limited evidence for clozapine is conflicting (Ref)

• Specific antipsychotic: Clozapine has a very low propensity to cause EPS in adults (Ref)

Acute dystonia:

• Males (Ref)

• Young age (Ref)

Drug-induced parkinsonism:

• Females (Ref)

• Older patients (Ref)

Akathisia:

• Higher antipsychotic dosages (Ref)

• Polypharmacy (Ref)

• Mood disorders (Ref)

• Females (Ref)

• Older patients (Ref)

Tardive dyskinesia: Note: It is unlikely that clozapine causes tardive dyskinesia (Ref)

• Age >55 years (Ref)

• Cognitive impairment (Ref)

• Concomitant treatment with anticholinergic medications (Ref)

• Diabetes (Ref)

• Diagnosis of schizophrenia or affective disorders (Ref)

• Females (Ref)

• Greater total antipsychotic exposure (especially first-generation antipsychotics) (Ref)

• History of extrapyramidal symptoms (Ref)

• Substance misuse or dependence (Ref)

• Race (White or African descent). Note: Although early literature supported race as a potential risk factor for tardive dyskinesia (Ref), newer studies have challenged this assertion (Ref)

Esophageal dysfunction:

• Older adults (Ref)

Fever

Drug-induced fever is common with clozapine following initiation. It is usually benign, transient, and self-limiting (lasting an average of 2.5 days and resolving by day 16 even if therapy is continued). However, fever warrants further investigation to rule out other nonbenign potential causes (eg, neuroleptic malignant syndrome [NMS], severe neutropenia, infection, myocarditis, clozapine-induced hypothermia) (Ref).

Mechanism: Unknown; various underlying mechanisms have been proposed (eg, infection, mild form of NMS, allergic reaction), but recent evidence suggests that clozapine-induced fever is due to a generalized inflammatory response to the immunomodulating effects of clozapine on the cytokine system, particularly due to increased levels of interleukin-6 and C-reactive protein (Ref).

Onset: Intermediate; usually occurs in the first 3 to 4 weeks of treatment (Ref).

Risk factors:

• Titration-related (potential risk factor with dose increases >50 mg/week) (Ref). Note: Fever does not seem to be dose-related (Ref)

Gastrointestinal hypomotility

Clozapine-induced decreased gastrointestinal motility is common and may result in delayed gastric emptying, GI dysmotility (small bowel or colon), and constipation (the cardinal feature), but it may also progress to severe and potentially life-threatening events, including paralytic ileus, intestinal obstruction, gastrointestinal infarction (including ischemia), and bowel perforation. Mortality related to serious GI hypomotility events is high and may be as high as 12-fold that of agranulocytosis. Preventative measures are recommended for constipation (Ref).

Mechanism: Not been fully elucidated but has been mainly attributed to clozapine’s anticholinergic and antiserotonergic effects. Clozapine antagonizes cholinergic M1 and M3 receptors which can interfere with autonomic regulation of the intestine, inhibitor smooth muscle contraction, and slow intestinal transit. Antagonism of serotonin 5-HT2, 5-HT3, 5-HT6, and 5-HT7 receptors also play a role in GI motor and sensory functions (Ref). Antiadrenergic effects may also play a role (Ref).

Risk factors:

• Older adults (Ref)

• Concomitant use of anticholinergics (Ref)

• Higher daily doses (Ref)

Hepatic effects

Increased serum hepatic transaminases are common with use, including elevations 2 to 3 times greater than normal. Increased liver enzymes are usually transient and asymptomatic, with the majority not requiring discontinuation or a dose reduction unless elevations are persistent and/or accompanied by symptoms. However, there have been rare case reports of severe hepatotoxicity including hepatitis, acute hepatotoxicity, and fulminant hepatic failure (including fatal cases) (Ref)

Mechanism: Mechanism is unknown, although clozapine is extensively metabolized by the liver, partially via the cytochrome P450 pathway, including CYP1A2 (Ref); production of a toxic intermediate of metabolism has been suggested as a potential cause of hepatic effects (Ref).

Onset: Varied; increased transaminases usually occur within first several weeks following initiation and most resolve after 6 to 12 weeks; in the case reports describing serious hepatic events, onset is typically within a few days to several weeks (ie, 4 to 6 weeks) following initiation (Ref)

Hyperglycemia

Clozapine is strongly associated with hyperglycemia, which is a component of the metabolic syndrome observed with this pharmacologic class. Glycemic abnormalities range from mild insulin resistance to new-onset diabetes mellitus, exacerbation of diabetes mellitus, hyperosmolar coma, and diabetic ketoacidosis (DKA), including fatal cases (Ref). A 10-year naturalistic study of clozapine-treated adult patients suggested an increased risk of mortality from cardiovascular disease (CVD) secondary to disorders such as obesity, diabetes, hypertension, and hyperlipidemia; however, patients with schizophrenia have a higher risk of CVD than the general population due to lifestyle habits (eg, smoking, physical inactivity, unhealthy diet), regardless of medication use (Ref).

Mechanism: The mechanism is not entirely understood and is likely multifactorial (Ref).

Onset: Varied; new-onset diabetes has been observed within the first 3 months to a median onset of 3.9 years of antipsychotics (Ref). In a review of clozapine-associated diabetes reports, most cases of hyperglycemia appeared within 6 months of initiation (Ref). Clozapine-related DKA typically occurs early in the treatment course (Ref).

Risk factors:

• African American race (Ref)

• Males (Ref)

• Age <35 years (Ref)

• Patients with preexisting obesity, poor exercise habits, or other risk factors for diabetes, including family history of diabetes (Ref)

• Exposures to other agents that also increase the risk of hyperglycemia (Ref)

• Treatment duration (Ref)

• Specific antipsychotic: Risk of metabolic disturbances appears to be high with clozapine (Ref).

Mortality in older patients

Older adults with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature (Ref). For clozapine, several large epidemiological cohort studies in mostly schizophrenia patients have found an association between clozapine and lower all-cause mortality; however, these studies were not exclusive to older adults and the median or mean age at the start of the study ranging from 36 to 49 years of age (Ref). In a retrospective analysis of older adults >60 years of age (mean age: 70 years) with treatment-resistant schizophrenia treated with clozapine, mortality was found to be similar with clozapine compared to other first- and second-generation antipsychotics (Ref). In addition, an increased incidence of cerebrovascular effects (eg, cerebrovascular accident, transient ischemic attacks), including fatalities, have been reported in some second-generation antipsychotic placebo-controlled trials, such as risperidone and olanzapine, in older adults with dementia-related psychosis (Ref). Of note, clozapine is not approved for the treatment of dementia-related psychosis.

Mechanism: Unknown; possible mechanisms include arrhythmia, cardiac arrest, and extrapyramidal effects that may increase the risk of falls, aspiration, and pneumonia (Ref).

Risk factors:

• Higher antipsychotic dosage (Ref)

• Dementia-related psychosis

• Older adults

Myocarditis/cardiomyopathy

Clozapine-induced myocarditis, a rare/infrequent but potentially fatal adverse event, typically occurs early in the course of therapy (ie, first 1 to 2 months) with ensuing clozapine-induced cardiomyopathy typically presenting later during therapy. Clinical signs and symptoms are highly variable and range from asymptomatic to nonspecific signs such as fever, chest pain, hypotension, flu-like symptoms, eosinophilia, elevated C-reactive protein, increased troponin, ECG changes, signs of heart failure, palpitations, dyspnea, and/or sinus tachycardia. Clozapine-induced myocarditis is associated with high mortality if not recognized early; prompt therapy discontinuation is required to prevent disease progression (Ref). Cases of sudden cardiac death subsequently identified on autopsy as myocarditis with eosinophilic infiltrates have also been reported in patients newly initiated on clozapine (Ref).

Mechanism: Unclear; however, several hypotheses have been proposed for clozapine-induced cardiotoxicity, including a type 1 acute hypersensitivity reaction mediated by Ig-E, a pro-inflammatory cytokine pathway involving TNF-alpha, and a hypercatecholaminergic state contributing to increased production of free radicals and subsequent oxidative stress (Ref). A role of viral infections has also been suggested (Ref).

Onset: Varied; myocarditis usually occurs within the first 8 weeks of therapy and cardiomyopathy usually presents months or years after therapy (Ref).

Risk factors:

• Rapid titration and higher doses early in clozapine titration (potential risk factor) (Ref)

• Concomitant sodium valproate (potential risk factor) (Ref)

• Patients living in Australia or New Zealand (potential risk factor). Note: Although event rates are higher in Australia and New Zealand, it is unknown if this is due to observation bias or unidentified genetic and/or environmental factors (Ref)

Neuroleptic malignant syndrome

All antipsychotics have been associated with neuroleptic malignant syndrome (NMS), although the incidence is less with second-generation (atypical) antipsychotics compared to first-generation (typical) antipsychotics. There are case reports of NMS with clozapine, including monotherapy. Furthermore, clozapine-associated NMS may present with atypical features, such as absent or less intense rigidity, fever, and/or fewer extrapyramidal symptoms in general (Ref).

Mechanism: Non–dose-related; idiosyncratic. Believed to be due to a reduction in CNS dopaminergic tone, along with the dysregulation of autonomic nervous system activity (Ref).

Onset: Varied; in general, most patients develop NMS within 2 weeks of initiating an antipsychotic, and in some patients, prodromal symptoms emerge within hours of initiation; once the syndrome starts, the full syndrome usually develops in 3 to 5 days (Ref). However, there are many cases of NMS occurring months or even years after stable antipsychotic therapy, including clozapine treatment (Ref).

Risk factors:

Antipsychotics in general:

• Males are twice as likely to develop NMS compared to females (Ref)

• Dehydration (Ref)

• High-dose antipsychotic treatment (Ref)

• Concomitant lithium or a benzodiazepine (potential risk factors) (Ref)

• Catatonia (Ref)

• Disorganized speech or behavior (Ref)

• Polypharmacy (Ref)

• Pharmacokinetic interactions (Ref)

• IM administration of an antipsychotic (Ref)

• Rapid dosage escalation (Ref)

• Psychomotor agitation (Ref)

Orthostatic hypotension

Clozapine commonly causes significant orthostatic hypotension and accompanying reflex tachycardia, bradycardia, and dizziness in adults, particularly with rapid titration. Older adults are especially vulnerable to orthostatic hypotension, and coupled with clozapine’s sedative properties, these effects increase the risk for subsequent falling. Once the dose is stabilized, giving the full dose or the majority of the full daily dose at bedtime may help reduce risk of orthostatic hypotension. If therapy is interrupted even for a brief interval (≥2 days), therapy should be retitrated to reduce the risk of orthostatic hypotension. Of note, tachycardia, not limited to reflex tachycardia, is also common with clozapine therapy (Ref).

Mechanism: Dose-related; orthostatic hypotension is attributed to alpha-1 adrenergic receptor antagonism (Ref).

Onset: Rapid; per the manufacturer's labeling, risk of orthostatic hypotension is highest during the initial dose titration but can also occur following reinitiation of therapy after periods of interrupted therapy and/or subsequent dose increases.

Risk factors:

• Known cardiovascular diseases (history of myocardial infarction or ischemic heart disease, heart failure, or conduction abnormalities) or cerebrovascular disease

• Known predisposing conditions (eg, hypovolemia/dehydration)

• Concomitant medications that also cause or exacerbate orthostatic hypotension (eg, tricyclic antidepressants, antihypertensive medications)

• Older adults (due to reduced autonomic function) (Ref)

• Rapid dose titration (slow titration is recommended) (Ref)

• Higher doses (ie, temporarily lowering the dose may help manage orthostatic hypotension) (Ref)

QTc prolongation

Clozapine has been associated with dose-dependent prolonged QT interval on ECG. In general, clozapine’s effect on QTc prolongation is typically benign in patients without additional risk factors (Ref). The risk for torsades de pointes (TdP) is considered to be possible, but evidence supporting causality is lacking (Ref). In a review of reports of QTc prolongation and/or TdP associated with clozapine at therapeutic doses, the vast majority of QTc prolongation cases (and both the TdP cases) were confounded by concomitant risk factors (eg, comedications known to prolong the QTc interval, comorbidities). Similarly, many reports of sudden death associated with clozapine therapy occurred in a setting of potentially confounding factors (Ref). Of note, clozapine is also associated with other cardiac effects, such as myocarditis and cardiomyopathy, which may also play a role in risk for QTc prolongation and/or sudden death (Ref).

Mechanism: Dose-dependent; clozapine prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current (Ikr); however, clozapine also interacts with multiple receptors including dopamine, adrenergic, serotonin, muscarinic, and histamine, which may balance or mitigate its effect on the HERG K+ channel. Clozapine also affects heart rate which may influence QTc determination (Ref).

Risk factors:

Drug-induced QTc prolongation/TdP (in general):

• Females (Ref)

• Age >65 years (Ref)

• Structural heart disease (eg, history of myocardial infarction or heart failure with a reduced ejection fraction) (Ref)

• History of drug-induced TdP (Ref)

• Genetic defects of cardiac ion channels (Ref)

• Congenital long QT syndrome (Ref)

• Baseline QTc interval prolongation (eg, >500 msec) or lengthening of the QTc by ≥60 msec (Ref)

• Electrolyte disturbances (eg, hypokalemia, hypocalcemia, hypomagnesemia) (Ref)

• Bradycardia (Ref)

• Hepatic impairment (Ref)

• Kidney impairment (Ref)

• Co-administration of multiple medications (≥2) that prolong the QT interval or increase drug interactions that increase serum drug concentrations of QTc prolonging medications (Ref)

• Substance use (Ref)

Sedation

Sedated state (drowsiness) is common with use and may cause nonadherence, impair physical and mental abilities, and may result in subsequent falling, particularly in older adults (Ref). Most patients tolerate sedation within 6 weeks of therapy initiation; however, it may persist in many patients, particularly older adults (Ref).

Mechanism: Sedation is primarily attributed to H1 antagonism; clozapine is considered to have high affinity for H1 receptors (Ref).

Risk factors:

• Older adults (sedation may be persistent rather than transient in this population) (Ref)

• Higher doses (potential risk factor but not conclusive since a dose-reduction does not always mitigate effect) (Ref)

• Specific antipsychotic: Clozapine is considered highly sedating (Ref)

Seizures or myoclonus

Clozapine is strongly associated with dose-dependent seizure. Clozapine also commonly causes EEG pattern changes. Tonic-clonic seizure is the most commonly described seizure with clozapine use followed by myoclonic seizure and atonic seizure. Myoclonus has also been reported in several case reports (Ref).

Mechanism: Dose-dependent (although exact dose-relationship is unclear); precise mechanism is unclear, although a role of inhibiting D4 (dopamine) mesolimbic and cortical receptors has been suggested. Other possible mechanisms have been suggested, such as interactions with NMDA, GABA, and glutamate receptors (Ref).

Risk factors:

• Specific antipsychotic: Among the second-generation antipsychotics, clozapine appears to have the highest risk of seizure induction (Ref)

• Higher doses (doses >600 mg/day have been historically associated with increased risk of seizure, although seizures have been reported with doses as low as 200 to 300 mg/day) (Ref)

Antipsychotics in general:

• History of seizure activity (Ref)

• Concurrent use of drugs that lower seizure threshold (Ref)

• Rapid dose titration or sudden increase in dose (Ref)

• Slow drug metabolism (Ref)

• Metabolic factors (Ref)

• Drug-drug interactions (Ref)

• Organic brain disorders (Ref)

Severe neutropenia/agranulocytosis

Clozapine may cause severe neutropenia (ANC <500/mm3) and potentially life-threatening agranulocytosis (ANC <100/mm3) (Ref). Due to the risk, clozapine is only available under a Risk Evaluation Mitigation Strategy (REMS), and baseline and regular ANC monitoring is required. Patients with benign ethnic neutropenia are not at increased risk for developing clozapine-induced severe neutropenia and may receive clozapine, but these patients require a different ANC monitoring algorithm and frequently have ANC values in the typical neutropenia range (Ref).

Mechanism: Non–dose-related; idiosyncratic. Mechanism has not been fully elucidated, although an immune-mediated mechanism has been proposed. Clozapine has a high potential to undergo oxidate degradation and form nitrenium ion. The nitrenium ion may cause direct toxicity or stimulate an immune response following covalent binding to human leukocytes and forming an antigen (Ref).

Onset: Varied; clozapine-induced agranulocytosis typically occurs in the first 18 weeks of therapy, with a few cases developing after 6 months of use. Risk is further decreased after 1 year of treatment (Ref).

Risk factors:

• History of drug-induced neutropenia or preexisting low WBC or ANC

• Age between 40 and 59 years (Ref). Note: It has also been suggested that children and adolescents are at increased risk for neutropenia (Ref)

• Males (Ref)

• White ethnicity (Ref). Note: It has also been suggested that Asian ethnicities may be at a higher risk for agranulocytosis, and African American and Middle Eastern ethnicities may have a higher risk for benign ethnic neutropenia (Ref)

• Genetic variants of several genes (eg, HLA-DQB1 [HLA-DQB1*05:02], HLA-B alleles with a threonine at position 158 in the protein sequence [HLA-B*38,39,67], and SLCO1B3/SLCO1B7), although further studies are needed (Ref)

Sialorrhea

Clozapine-induced sialorrhea, also known as hypersalivation or drooling, is common, may be severe, and may cause nonadherence. It can occur during the daytime but is typically much worse during sleep and may result in choking sensations during the night, nighttime awakening, hoarseness or dysphonia of the voice, and a chronic cough. Clozapine-induced sialorrhea may contribute to and increase the risk of potentially life-threatening aspiration pneumonia (Ref).

Mechanism: Dose-related (potentially); mechanism is unclear although it is believed to be due to muscarinic M4 receptor agonism, alpha-2 adrenergic receptor antagonism, as well as alterations in the swallowing reflex and a decrease in laryngeal peristalsis. M1 agonism by the N-desmethylclozapine metabolite has also been postulated (Ref).

Risk factors:

• Rapid titration (titrate slowly to reduce risk)

• Higher doses (potential risk factor). Note: Conflicting evidence exists on whether this is dose-related or not; however, a dose reduction may be considered to mitigate symptoms (Ref)

• Extremes of age (may be more sensitive to complications from sialorrhea) (Ref)

Temperature dysregulation

Antipsychotics, including clozapine, may impair the body's ability to regulate core body temperature, which may cause a potentially life-threatening heatstroke during predisposing conditions such as a heat wave or strenuous exercise (Ref). There are also a numerous case reports of potentially life-threatening hypothermia associated with clozapine use (Ref).

Mechanism: Non–dose-related; idiosyncratic. Exact mechanism is unknown; however, body temperature is regulated by the hypothalamus with involvement of the dopamine, serotonin, and norepinephrine neurotransmitters. D2 antagonism may cause an increase in body temperature, while 5-HT2a (serotonin) receptor antagonism may cause a decrease in body temperature. Of note, clozapine has a stronger affinity for serotonin 5-HT2a receptors compared to D2 receptors where it displays a much lower affinity. Clozapine and its metabolite, N-desmethylclozapine, bind to many different receptors so it is also likely that other mechanisms are involved. In addition, antagonism of peripheral alpha-2 adrenergic receptors has also been suggested as a factor in the hypothermic effect by inhibiting peripheral responses to cooling (vasoconstriction and shivering) (Ref).

Onset: Hypothermia: Varied; antipsychotic-induced hypothermia cases indicate a typical onset in the period shortly after initiation of therapy or a dosage increase (first 7 to 10 days) (Ref). In clozapine hypothermia case reports, the majority occurred within the first month, but some cases have developed years after initiation (Ref).

Risk factors:

Heat stroke:

• Psychiatric illness (regardless of medication) (Ref)

• Strenuous exercise, heat exposure, and dehydration (Ref)

• Concomitant medication possessing anticholinergic effects (Ref)

Hypothermia:

• In general, predisposing risk factors include: Older age, cerebrovascular accident, preexisting brain damage, hypothyroidism, malnutrition, shock, sepsis, adrenal insufficiency, diabetes, disability, burns, exfoliative dermatitis, benzodiazepine use, alcohol intoxication, kidney or liver failure (Ref)

• Schizophrenia (regardless of antipsychotic use) (Ref)

Venous thromboembolism

Multiple cases reports and case series of deep vein thrombosis (DVT) and pulmonary embolism (PE) (some fatal) have been associated with clozapine therapy (Ref). There is also a case report of an upper-extremity deep vein thrombosis (UEDVT) in a patient with a prothrombin mutation (Ref) and a case report of a cerebral venous thrombosis, a potentially life-threatening event, in a patient receiving clozapine (Ref).

Mechanism: Likely multifactorial; clozapine-associated sedation, obesity, and a sedentary lifestyle may increase the risk for DVT via venous stasis. Of note, independent of drug therapy, obesity is associated with inflammation and hypercoagulability and psychiatric disorders are associated with a sedentary lifestyle. In addition, clozapine's affinity for serotonin 5-HT2A receptors may affect platelet aggregation. It has also been suggested that clozapine may also have an effect on activated partial thromboplastin time, antiphospholipid antibodies, and C-reactive protein, although more research is needed (Ref).

Onset: Varied; in a systematic review of PE case reports, the authors found the highest incidence within the first 6 months of treatment (Ref); however, in another systemic review PE cases, the authors describe an anywhere from a few days to several years after initiation of therapy (Ref).

Risk factors:

DVT/PE, in general:

• Obesity (Ref)

• Genetic factors (eg, factor V Leiden mutation) (Ref)

• Gynecologic/pelvic surgery (Ref)

• Indwelling venous catheter (Ref)

• Pregnancy (Ref)

• Malignancy (Ref)

• Drugs such as oral contraceptives (Ref)

• Recent immobility (Ref)

• Recent surgery (Ref)

• Major trauma (Ref)

Weight gain

Clozapine is strongly associated with significant weight gain (increase of ≥7% from baseline) in children, adolescents, and adults, which is a component of the metabolic syndrome observed with this pharmacologic class (Ref). A 10-year naturalistic study of clozapine-treated adult patients suggested an increased risk of mortality from cardiovascular disease secondary to disorders such as obesity, diabetes, hypertension, and hyperlipidemia; however, patients with schizophrenia have a higher risk of cardiovascular disease than the general population due to lifestyle habits (eg, smoking, physical inactivity, unhealthy diet), regardless of medication use (Ref).

Mechanism: Multiple proposed mechanisms, including actions at serotonin, dopamine, histamine, and muscarinic receptors, with differing effects on weight gain by the different antipsychotic agents explained by differing affinity at these receptors (Ref).

Onset: Varied; antipsychotic-induced weight gain usually occurs rapidly in the period following initiation, then gradually decreases and flattens over several months with patients continuing to gain weight in the long term; the time before weight begins to plateau varies by antipsychotic, with a time of 42 to 46 months for clozapine before weight beings to plateau (Ref).

Risk factors:

• Genetic polymorphisms (some evidence suggests that clozapine-induced weight gain is associated with polymorphisms in genes encoding CYP2C19, leptin, leptin receptor, and the serotonin receptor HTR2C) (Ref)

• Family history of obesity (Ref)

• Parental BMI (Ref)

• Children and adolescents (antipsychotics in general; data are lacking to suggest there is a disproportionately higher weight gain with clozapine in this population compared to adults) (Ref)

• Factors associated with rapid weight gain in the initial period: Younger age, lower BMI, more robust response to antipsychotic, and increase in appetite; rapid weight gain of >5% in the first month has been observed as the best predictor for significant long-term weight gain (Ref)

• Duration of therapy (although weight gain plateaus, patients continue to gain weight over time) (Ref)

• Schizophrenia (regardless of medication) is associated with a higher prevalence of obesity compared to the general population due to components of the illness, such as negative symptoms, sedentary lifestyles, and unhealthy diets (Ref)

• Specific antipsychotic: Clozapine is considered to have a high propensity for causing weight gain (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Cardiovascular: Hypertension (4% to 12%), hypotension (9% to 13%), tachycardia (17% to 25%) (table 1)

Clozapine: Adverse Reaction: Tachycardia

Drug (Clozapine)

Comparator (Chlorpromazine)

Indication

Number of Patients (Clozapine)

Number of Patients (Chlorpromazine)

17%

11%

Treatment-resistant schizophrenia

126

142

25%

N/A

N/A

842

N/A

Endocrine & metabolic: Hypercholesterolemia (8% to 38%) (table 2), hyperglycemia (27% to 42%) (table 3), hypertriglyceridemia, weight gain (4% to 31%)

Clozapine: Adverse Reaction: Hypercholesterolemia

Drug (Clozapine)

Comparator (Chlorpromazine)

Indication

Number of Patients (Clozapine)

Number of Patients (Chlorpromazine)

Comments

38%

41%

Schizophrenia

79

34

Change (at least once) from baseline: Borderline (200 to 239 mg/dL) to high (≥240 mg/dL)

8%

2%

Schizophrenia

222

132

Change (at least once) from baseline: Normal (<200 mg/dL) to high (≥240 mg/dL)

Clozapine: Adverse Reaction: Hyperglycemia

Drug (Clozapine)

Comparator (Chlorpromazine)

Indication

Number of Patients (Clozapine)

Number of Patients (Chlorpromazine)

Comments

42%

28%

Schizophrenia

57

43

Change (at least once) from baseline in fasting blood glucose: Borderline (100 to 125 mg/dL) to high (≥126 mg/dL)

27%

10%

Schizophrenia

198

135

Change (at least once) from baseline in fasting blood glucose: Normal (<100 mg/dL) to high (≥126 mg/dL)

Gastrointestinal: Constipation (14% to 25%) (table 4), decreased gastrointestinal motility (literature suggests an incidence of 31%) (Cohen 2017), dyspepsia (14%), nausea (≤17%), sialorrhea (13% to 48%) (table 5), vomiting (≤17%)

Clozapine: Adverse Reaction: Constipation

Drug (Clozapine)

Comparator (Chlorpromazine)

Comparator (Olanzapine)

Indication

Number of Patients (Clozapine)

Number of Patients (Comparator)

25%

N/A

10%

Suicidal behavior in schizophrenia or schizoaffective disorder

479

477

16%

12%

N/A

Treatment-resistant schizophrenia

126

142

14%

N/A

N/A

N/A

842

N/A

Clozapine: Adverse Reaction: Sialorrhea

Drug (Clozapine)

Comparator (Chlorpromazine)

Comparator (Olanzapine)

Indication

Number of Patients (Clozapine)

Number of Patients (Comparator)

48%

N/A

6%

Suicidal behavior in schizophrenia or schizoaffective disorder

479

477

13%

1%

N/A

Treatment-resistant schizophrenia

126

142

31%

N/A

N/A

N/A

842

N/A

Nervous system: Dizziness (14% to 27%) (table 6), drowsiness (≤46%) (table 7), EEG pattern changes (literature suggests an incidence of 63%) (Goyal 2011), insomnia (2% to 20%), sedated state (≤39%) (table 8), vertigo (≤19%)

Clozapine: Adverse Reaction: Dizziness

Drug (Clozapine)

Comparator (Chlorpromazine)

Comparator (Olanzapine)

Indication

Number of Patients (Clozapine)

Number of Patients (Comparator)

Comments

27%

N/A

12%

Suicidal behavior in schizophrenia or schizoaffective disorder

479

477

N/A

14%

16%

N/A

Treatment-resistant schizophrenia

126

142

N/A

19%

N/A

N/A

N/A

842

N/A

Defined as "dizziness/vertigo"

Clozapine: Adverse Reaction: Drowsiness

Drug (Clozapine)

Comparator (Olanzapine)

Indication

Number of Patients (Clozapine)

Number of Patients (Olanzapine)

Comments

46%

25%

Suicidal behavior in schizophrenia or schizoaffective disorder

479

477

N/A

39%

N/A

N/A

842

N/A

Defined as "drowsiness/sedation"

Clozapine: Adverse Reaction: Sedated State

Drug (Clozapine)

Comparator (Chlorpromazine)

Indication

Number of Patients (Clozapine)

Number of Patients (Chlorpromazine)

Comments

21%

13%

Treatment-resistant schizophrenia

126

142

N/A

39%

N/A

N/A

842

N/A

Defined as "drowsiness/sedation"

Miscellaneous: Fever (5% to 13%) (table 9)

Clozapine: Adverse Reaction: Fever

Drug (Clozapine)

Comparator (Chlorpromazine)

Indication

Number of Patients (Clozapine)

Number of Patients (Chlorpromazine)

13%

4%

Treatment-resistant schizophrenia

126

142

5%

N/A

N/A

842

N/A

1% to 10%:

Cardiovascular: Syncope (6%)

Dermatologic: Diaphoresis (6%), skin rash (2%)

Gastrointestinal: Abdominal distress (≤4%), diarrhea (2%), heartburn (≤4%), xerostomia (5% to 6%) (table 10)

Clozapine: Adverse Reaction: Xerostomia

Drug (Clozapine)

Comparator (Chlorpromazine)

Indication

Number of Patients (Clozapine)

Number of Patients (Chlorpromazine)

5%

20%

Treatment-resistant schizophrenia

126

142

6%

N/A

N/A

842

N/A

Genitourinary: Urine abnormality (2%)

Hematologic & oncologic: Agranulocytosis (literature suggests an incidence up to 1% to 2%) (Alvir 1993), eosinophilia (1%), leukopenia (≤3%), neutropenia (≤3%, can be severe neutropenia)

Nervous system: Agitation (4%), akathisia (3%), confusion (3%), fatigue (2%), headache (7% to 10%), nightmares (≤4%), restlessness (4%), seizure (3%; dose related), sleep disturbance (≤4%)

Neuromuscular & skeletal: Akinesia (≤4%), hypokinesia (≤4%), muscle rigidity (3%), tremor (6%)

Ophthalmic: Visual disturbance (5%)

Frequency not defined:

Cardiovascular: Bradycardia, orthostatic hypotension

Nervous system: Tardive dyskinesia

Postmarketing:

Cardiovascular: Acute myocardial infarction (Wang 2020), atrial fibrillation (Low 1998), cardiomyopathy (Garg 2020), cerebral thrombosis (venous) (Srinivasaraju 2010), deep vein thrombosis (including upper extremity deep vein thrombosis) (Tripp 2011, Vayá 2008), hypersensitivity angiitis (Penaskovic 2005), mitral valve insufficiency, myocarditis (Datta 2018), palpitations (Kumar 2020), prolonged QT interval on ECG (Sharma 2011), pulmonary embolism (Poudyal 2019), supraventricular tachycardia (Kirpekar 2015), torsades de pointes, ventricular ectopy (Kumar 2020), ventricular fibrillation, ventricular tachycardia

Dermatologic: Dermatologic reaction (symmetrical drug-related intertriginous and flexural exanthema [SDRIFE]) (Suvarna 2020), dyschromia, erythema multiforme, skin photosensitivity, Stevens-Johnson syndrome (Wu 2015)

Endocrine & metabolic: Diabetes mellitus (new onset) (Koller 2001), diabetic ketoacidosis (Pierides 1997), exacerbation of diabetes mellitus (Koller 2001), hyperuricemia, hyponatremia, increased libido (Thomson 2018), pheochromocytoma (pseudo) (Li 1997), weight loss

Gastrointestinal: Acute pancreatitis (DeRemer 2019), cholestasis, colitis (Rask 2020), dysphagia, fecal impaction (Osterman 2017), gastrointestinal infarction (including ischemia), gastrointestinal necrosis (Osterman 2017), intestinal obstruction, non-Hirschsprung megacolon, paralytic ileus, sialadenitis (parotitis) (Hinze-Selch 1996)

Genitourinary: Priapism (Donizete da Costa 2015), retrograde ejaculation

Hematologic & oncologic: Granulocytopenia, increased erythrocyte sedimentation rate, increased hematocrit, increased hemoglobin, thrombocythemia, thrombocytopenia

Hepatic: Acute hepatotoxicity (Kane 2014), hepatic cirrhosis, hepatic failure (Chang 2009), hepatic fibrosis, hepatic necrosis (Chang 2009), hepatitis (Wu Chou 2014), hepatotoxicity (Wu Chou 2014), jaundice (Chang 2009), liver steatosis

Hypersensitivity: Angioedema (Tatar 2014), hypersensitivity reaction (Dimitri Valente 2018)

Immunologic: Drug reaction with eosinophilia and systemic symptoms (Moazez 2018)

Infection: Sepsis (Senn 1977)

Nervous system: Abnormal electroencephalogram, cataplexy, cognitive dysfunction (Rajji 2010), delirium, diabetes mellitus with hyperosmolar coma, dystonia (acute) (Kaplan 2019), heatstroke (Hoffmann 2016), hypothermia (Burk 2020), myasthenia, myoclonus (Praharaj 2010b), neuroleptic malignant syndrome (Corallo 2007), nocturnal enuresis, obsessive compulsive disorder (symptoms), paresthesia, restless leg syndrome, sleep apnea, status epilepticus

Neuromuscular & skeletal: increased creatine phosphokinase in blood specimen, polyserositis (Catalano 1997), rhabdomyolysis (Koren 1998), systemic lupus erythematosus

Ophthalmic: Angle-closure glaucoma, periorbital edema

Renal: Acute interstitial nephritis (Au 2004), renal failure syndrome (Davis 2019)

Respiratory: Lower respiratory tract infection, obstructive sleep apnea syndrome (Shirani 2011), pleural effusion (Kane 2014), pneumonia, pneumonitis (Torrico 2020), pulmonary aspiration (Saenger 2016)

Contraindications

Serious hypersensitivity to clozapine or any component of the formulation (eg, photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson syndrome [SJS])

Canadian labeling: Additional contraindications (not in US labeling): Myeloproliferative disorders; history of toxic or idiosyncratic agranulocytosis or severe granulocytopenia (unless due to previous chemotherapy); concomitant use with other agents that suppress bone marrow function; active hepatic disease associated with nausea, anorexia, or jaundice; progressive hepatic disease or hepatic failure; paralytic ileus; uncontrolled epilepsy; severe CNS depression or comatose states; severe renal impairment; severe cardiac disease (eg, myocarditis); patients unable to undergo blood testing

Warnings/Precautions

Concerns related to adverse effects:

• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased GI motility, urinary retention, benign prostatic hyperplasia, xerostomia, or visual problems. Avoid concomitant use, when possible, with anticholinergic medications due to increased risk for toxicity or severe GI adverse reactions. Bowel regimens and monitoring are recommended (De Hert 2011; Nielsen 2012; Palmer 2008). If ileus or subileus occur discontinue clozapine and reintroduce after addressing inadequate dietary and bowel habits (Nielsen 2013). Relative to other neuroleptics, clozapine has a high potency of cholinergic blockade (Richelson 1999).

• Cardiovascular events:

- [US Boxed Warning]: Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have been reported with clozapine treatment. Risk is highest during the initial titration period especially with rapid dose increases. Symptoms can develop with the first dose and with doses as low as 12.5 mg per day. Initiate treatment with no more than 12.5 mg once daily or twice daily; titrate slowly, and use divided doses. Use with caution in patients at risk for these effects (eg, cerebrovascular disease, cardiovascular disease) or with predisposing conditions for hypotensive episodes (eg, hypovolemia, concurrent antihypertensive medication); reactions can be fatal. Consider dose reduction if hypotension occurs. If patients have had even a brief interval off clozapine (≥2 days), reinitiate treatment at 12.5 mg once daily or twice daily. If the first several doses are tolerated, clozapine may be re-titrated more quickly when the risk of adverse events is low. May also cause tachycardia; tachycardia is not limited to a reflex response to orthostatic hypotension.

- [US Boxed Warning]: Fatalities due to myocarditis and cardiomyopathy have been reported. Upon suspicion of these reactions, discontinue clozapine and obtain a cardiac evaluation. Signs and symptoms may include chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, ECG changes, eosinophilia, and/or elevated C-reactive protein. Patients with clozapine-related myocarditis or cardiomyopathy should generally not be rechallenged with clozapine. If the benefit of treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, rechallenge may be considered in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring. Myocarditis and cardiomyopathy may occur at any period during clozapine treatment; however, typically myocarditis presents within the first 2 months and cardiomyopathy after 8 weeks of treatment. Mitral valve incompetence has been reported in patients who are diagnosed with cardiomyopathy while taking clozapine. In a scientific statement from the American Heart Association, clozapine has been determined to be an agent that may cause direct myocardial toxicity (magnitude: major) (AHA [Page 2016]).

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Dyslipidemia: Undesirable changes in lipids have been observed with antipsychotic therapy; incidence varies with product. Periodically monitor total serum cholesterol, triglycerides, LDL, and HDL concentrations. Compared with other antipsychotics, the risk of dyslipidemia is high (Solmi 2017).

• Eosinophilia: Eosinophilia (ie, an eosinophil count >700/mm3) has been reported to occur (usually within first month) with clozapine treatment. If eosinophilia develops, evaluate for signs or symptoms of systemic reactions (eg, rash or other allergic symptoms), myocarditis, or organ-specific disease. If systemic disease is suspected, discontinue clozapine immediately. If a cause of eosinophilia unrelated to clozapine is identified, treat the underlying cause and continue clozapine. If cause of eosinophilia is related to clozapine, but is in the absence of organ involvement, continue clozapine under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, base decision to interrupt treatment and rechallenge (after eosinophil count decreases) on an overall clinical assessment, in consultation with internist or hematologist.

• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; risk increases with age. Use with caution in patients at risk for aspiration pneumonia (eg, Alzheimer disease), particularly in patients >75 years of age (Herzig 2017; Maddalena 2004). Clozapine-induced sialorrhea may also increase the risk of aspiration pneumonia (Gurrera 2016).

• Extrapyramidal symptoms: May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics; frequencies reported are similar to placebo). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Keepers 2020]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.

• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability.

• Fever: Benign transient temperature elevation (>38°C or 100.4°F) may occur; peaking within the first 3 weeks of treatment. May be associated with an increase or decrease in WBC count. Rule out infection, severe neutropenia, myocarditis, and neuroleptic malignant syndrome (NMS) in patients presenting with fever. While it may be appropriate to withhold clozapine doses temporarily while ruling out serious causes of fever, treatment should not be abruptly discontinued for a benign fever with unknown cause (Nielsen 2013).

• GI effects: Severe GI adverse effects have occurred and may range from constipation to paralytic ileus. Increased frequency of constipation and delayed diagnosis and treatment can increase the risk of severe complications of GI hypomotility and result in intestinal obstruction, fecal impaction, megacolon, and intestinal ischemia or infarction; may result in hospitalization, surgery, or death. Prior to use, screen for constipation and treat as necessary; reassess bowel function and symptoms of complications of hypomotility frequently. Monitor and treat as medically appropriate if constipation or GI hypomotility occur; consider prophylactic laxatives in high-risk patients.

• Hepatotoxicity: Severe, life-threatening and sometimes fatal hepatotoxicity, including hepatic failure, hepatic necrosis, and hepatitis have been reported. Monitor for signs and symptoms of hepatotoxicity including fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy. Consider permanently discontinuing therapy if hepatitis or transaminase elevations combined with other systemic symptoms occur during clozapine therapy.

• Hyperglycemia: Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. In some cases, hyperglycemia resolved after discontinuation of the antipsychotic; however, some patients have required continuation of antidiabetic treatment. All patients should be monitored for symptoms of hyperglycemia (eg, polydipsia, polyuria, polyphagia, weakness). Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control during therapy. Patients with risk factors for diabetes (eg, obesity or family history) should have a baseline fasting blood sugar (FBS) and periodically during treatment. Discontinue immediately in cases of diabetic ketoacidosis or hyperosmolar coma; cautiously restart with monitoring after sustained control of diabetes and removal of potential diabetogenic medications or treatment of diabetogenic comorbidities (Nielsen 2013). Compared with other antipsychotics, the risk of hyperglycemia is high (Solmi 2017).

• Neuroleptic malignant syndrome: Use may be associated with NMS; monitor for mental status changes, fever, muscle rigidity and/or autonomic instability. NMS can recur. Following recovery from NMS, reintroduction of drug therapy should be carefully considered; if an antipsychotic agent is resumed, monitor closely for NMS.

• Neutropenia: [US Boxed Warning]: Clozapine treatment has caused severe neutropenia, defined as an absolute neutrophil count (ANC) less than 500/mm3. Severe neutropenia can lead to serious infection and death. Prior to initiating treatment, a baseline ANC must be ≥1,500/mm3 for the general population and must be ≥1,000/mm3 for patients with documented Benign Ethnic Neutropenia. During treatment, patients must have regular ANC monitoring. Advise patients to immediately report symptoms consistent with severe neutropenia or infection (eg, fever, weakness, lethargy, sore throat). Risk is greatest within the first 18 weeks of therapy. The mechanism of clozapine-induced neutropenia is unknown and is not dose-dependent. Because of the risk of severe neutropenia, clozapine is available only through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program.

• QT prolongation: Clozapine is associated with QT prolongation and ventricular arrhythmias including torsade de pointes; cardiac arrest and sudden death may occur. Use caution in patients with conditions that may increase the risk of QT prolongation, including history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of clozapine, hypokalemia, and hypomagnesemia. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities prior to initiating therapy. Discontinue clozapine if QTc interval >500 msec.

• Seizures: [US Boxed Warning]: Seizures have been associated with clozapine use in a dose-dependent manner. Initiate treatment with no more than 12.5 mg, titrate gradually using divided dosing. Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors (Gareri 2008).

• Sialorrhea: Sialorrhea and drooling may occur with clozapine use; symptoms may be more profound during sleep and may be dose-related. As a result of excessive saliva, patients may initially experience choking sensations that cause nighttime awakening, hoarseness or dysphonia of the voice, and a chronic cough. Skin irritation and infections, aspiration pneumonia, chronic sleep disturbances with daytime fatigue and somnolence, painful swelling of the salivary glands, and symptomatic aerophagia with resultant gas bloating, pain, and flatus may also develop. Titrate clozapine slowly to minimize the chances of inducing sialorrhea; consider dose reduction with or without therapeutic augmentation, or therapeutic substitution, if symptoms develop. Nonpharmacological strategies such as propping head up on several pillows while sleeping, sleeping on the side, placing a towel over pillow to prevent soaking, or chewing sugar free gum may be considered in milder cases (Praharaj 2006). Limited evidence exists for pharmacologic interventions; use extreme caution with drugs that have anticholinergic effects to avoid additive adverse effects with clozapine including constipation or cognitive impairment (APA [Keepers 2020]; Praharaj 2006).

• Suicidal ideation: The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder; use with caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.

• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects (Kerwin 2004; Safferman 1991).

• Thromboembolism: Cases of deep vein thrombosis and pulmonary embolism (some fatal) have been associated with clozapine. Avoidance of risk factors such as weight gain and sedentary lifestyle may minimize the risk (Paciullo 2008). Balance the benefits and risks of continuing clozapine if thromboembolism occurs; discontinue if there is a recurrence of thromboembolism despite prophylactic treatment (Nielsen 2013).

• Weight gain: Significant weight gain has been observed with antipsychotic therapy; incidence varies with product. Monitor waist circumference and BMI. Compared with other antipsychotics, the risk of weight gain is high (Solmi 2017).

Disease-related concerns:

• Acute infectious/inflammatory processes: Elevation of serum clozapine levels have been reported in the setting of acute infection or inflammatory process. Reactions ranging from mild sedation to symptoms requiring an ICU level of care have been reported. Significant increases of serum levels do not always correlate with clinical signs and symptoms of clozapine toxicity. Signs and symptoms such as hypotension, sialorrhea, and sedation that cannot be explained by other medications or conditions may necessitate a temporary dose reduction or discontinuation, depending on the severity (Clark 2017; Leung 2014).

• Benign ethnic neutropenia: Patients with benign ethnic neutropenia (BEN) have different ANC monitoring parameters due to their lower baseline ANC levels. BEN is a condition observed in certain groups whose average ANC values are lower than standard laboratory ranges for neutrophils. Patients of African, Caribbean, West Indian, Middle Eastern, or Arab descent and Yemenite Jews may be at higher risk of developing chronic neutropenia due to BEN (Atallah-Yunes 2019; Mijovic 2020). BEN is more common in men. Patients with BEN are not at increased risk for developing clozapine-induced neutropenia. Consider hematology consultation prior to initiation.

• Cardiovascular disease: Use with caution in patients with cardiovascular disease; gradually increase dose.

• Dementia: [US Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death (APA [Reus 2016]). Clozapine is not approved for the treatment of dementia-related psychosis.

• Hepatic impairment: Use with caution in patients with hepatic disease or impairment; monitor hepatic function regularly. Dosage reduction may be necessary in patients with significant hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment. Dosage reduction may be necessary in patients with significant renal impairment.

Special populations:

• CYP2D6 poor metabolizers: Clozapine concentrations may be increased in CYP2D6 poor metabolizers. Dose reduction may be necessary.

• Elderly: The elderly are more susceptible to adverse effects (including agranulocytosis, cardiovascular, anticholinergic, and tardive dyskinesia).

• Smokers: Clozapine levels may be lower in patients who smoke. Smokers may require twice the daily dose as nonsmokers in order to obtain an equivalent clozapine concentration (Tsuda 2014). Smoking cessation may cause toxicity in a patient stabilized on clozapine. Monitor change in smoking patterns. Consider baseline serum clozapine levels and/or empiric dosage adjustments (30% to 40% reduction) in patients expected to have a prolonged hospital stay with forced smoking cessation. Case reports suggest symptoms from increasing clozapine concentrations may develop 2 to 4 weeks after smoking cessation (Lowe 2010).

Dosage form specific issues:

• Brand/generic: Use caution when converting from brand to generic formulation; poor tolerability, including relapse, has been reported usually soon after product switch (1 to 3 months); monitor closely during this time (Bobo 2010).

• Phenylalanine: FazaClo oral disintegrating tablets contain phenylalanine.

Other warnings/precautions:

• Discontinuation of therapy: In general, when discontinuing antipsychotic therapy, gradually taper antipsychotics to avoid physical withdrawal symptoms and rebound symptoms (APA [Keepers 2020]; WFSBP [Hasan 2012]); the manufacturer recommends reducing the clozapine dose gradually over a period of 1 to 2 weeks if termination of therapy is not related to neutropenia. Withdrawal symptoms may include agitation, alternating feelings of warmth and cold, anxiety, diaphoresis, dyskinesia, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, and vertigo (Lambert 2007; Moncrieff 2020). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). Patients with chronic symptoms, repeated relapses, and clear diagnostic features of schizophrenia are at risk for poor outcomes if medications are discontinued (APA [Keepers 2020]).

Warnings: Additional Pediatric Considerations

All reported serious adverse effects have also been observed in children and adolescents. Children and adolescents may be more sensitive to neutropenia compared to adults (Maher 2013; Sporn 2007); a retrospective review of 87 pediatric patients reported higher rates of neutropenia than had been previously reported in adults; 20% had an ANC <1,500/mm3, with male gender as a significant risk factor for this level of neutropenia; ultimately, 86 patients were able to continue clozapine (Maher 2013). Patients should be carefully monitored and counseled to report mouth sores, flu-like symptoms, or weakness. Incidence of extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia may be as high as 15% in children and adolescents (Sporn 2007).

Similar to adult experience, the American Academy of Child and Adolescent Psychiatry (AACAP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (AACAP [McClellan 2007]).

Metabolism/Transport Effects

Substrate of CYP1A2 (major), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy

Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Alpha-/Beta-Agonists: CloZAPine may diminish the therapeutic effect of Alpha-/Beta-Agonists. Risk C: Monitor therapy

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification

Amiodarone: May enhance the QTc-prolonging effect of CloZAPine. Amiodarone may increase the serum concentration of CloZAPine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification

Amisulpride (Oral): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of neuroleptic malignant syndrome may be increased. Risk X: Avoid combination

Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Risk C: Monitor therapy

Anticholinergic Agents: May enhance the constipating effect of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider therapy modification

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (Second Generation [Atypical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider avoiding atypical antipsychotic use in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Benzodiazepines: May enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Risk D: Consider therapy modification

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Broccoli: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination

Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy

Cabergoline: May diminish the therapeutic effect of Antipsychotic Agents. Risk X: Avoid combination

Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

CarBAMazepine: May enhance the myelosuppressive effect of CloZAPine. More specifically, the risk of bone marrow suppression with this combination may be increased due to the independent myelosuppressive effects of the drugs. CarBAMazepine may decrease the serum concentration of CloZAPine. Management: Avoid use with strong CYP3A4 inducers when possible. If combined, monitor patients closely and consider clozapine dose increases. Consider increased monitoring for neutropenia Risk D: Consider therapy modification

Ceritinib: May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Cimetidine: May increase the serum concentration of CloZAPine. Risk C: Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Risk X: Avoid combination

Ciprofloxacin (Systemic): May enhance the QTc-prolonging effect of CloZAPine. Ciprofloxacin (Systemic) may increase the serum concentration of CloZAPine. Management: Reduce the clozapine dose to one-third of the original dose when adding ciprofloxacin and monitor closely for evidence of excessive QTc prolongation and clozapine toxicity. Resume the previous clozapine dose following ciprofloxacin discontinuation. Risk D: Consider therapy modification

Clarithromycin: QT-prolonging Antipsychotics (Moderate Risk) may enhance the QTc-prolonging effect of Clarithromycin. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP1A2 Inducers (Moderate): May decrease the serum concentration of CloZAPine. Risk C: Monitor therapy

CYP1A2 Inducers (Weak): May decrease the serum concentration of CloZAPine. Risk C: Monitor therapy

CYP1A2 Inhibitors (Moderate): May increase the serum concentration of CloZAPine. Risk C: Monitor therapy

CYP1A2 Inhibitors (Strong): May increase the serum concentration of CloZAPine. Management: Reduce the dose of clozapine to one-third of the original dose when adding a strong CYP1A2 inhibitor and monitor patient response closely. Return to the original clozapine dose when the strong CYP1A2 inhibitor is discontinued. Risk D: Consider therapy modification

CYP1A2 Inhibitors (Weak): May increase the serum concentration of CloZAPine. Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May increase the serum concentration of CloZAPine. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of CloZAPine. Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CloZAPine. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of CloZAPine. Management: Avoid use with strong CYP3A4 inducers when possible. If combined, monitor patients closely and consider clozapine dose increases. Clozapine dose reduction and further monitoring may be required when strong CYP3A4 inducers are discontinued. Risk D: Consider therapy modification

CYP3A4 Inducers (Weak): May decrease the serum concentration of CloZAPine. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of CloZAPine. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of CloZAPine. Risk C: Monitor therapy

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Deutetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Risk C: Monitor therapy

Dexmethylphenidate-Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Dexmethylphenidate-Methylphenidate. Dexmethylphenidate-Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of extrapyramidal symptoms may be increased when these agents are combined. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Fexinidazole: May enhance the QTc-prolonging effect of CloZAPine. Fexinidazole may increase the serum concentration of CloZAPine. Management: Monitor for increased clozapine toxicities, including QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor therapy

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Risk X: Avoid combination

Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Guanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. Risk C: Monitor therapy

Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Risk C: Monitor therapy

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Risk X: Avoid combination

Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to one of these agents when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk C: Monitor therapy

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Risk C: Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Myelosuppressive Agents: May enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nirmatrelvir: May increase the serum concentration of CloZAPine. Risk X: Avoid combination

Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Omeprazole: May decrease the serum concentration of CloZAPine. Omeprazole may increase the serum concentration of CloZAPine. Risk C: Monitor therapy

Ondansetron: May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Pentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Phenylephrine (Systemic): CloZAPine may diminish the therapeutic effect of Phenylephrine (Systemic). Risk C: Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Risk X: Avoid combination

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Risk X: Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Risk X: Avoid combination

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

QT-prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect of CloZAPine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification

QT-prolonging Antidepressants (Moderate Risk): QT-prolonging Antipsychotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Kinase Inhibitors (Moderate Risk): CloZAPine may enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Miscellaneous Agents (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Risk C: Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

QuiNIDine: CloZAPine may enhance the anticholinergic effect of QuiNIDine. CloZAPine may enhance the QTc-prolonging effect of QuiNIDine. QuiNIDine may increase the serum concentration of CloZAPine. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modification

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy

Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Risk X: Avoid combination

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Saquinavir: May enhance the QTc-prolonging effect of CloZAPine. Risk X: Avoid combination

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: Consider therapy modification

Serotonergic Agents (High Risk): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Risk X: Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Risk X: Avoid combination

Tobacco (Smoked): May decrease the serum concentration of CloZAPine. Risk C: Monitor therapy

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Risk C: Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Vasopressin: Drugs Suspected of Causing Diabetes Insipidus may diminish the therapeutic effect of Vasopressin. Specifically, the pressor and antidiuretic hormone effects of vasopressin may be decreased. Risk C: Monitor therapy

Voriconazole: May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Pregnancy Considerations

Clozapine crosses the placenta and can be detected in the fetal blood and amniotic fluid (Barnas 1994; Imaz 2018).

Outcome information following maternal use of clozapine during pregnancy is limited (Beex-Oosterhuis 2020; Larsen 2015; Mehta 2017; Nguyen 2020). Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms) and/or withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization.

The American College of Obstetricians and Gynecologists (ACOG) recommends that therapy during pregnancy be individualized; treatment with psychiatric medications during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary healthcare provider, and pediatrician. Safety data related to atypical antipsychotics during pregnancy is limited and routine use is not recommended. However, if a woman is inadvertently exposed to an atypical antipsychotic while pregnant, continuing therapy may be preferable to switching to an agent that the fetus has not yet been exposed to; consider risk:benefit (ACOG 2008). An increased risk of exacerbation of psychosis should be considered when discontinuing or changing treatment during pregnancy and postpartum. In general, other agents are preferred for use in pregnancy; however, clozapine may be used in women who cannot be switched to recommended antipsychotics (Larsen 2015).

Health care providers are encouraged to enroll women 18 to 45 years of age exposed to clozapine during pregnancy in the Atypical Antipsychotics Pregnancy Registry (1-866-961-2388 or http://www.womensmentalhealth.org/pregnancyregistry).

Breastfeeding Considerations

Clozapine is present in breast milk.

Clozapine breast milk concentrations were higher than the maternal plasma in one case report (Barnas 1994).

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother; breastfed infants should be monitored for excess sedation. Due to the potential for adverse effects to an infant exposed via breast milk, use of clozapine is not recommended in breastfeeding women (Larsen 2015).

Dietary Considerations

Some products may contain phenylalanine.

Monitoring Parameters

The only mandatory monitoring is the routine ANC, however, monitoring of several other clinical outcomes is recommended. Clozapine-treated patients should be monitored as frequently as possible in the first few weeks during titration.

Frequency of Antipsychotic Monitoringa,b

Monitoring parameter

Frequency of monitoring

Comments

a For all monitoring parameters, it is appropriate to check at baseline and when clinically relevant (based on symptoms or suspected adverse reactions) in addition to the timeline.

b ADA 2004, APA [Keepers 2020], De Hert 2011a, De Hert 2011b, Gugger 2011, Knoph 2018; Nielsen 2012, Palmer 2008, manufacturer's labeling.

c Signs and symptoms of myocarditis include asymptomatic tachycardia, chest pain, eosinophilia, fatigue, fever, palpitations, peripheral edema, and shortness of breath.

d Risk factors for extrapyramidal symptoms (EPS) include prior history of EPS, high doses of antipsychotics, young age (children and adolescents at higher risk than adults), and dopaminergic affinity of individual antipsychotic.

e Risk factors for tardive dyskinesia include age >55 years; females; White or African ethnicity; presence of a mood disorder, intellectual disability, or central nervous system injury; and past or current EPS.

Adherence

Every visit

Blood chemistries (electrolytes, renal function, liver function, thyroid stimulating hormone)

Annually

Bowel function

Every visit

CBC (ANC)

Refer to “ANC monitoring” section following this table (~Weekly for 6 months, biweekly for 6 months, then monthly after 1 year).

ECG

Check at baseline to monitor for myocarditis only if there are cardiac risk factors; repeat if significant change in dose or addition of other QTc-prolonging drugs in patients with risk factors or elevated baseline QTc.

Echocardiogram

Check at baseline only if there are cardiac risk factors; repeat if signs or symptoms of myocarditis develop.c

To monitor for myocarditis

Extrapyramidal symptoms

Every visit; 4 weeks after initiation and dose change; annually. Use a formalized rating scale at least annually or every 6 months if high risk.d

Fall risk

Every visit

Fasting plasma glucose/HbA1c

12 weeks after initiation and dose change; annually.

Check more frequently than annually if abnormal. Follow diabetes guidelines.

Lipid panel

12 weeks after initiation and dose change; annually.

Check more frequently than annually if abnormal. Follow lipid guidelines.

Mental status

Every visit

Metabolic syndrome history

Annually

Evaluate for personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease.

Myocarditis monitoring (C-reactive protein, eosinophils, troponin)

Repeat weekly during first 6 weeks of treatment OR if signs or symptoms of myocarditis develop.c

Prolactin

Ask about symptoms at every visit until dose is stable. Check prolactin level if symptoms are reported.

Hyperprolactinemia symptoms: Changes in menstruation, libido, gynecomastia, development of galactorrhea, and erectile and ejaculatory function.

Smoking patterns

Regularly; assess with hospitalization.

Cessation may cause toxicity in a patient stabilized on clozapine. In patients expected to have a prolonged hospital stay with forced smoking cessation, consider baseline serum clozapine levels and/or empiric dosage adjustments.

Tardive dyskinesia

Every visit; annually. Use a formalized rating scale at least annually or every 6 months if high risk.e

Vital signs (BP, orthostatics, temperature, pulse, signs of infection)

Every visit (at least weekly during first 3 to 4 weeks of treatment); 4 weeks after dose change. May stop monitoring temperature after first 8 weeks of treatment.

Weight/height/BMI

8 and 12 weeks after initiation and dose change; quarterly.

Consider monitoring waist circumference at baseline and annually, especially in patients with or at risk for metabolic syndrome. Consider changing antipsychotic if BMI increases by ≥1 unit. Some experts recommend checking weight and height at every visit.

ANC monitoring:

US labeling:

Note: See below for considerations during COVID-19 quarantine, in patients with benign ethnic neutropenia (BEN), hospice situations, use of concurrent medications that cause neutropenia, and Canadian labeling. Laboratory hematology results may be presented in different units; 1 mcL = 1 mm3.

General population: Prior to initiating treatment, obtain a baseline ANC; the ANC must be ≥1,500/mm3 for the general population in order to initiate treatment. During the first 6 months of treatment, monitor the ANC weekly. If the ANC remains ≥1,500/mm3, the monitoring frequency can be reduced to every 2 weeks for the next 6 months. If the ANC remains ≥1,500/mm3 for the second 6 months of continuous therapy, the ANC monitoring frequency can be reduced to once every 4 weeks.

Treatment interruption: If ANC is ≥1,500/mm3 and treatment is interrupted for <30 days, continue monitoring as before; if ≥30 days, monitor as if a new patient.

Treatment discontinuation: For abrupt clozapine discontinuation for a reason unrelated to neutropenia in the general population, continuation of ANC monitoring is recommended until the ANC is ≥1,500/mm3. Additional ANC monitoring is required for any patient reporting onset of fever, defined as a temperature of ≥38.5°C (≥101.3°F), during the 2 weeks after discontinuation.

Monitor patients for psychosis and cholinergic rebound (eg, headache, nausea, vomiting, diarrhea, profuse diaphoresis).

Hematologic toxicity monitoring: Confirm all initial reports of ANC <1,500/mm3 with a repeat ANC within 24 hours.

Fever: Interrupt clozapine as a precautionary measure in any patient who develops a fever, defined as a temperature of ≥38.5°C (≥101.3°F), and obtain an ANC level. Fever is often the first sign of neutropenic infection, however, it is also a symptom of BEN.

Mild neutropenia (1,000 to 1,499/mm3): Continue treatment; monitor ANC 3 times weekly until ≥1,500/mm3 and then return to previous monitoring schedule.

Moderate neutropenia (500 to 999/mm3): Interrupt therapy, recommend hematology consultation, and begin daily ANC monitoring until ANC ≥1,000/mm3 and then may consider restarting therapy. Follow with 3 times weekly monitoring until ANC ≥1,500/mm3. Once ANC ≥1,500/mm3, check ANC weekly for 4 weeks and then return to previous monitoring schedule.

If fever occurs in any patient with an ANC <1,000/mm3, initiate appropriate workup and treatment for infection.

Severe neutropenia (<500/mm3): Interrupt therapy, recommend hematology consultation, and begin daily ANC monitoring until ANC ≥1,000/mm3. Follow with 3 times weekly monitoring until ANC ≥1,500/mm3. Do not rechallenge unless prescriber determines benefits outweigh risks. If rechallenged, resume treatment as a new patient once ANC ≥1,500/mm3.

Benign ethnic neutropenia: Prior to initiating treatment, obtain at least 2 baseline ANC levels, including the ANC; the ANC must be ≥1,000/mm3 for patients with documented BEN in order to initiate treatment. During the first 6 months of treatment, monitor the ANC weekly. If the ANC remains ≥1,000/mm3, the monitoring frequency can be reduced to every 2 weeks for the next 6 months. If the ANC remains ≥1,000/mm3 for the second 6 months of continuous therapy, the ANC monitoring frequency can be reduced to once every 4 weeks.

Treatment interruption: If ANC is ≥1,000/mm3 and treatment is interrupted for <30 days, continue monitoring as before; if ≥30 days, monitor as if a new patient.

Treatment discontinuation: For abrupt clozapine discontinuation for a reason unrelated to neutropenia in patients with BEN, continuation of ANC monitoring is recommended until the ANC is ≥1,000/mm3 or above the baseline. Additional ANC monitoring is required for any patient reporting onset of fever, defined as a temperature of ≥38.5°C (≥101.3°F), during the 2 weeks after discontinuation.

Monitor patients for psychosis and cholinergic rebound (eg, headache, nausea, vomiting, diarrhea, profuse diaphoresis).

Hematologic toxicity monitoring: Confirm all initial reports of ANC <1,500/mm3 with a repeat ANC within 24 hours.

Fever: Interrupt clozapine as a precautionary measure in any patient who develops a fever, defined as a temperature of ≥38.5°C (≥101.3°F), and obtain an ANC level. Fever is often the first sign of neutropenic infection, however, it is also a symptom of BEN.

BEN (500 to 999/mm3): Continue therapy, recommend hematology consultation, and begin 3 times weekly ANC monitoring until ANC ≥1,000/mm3 or greater than or equal to patient's known baseline. Once ANC ≥1,000/mm3 or patient's known baseline, check ANC weekly for 4 weeks and then return to previous monitoring schedule.

If fever occurs in any patient with an ANC <1,000/mm3, initiate appropriate workup and treatment for infection.

Severe BEN (<500/mm3): Interrupt therapy, recommend hematology consultation, and begin daily ANC monitoring until ANC ≥500/mm3. Follow with 3 times weekly monitoring until ANC greater than or equal to patient's baseline. Do not rechallenge unless prescriber determines benefits outweigh risks. If rechallenged, resume treatment as a new patient once ANC ≥1,000/mm3.

COVID-19 considerations: Due to challenges with self-isolation or quarantine, the FDA recommends considering whether or not there are compelling reasons to complete required laboratory testing and to weigh the benefits and risks of continuing treatment in the absence of laboratory testing. The FDA does not intend to take action for failing to adhere to REMS requirements (FDA 2020).

A meta-analysis of 7 studies suggests the risk for neutropenia peaks within the first month of therapy and drops over time to negligible levels by 1 year of treatment (Myles 2018). Some experts suggest it may be reasonable to forego testing in patients who have received clozapine for ≥1 year and have never had an ANC <2,000/mm3 (or <1,500/mm3 if history of benign ethnic neutropenia). Patients without ANC monitoring who develop symptoms such as sore throat and fever should be assessed for neutropenia and COVID-19 (Freudenreich 2020). Expert consensus guidelines suggest the following modifications for consideration (Siskind 2020):

ANC monitoring:

Continuous clozapine treatment for 1 year: If there is no safe or practical access to lab draws, may reduce frequency of ANC testing to every 3 months and dispense a 90-day supply if patient has never had an ANC <2,000/mm3 (or <1,500/mm3 if history of benign ethnic neutropenia).

Continuous clozapine treatment for 6 to 12 months: Make decisions about ANC monitoring on a case by case basis.

Initiating clozapine: Adhere to standard protocols for ANC monitoring for the first 6 months.

Infection symptoms:

Patients without ANC monitoring who develop symptoms such as sore throat and fever should be assessed for neutropenia and COVID-19 (Freudenreich 2020). Considerations with COVID-19 and other infections include:

• In patients with any symptoms of infection such as cough, fever and chills, sore throat, or other flu-like symptoms, complete an urgent physician assessment including an ANC. Clozapine may be associated with a higher risk of pneumonia due to sialorrhea and aspiration.

• Clozapine levels may increase with acute systemic infections and lead to symptoms of acute clozapine toxicity including sedation, myoclonus, and seizures. In addition, patients with respiratory infections may reduce or cease smoking, also leading to increased clozapine levels. If patients with fever and flu-like symptoms develop symptoms of clozapine toxicity, consider reducing the clozapine dose by up to 50%. Continue the lower dose until 3 days after the fever has subsided, then increase slowly to the pre-fever dose. Use clozapine serum levels as needed to assist with dosing adjustments, particularly after large dose changes, inadequate response, or unexpected adverse effects (Siskind 2020).

Hospice patients: For hospice patients (ie, terminally ill patients with an estimated life expectancy of ≤6 months), ANC monitoring may be reduced to a frequency of once every 6 months after a discussion with the patient and caregiver. Base ANC monitoring on individual treatment needs to control psychiatric symptoms and terminal illness.

Concurrent use of other drugs associated with neutropenia: If clozapine is used concurrently with an agent known to cause neutropenia (eg, some chemotherapeutic agents), consider monitoring patients more closely. Consult with treating oncologist in patients receiving concomitant chemotherapy.

Canadian labeling:

Prior to initiating treatment, obtain a baseline ANC; the ANC must be ≥2,000/mm3 in order to initiate treatment. Initiate treatment in an inpatient setting or an outpatient setting with medical supervision and monitor of vital signs for at least 6 to 8 hours after the first few doses. During the first 6 months (26 weeks) of treatment, ANC should be obtained at baseline and at least weekly. If count remains acceptable (ANC ≥2,000/mm3) during this time period, then may be monitored every other week for the next 6 months (26 weeks). If ANC continues to remain within these acceptable limits after the second 6 months (26 weeks) of therapy, monitoring can be decreased to every 4 weeks.

Special populations: Patients with low WBC counts because of benign ethnic neutropenia should be given special consideration and may be started on clozapine after consultation with a hematologist. Patients with a history of bone marrow disorders should be evaluated by a hematologist prior to starting clozapine; therapy may be initiated if the benefit outweighs the risk.

Treatment interruption: Note: Only applies to patients with ANC ≥2,000/mm3. If treatment is interrupted for <3 days, continue monitoring as before. If ≥3 days of therapy interruption, resume weekly hematologic monitoring for an additional 6 weeks, then resume previous monitoring schedule. If treatment is interrupted for >4 weeks, monitor as if a new patient.

Hematologic toxicity monitoring:

ANC 1,500 to 2,000/mm3: Continue treatment; monitor ANC twice weekly until counts stabilize or increase, then return to previous monitoring schedule.

ANC <1,500/mm3: Discontinue treatment and do not rechallenge patient; continue to monitor WBC/ANC daily until hematologic abnormality is resolved; monitor for signs of infection. If WBC falls <1,000/mm3 or ANC falls <500/mm3, place patient in protective isolation with close observation.

Eosinophilia (eosinophil count >3,000/mm3): Discontinue treatment and restart only after the eosinophil count is <1,000/mm3. Patients with both eosinophilia and clozapine-induced myocarditis should not be re-exposed to clozapine.

Thrombocytopenia (platelet count <50,000/mm3): Discontinue treatment.

Reference Range

Timing of serum samples: Draw trough just before next dose.

Therapeutic reference range (clozapine only): 350 to 600 ng/mL (SI: 1,071 to 1,836 nmol/L). Ratios of clozapine to the metabolite norclozapine may provide perspectives on the metabolism of clozapine. A clozapine:norclozapine ratio <2 suggests the involvement of factors that induce clozapine metabolism, including cigarette smoking and interacting medications. A ratio >2 suggests a nontrough sample, a recent missed dose, or metabolism inhibition or saturation (Costa-Dookhan 2020).

Laboratory alert level (clozapine): 1,000 ng/mL (SI: 3,060 nmol/L) (Hiemke 2018).

Mechanism of Action

The therapeutic efficacy of clozapine (dibenzodiazepine antipsychotic) is proposed to be mediated through antagonism of the dopamine type 2 (D2) and serotonin type 2A (5-HT2A) receptors. In addition, it acts as an antagonist at alpha-adrenergic, histamine H1, cholinergic, and other dopaminergic and serotonergic receptors.

Pharmacokinetics

Onset of action: Oral:

Bipolar disorder, acute mania: Initial effects may be observed within days of treatment with continued improvements over 1 to 2 weeks (Goikolea 2013; Tohen 2000; Welten 2016).

Parkinson disease psychosis: Initial effects may be observed within 1 week with continued improvements over 2 to 3 months (Pintor 2012; Pollak 2004).

Schizophrenia: Initial effects may be observed within 1 to 2 weeks of treatment with continued improvements through 4 to 6 weeks (Agid 2003; Levine 2010). In treatment resistant patients receiving clozapine longer trials of 8 to 12 weeks are recommended (CPA [Remington 2017]; Lee 2015).

Duration of action: Variable

Protein binding: 97% to serum proteins

Metabolism: Extensively hepatic via CYP1A2 (primary), 2C19, 3A4 and 2D6; forms metabolites with limited (desmethyl metabolite) or no activity (hydroxylated and N-oxide derivative derivatives). Note: A pediatric pharmacokinetic study (n=6; age: 9 to 16 years) found higher concentrations of the desmethyl metabolite in comparison to clozapine (especially in females) when compared to data from adult studies; the authors suggest that both the parent drug and desmethyl metabolite contribute to the efficacy and adverse effect profile in children and adolescents (Frazier 2003; Sheehan 2010).

Bioavailability: 27% to 50% (not affected by food); orally disintegrating tablets, regular tablets, and oral suspension are bioequivalent (Gareri 2003; Guitton 1998).

Half-life elimination: Steady state: 12 hours (range: 4 to 66 hours)

Time to peak: Suspension: 2.2 hours (range: 1 to 3.5 hours); Tablets: 2.5 hours (range: 1 to 6 hours); Dispersible tablets: 2.3 hours (range: 1 to 6 hours)

Excretion: Urine (~50%) and feces (30%) with trace amounts of unchanged drug

Pharmacokinetics: Additional Considerations

Renal function impairment: Clozapine concentrations may be increased.

Hepatic function impairment: Clozapine concentrations may be increased.

Pricing: US

Suspension (Versacloz Oral)

50 mg/mL (per mL): $9.62

Tablet, orally-disintegrating (cloZAPine Oral)

12.5 mg (per each): $2.23

25 mg (per each): $3.00

100 mg (per each): $8.18

150 mg (per each): $20.72

200 mg (per each): $27.62

Tablets (cloZAPine Oral)

25 mg (per each): $0.43 - $1.32

50 mg (per each): $1.58 - $1.67

100 mg (per each): $1.12 - $3.43

200 mg (per each): $2.46 - $6.51

Tablets (Clozaril Oral)

25 mg (per each): $6.78

50 mg (per each): $12.18

100 mg (per each): $17.58

200 mg (per each): $35.15

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Anzapine (MY);
  • Azaleptol (UA);
  • Azapin (UA);
  • Chrozap (LK);
  • Clipin (LK);
  • Cloment (ZA);
  • Clopaz (IN);
  • Clopin (CH);
  • Clopine (AU, ID, MY, NZ, TW);
  • Clopixene (PH);
  • Clopsine (BZ, CR, DO, GT, HN, MX, NI, PA, SV);
  • Cloril (TH);
  • Clozamed (TH);
  • Clozapex (EG);
  • Clozarem (MT, MY);
  • Clozaril (AU, BB, GB, HK, ID, IE, JP, KR, MY, NZ, PK, SG, TW);
  • Denzapine (GB, IE);
  • Dicomex (CL);
  • Froidir (FI);
  • Klozapol (PL);
  • Lanolept (AT, LB);
  • Lapenax (AR);
  • Leponex (AE, AT, BE, BG, BH, BR, CH, CL, CO, CY, CZ, DE, DK, EE, EG, ES, FI, FR, GR, HN, HR, IL, IQ, IR, IS, IT, JO, KW, LB, LT, LU, LV, LY, MT, MX, NL, NO, OM, PE, PH, PL, PT, QA, RO, SA, SE, SI, SK, SY, TR, UA, UY, VE, VN, YE, ZA);
  • Lodux (CL);
  • Lozapin (IN);
  • Lozapine (IL);
  • Luften (ID);
  • Nemea (ES);
  • Nirva (PH);
  • Ozadep (VN);
  • Ozapim (PT);
  • Pinazan (BR);
  • Plizarem (EG);
  • Refraxol (PE);
  • Schizonex (EG);
  • Sensipin (BD);
  • Sequax (AR);
  • Sizopin (BD, IN);
  • Sizoril (ID);
  • Syclop (PH);
  • Tanyl (CO);
  • Zapen (CO);
  • Zapenia (BD);
  • Zapine (TW);
  • Ziproc (PH)


For country abbreviations used in Lexicomp (show table)

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