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Special Alerts
Antipsychotics: Newborn Extrapyramidal and Withdrawal Symptoms with Third Trimester Exposure (Update)
June 2011
The U.S. Food and Drug Administration (FDA) and Health Canada have updated or are in the process of updating the pregnancy sections of their respective prescribing information for antipsychotics to contain detailed information about nonteratogenic effects following maternal use during pregnancy. Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms; EPS) and withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor. These effects vary in severity and may be self-limiting (subsiding within hours or days) or require hospitalization. In the cases reported to the FDA, concomitant use of other medications (known to precipitate withdrawal symptoms) may have contributed to the effects, although in some cases, antipsychotic medication use was the only contributing factor for the EPS and withdrawal symptoms.
Women who are taking antipsychotics should not stop them if they become pregnant (abrupt discontinuation is not recommended), but should notify their healthcare provider. Women taking antipsychotics who intend to become pregnant should discuss treatment concerns with their healthcare provider. Any adverse effects noted in newborns should be reported in the U.S. to the FDA's Medwatch program (1-800-332-1088 or https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm) or in Canada to Health Canada's Canada Vigilance Program (1-866-234-2345 or http://www.hc-sc.gc.ca/dhp-mps/medeff/index-eng.php).
For additional information, please refer to:
U.S.: http://www.fda.gov/Drugs/DrugSafety/ucm243903.htm#aihp
Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_78-eng.php
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(KLOE za peen)
Generic Available (U.S.)
Yes: Excludes orally-disintegrating tablet
Prescribing and Access Restrictions
U.S.: Clozaril® is deemed to have an approved REMS program. As a requirement of the REMS program, access to this medication is restricted. Patient-specific registration is required to dispense clozapine. Monitoring systems for individual clozapine manufacturers are independent. If a patient is switched from one brand/manufacturer of clozapine to another, the patient must be entered into a new registry (must be completed by the prescriber and delivered to the dispensing pharmacy). Healthcare providers, including pharmacists dispensing clozapine, should verify the patient's hematological status and qualification to receive clozapine with all existing registries. The manufacturer of Clozaril® requests that healthcare providers submit all WBC/ANC values following discontinuation of therapy to the Clozaril National Registry for all nonrechallengable patients until WBC is ≥3500/mm3 and ANC is ≥2000/mm3.
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. Information specific to each monitoring program is available from the individual manufacturers.
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment-refractory schizophrenia; to reduce risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder
Use: Unlabeled
Schizoaffective disorder, bipolar disorder, childhood psychosis, severe obsessive-compulsive disorder; psychosis/agitation related to Alzheimer's dementia
Pregnancy Risk Factor
B
Pregnancy Considerations
Teratogenic effects were not seen in animal studies. Clozapine crosses the placenta and can be detected in the fetal blood and amniotic fluid. Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and 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. Healthcare providers are encouraged to enroll women 18-45 years of age exposed to clozapine during pregnancy in the Atypical Antipsychotics Pregnancy Registry (1-866-961-2388). Women with amenorrhea associated with use of other antipsychotic agents may return to normal menstruation when switching to clozapine therapy. Reliable contraceptive measures should be employed by women of childbearing potential switching to clozapine therapy.
Lactation
Enters breast milk/not recommended (AAP rates “of concern”; AAP 2001 update pending)
Breast-Feeding Considerations
Clozapine was found to accumulate in breast milk in concentrations higher than the maternal plasma.
Contraindications
Hypersensitivity to clozapine or any component of the formulation; history of agranulocytosis or severe granulocytopenia with clozapine; uncontrolled epilepsy, severe central nervous system depression or comatose state; paralytic ileus; myeloproliferative disorders or use with other agents which have a well-known risk of agranulocytosis or bone marrow suppression
Canadian labeling: Additional contraindications (not in U.S. labeling): Active hepatic disease associated with nausea, anorexia, or jaundice; progressive hepatic disease or hepatic failure; severe renal impairment; severe cardiac disease (eg, myocarditis); patients unable to undergo blood testing
Warnings/Precautions
Boxed warnings:
• Agranulocytosis: See “Concerns related to adverse effects” below.
• Cardiovascular events: See “Concerns related to adverse effects” below.
• Dementia: See “Disease-related concerns” below.
• Orthostatic hypotension: See “Concerns related to adverse effects” below.
• Seizures: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Agranulocytosis: [U.S. Boxed Warning]: Significant risk of agranulocytosis, potentially life-threatening. Therapy should not be initiated in patients with WBC <3500 cells/mm3 or ANC <2000 cells/mm3 or history of myeloproliferative disorder. WBC testing should occur periodically on an on-going basis (see prescribing information for monitoring details) to ensure that acceptable WBC/ANC counts are maintained. Initial episodes of moderate leukopenia or granulopoietic suppression confer up to a 12-fold increased risk for subsequent episodes of agranulocytosis. WBCs must be monitored weekly for at least 4 weeks after therapy discontinuation or until WBC is ≥3500/mm3 and ANC is ≥2000/mm3. Use with caution in patients receiving other marrow suppressive agents. Eosinophilia has been reported to occur with clozapine. Interrupt therapy for eosinophil count >4000/mm3. May resume therapy when eosinophil count <3000/mm3. (Note: The Canadian labeling recommends discontinuing therapy for eosinophil count >3000/mm3; may resume therapy when eosinophil count <1000/mm3). Due to the significant risk of agranulocytosis, it is strongly recommended that a patient must fail at least two trials of other primary medications for the treatment of schizophrenia (of adequate dose and duration) before initiating therapy with clozapine.
• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems.
• Cardiovascular events: Myocarditis, pericarditis, pericardial effusion, cardiomyopathy, and HF have also been associated with clozapine. [U.S. Boxed Warning]: Fatalities due to myocarditis have been reported; highest risk in the first month of therapy, however, later cases also reported. Myocarditis or cardiomyopathy should be considered in patients who present with signs/symptoms of heart failure (dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea, peripheral edema), chest pain, palpitations, new electrocardiographic abnormalities (arrhythmias, ST-T wave abnormalities), or unexplained fever. Patients with tachycardia during the first month of therapy should be closely monitored for other signs of myocarditis. Discontinue clozapine if myocarditis is suspected; do not rechallenge in patients with clozapine-related myocarditis. The reported rate of myocarditis in clozapine-treated patients appears to be 17-322 times greater than in the general population. Clozapine should be discontinued in patients with confirmed cardiomyopathy unless benefit clearly outweighs risk.
• Cerebrovascular effects: An increased incidence of cerebrovascular effects (eg, transient ischemic attack, stroke), including fatalities, has been reported in placebo-controlled trials of atypical antipsychotics in elderly patients with dementia-related psychosis.
• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of pneumonia (eg, Alzheimer's disease).
• Extrapyramidal symptoms (EPS): May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients.
• Fever: Benign transient temperature elevation (>100.4°F) may occur; peaking within the first 3 weeks of treatment. Rule out infection, agranulocytosis, and neuroleptic malignant syndrome (NMS) in patients presenting with fever.
• Hyperglycemia: Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control.
• Neuroleptic malignant syndrome (NMS): Use may be associated with neuroleptic malignant syndrome (NMS); monitor for mental status changes, fever, muscle rigidity and/or autonomic instability.
• Orthostatic hypotension: [U.S. Boxed Warning]: May cause orthostatic hypotension (with or without syncope); generally occurs more frequently with initial titration and in association with rapid dose increases. Use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).
• Sedation: May be moderate to highly sedating, use with caution in disorders where CNS depression is a feature; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Use with caution in patients receiving general anesthesia.
• Seizures: [U.S. Boxed Warning]: Seizures have been associated with clozapine use in a dose-dependent manner; 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.
• 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.
• Tachycardia: May cause tachycardia (including sustained); sustained tachycardia is not limited to a reflex response to orthostatic hypotension, and is present in all positions.
• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.
• Thromboembolism: Rare cases of thromboembolism, including pulmonary embolism and stroke resulting in fatalities, have been associated with clozapine in patients with cardiovascular disease.
• Weight gain: Significant weight gain has been observed with antipsychotic therapy; incidence varies with product. Monitor waist circumference and BMI.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with cardiovascular disease; gradually increase dose.
• Dementia: [U.S. 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. Clozapine is not approved for the treatment of dementia-related psychosis.
• Glaucoma: Use with caution in patients with narrow-angle glaucoma; condition may be exacerbated by cholinergic blockade. Screening is recommended.
• Hepatic impairment: Use with caution in patients with hepatic disease or impairment; monitor hepatic function regularly. Hepatitis has been reported as a consequence of therapy. Discontinuation of therapy may be necessary with significant elevations in liver function tests; may reinitiate with close monitoring and if values return to normal.
• Myasthenia gravis: Use with caution in patients with myasthenia gravis; condition may be exacerbated by cholinergic blockade.
• Pulmonary disease: Use with caution; gradually increase dose.
• Renal impairment: Use with caution in patients with renal impairment.
Concurrent drug therapy issues:
• Benzodiazepines: Concurrent use with benzodiazepines may increase the risk of severe cardiopulmonary reactions.
Special populations:
• Elderly: Use in patients with dementia is associated with an increased risk of mortality and cerebrovascular accidents; avoid antipsychotic use for behavioral problems associated with dementia unless alternative nonpharmacologic therapies have failed and patient may harm self or others. In addition, use may cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults. May also be inappropriate in older adults depending on comorbidities (eg, dementia, delirium) due to its potent anticholinergic effects (Beers Criteria). 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. Smoking cessation may cause toxicity in a patient stabilized on clozapine. Monitor change in smoking patterns.
Dosage form specific issues:
• Phenylalanine: FazaClo® oral disintegrating tablets contain phenylalanine.
Other warnings/precautions:
• Abrupt discontinuation: Medication should not be stopped abruptly; taper off over 1-2 weeks. If conditions warrant abrupt discontinuation (leukopenia, myocarditis, cardiomyopathy), monitor patient for psychosis and cholinergic rebound (headache, nausea, vomiting, diarrhea).
Adverse Reactions
>10%:
Cardiovascular: Tachycardia (25%)
Central nervous system: Drowsiness (39% to 46%), dizziness (19% to 27%), insomnia (2% to 20%)
Gastrointestinal: Sialorrhea (31% to 48%), weight gain (4% to 31%), constipation (14% to 25%), nausea/vomiting (3% to 17%)
1% to 10%:
Cardiovascular: Hypotension (9%), syncope (6%), hypertension (4%), angina (1%), ECG changes (1%)
Central nervous system: Headache (7%), fever (5%), agitation (4%), akinesia (4%), nightmares (4%), restlessness (4%), akathisia (3%), confusion (3%), seizure (3%), anxiety (1%), ataxia (1%), depression (1%), lethargy (1%), myoclonic jerks (1%), slurred speech (1%)
Dermatologic: Rash (2%)
Gastrointestinal: Abdominal discomfort/heartburn (4% to 14%), xerostomia (6%), diarrhea (2%), anorexia (1%), throat discomfort (1%)
Genitourinary: Urinary abnormalities (eg, abnormal ejaculation, retention, urgency, incontinence; 1% to 2%)
Hematologic: Agranulocytosis (1%), eosinophilia (1%), leukocytosis, leukopenia
Hepatic: Liver function tests abnormal (1%)
Neuromuscular & skeletal: Tremor (6%), hypokinesia (4%), rigidity (3%), hyperkinesia (1%), weakness (1%), pain (1%), spasm (1%)
Ocular: Visual disturbances (5%)
Respiratory: Dyspnea (1%), nasal congestion (1%)
Miscellaneous: Diaphoresis (6%), tongue numbness (1%)
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Amentia, amnesia, anemia, arrhythmia (atrial or ventricular), aspiration, blurred vision, bradycardia, bronchitis, cardiomyopathy (usually dilated), cataplexy, CHF, cholestasis, CPK increased, cyanosis, delirium, delusions, dermatitis, diabetes mellitus, difficult urination, DVT, dysphagia, eczema, edema, EEG abnormal, erythema multiforme, esophageal dysmotility, ESR increased, fecal impaction, gastric ulcer, gastroenteritis, granulocytopenia, hallucinations, hematemesis, hepatitis, hypercholesterolemia (rare), hyperglycemia, hypersensitivity reaction, hypertriglyceridemia (rare), hyperuricemia, hyponatremia, hyperosmolar coma, hypothermia, impotence, interstitial nephritis (acute), intestinal obstruction, jaundice, ketoacidosis, loss of speech, metabolic syndrome (Lamberti, 2006), MI, mitral valve insufficiency, myasthenia syndrome, mydriasis, myocarditis, narrow-angle glaucoma, neuroleptic malignant syndrome, obsessive compulsive symptoms, palpitations, pancreatitis (acute), paralytic ileus, paresthesia, Parkinsonism, pericardial effusion, pericarditis, periorbital edema, phlebitis, photosensitivity, pleural effusion, pneumonia, priapism, pruritus, psychosis exacerbated, pulmonary embolism, rectal bleeding, respiratory arrest, rhabdomyolysis, salivary gland swelling, sepsis, status epilepticus, stroke, Stevens-Johnson syndrome, tardive dyskinesia, thrombocytopenia, thrombocytosis, thromboembolism, thrombophlebitis, urticaria, vasculitis, weight loss, wheezing
Metabolism/Transport Effects
Substrate of CYP1A2 (major), CYP2A6 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak), CYP2C19 (weak), CYP2C9 (weak), CYP2D6 (moderate), CYP2E1 (weak), CYP3A4 (weak)
Drug Interactions
Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotics. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Amphetamines: Antipsychotics may diminish the stimulatory effect of Amphetamines. Risk C: Monitor therapy
Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Levocabastine (Nasal); Paliperidone. Risk C: Monitor therapy
Anti-Parkinson's Agents (Dopamine Agonist): Antipsychotics (Atypical) may diminish the therapeutic effect of Anti-Parkinson's Agents (Dopamine Agonist). Risk D: Consider therapy modification
ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole systemic exposure/affects with concomitant use of a weak CYP3A4 inhibitor. Decrease aripiprazole dose to 25% of the usual dose in patients receiving both a CYP3A4 and a CYP2D6 inhibitor (regardless of potencies). Risk C: Monitor therapy
ARIPiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy
Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
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
CarBAMazepine: May increase the metabolism of CloZAPine. Risk D: Consider therapy modification
Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Cimetidine: May increase the serum concentration of CloZAPine. Management: Consider use of an alternative H2 antagonist. Monitor for increased toxic effects of clozapine if cimetidine is initiated/dose increased, or decreased effects if cimetidine is discontinued/dose decreased. Risk D: Consider therapy modification
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin (Systemic): May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy
CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification
CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Risk C: Monitor therapy
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination
Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy
Fosphenytoin: May decrease the serum concentration of CloZAPine. Risk C: Monitor therapy
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Indacaterol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Lithium formulations: May enhance the neurotoxic effect of Antipsychotics. Lithium formulations may decrease the serum concentration of Antipsychotics. Specifically noted with chlorpromazine. Risk C: Monitor therapy
Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Macrolide Antibiotics: May decrease the metabolism of CloZAPine. Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin; Spiramycin. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylphenidate: Antipsychotics may enhance the adverse/toxic effect of Methylphenidate. Methylphenidate may enhance the adverse/toxic effect of Antipsychotics. Risk C: Monitor therapy
Metoclopramide: May enhance the adverse/toxic effect of Antipsychotics. Risk X: Avoid combination
Metyrosine: May enhance the adverse/toxic effect of Antipsychotics. Risk C: Monitor therapy
Mifepristone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Management: Avoid use of mifepristone for treatment of hyperglycemia in Cushing's syndrome in patients receiving QT interval prolonging agents. Avoid initiation of QT prolonging agents for 2 weeks following mifepristone discontinuation. Risk X: Avoid combination
Myelosuppressive Agents: May enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased. Risk X: Avoid combination
Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy
Nefazodone: May decrease the metabolism of CloZAPine. Risk C: Monitor therapy
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Omeprazole: May increase the serum concentration of CloZAPine. Omeprazole may decrease the serum concentration of CloZAPine. Risk C: Monitor therapy
Phenytoin: May decrease the serum concentration of CloZAPine. Risk C: Monitor therapy
Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination
Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
QUEtiapine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Quinagolide: Antipsychotics may diminish the therapeutic effect of Quinagolide. Risk C: Monitor therapy
QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of CloZAPine. Risk D: Consider therapy modification
Serotonin Modulators: Antipsychotics may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Risk C: Monitor therapy
Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Risk D: Consider therapy modification
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotics. Risk C: Monitor therapy
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Toremifene: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Toremifene. The risk for potentially dangerous arrhythmias may be increased. Risk X: Avoid combination
Vandetanib: QTc-Prolonging Agents may enhance the arrhythmogenic effect of Vandetanib. Risk X: Avoid combination
Vemurafenib: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Vemurafenib. Risk X: Avoid combination
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Herb/Nutraceutical: St John's wort may decrease clozapine levels. Avoid kava kava, gotu kola, valerian, St John's wort (may increase CNS depression).
Storage
Store at ≤30°C (86°F).
FazaClo®: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture; do not remove from package until ready to use.
Mechanism of Action
Clozapine (dibenzodiazepine antipsychotic) exhibits weak antagonism of D1, D2, D3, and D5 dopamine receptor subtypes, but shows high affinity for D4; in addition, it blocks the serotonin (5HT2), alpha-adrenergic, histamine H1, and cholinergic receptors
Pharmacodynamics/Kinetics
Protein binding: 97% to serum proteins
Metabolism: Extensively hepatic; forms metabolites with limited or no activity
Bioavailability: 50% to 60% (not affected by food)
Half-life elimination: Steady state: 12 hours (range: 4-66 hours)
Time to peak: 2.5 hours (range: 1-6 hours)
Excretion: Urine (~50%) and feces (30%) with trace amounts of unchanged drug
Dosage
Oral:
Children and Adolescents: Childhood psychosis (unlabeled use): Initial: 12.5-25 mg/day; increase to a target dose of 25-400 mg/day (Kumra, 2008; Turetz, 1997)
Adults:
Schizophrenia: Initial: 12.5 mg once or twice daily; increased, as tolerated, in increments of 25-50 mg/day to a target dose of 300-450 mg/day after 2 weeks; may further titrate in increments not exceeding 100 mg and no more frequently than once or twice weekly. May require doses as high as 600-900 mg/day (maximum dose: 900 mg/day). Note: In some efficacy studies, total daily dosage was administered in 3 divided doses.
Suicidal behavior in schizophrenia or schizoaffective disorder: Initial: 12.5 mg once or twice daily; increased, as tolerated, in increments of 25-50 mg/day to a target dose of 300-450 mg/day after 2 weeks; mean dose is ~300 mg/day (range: 12.5-900 mg); treatment duration 2 years then reassess need. Note: If no longer a suicide risk, may resume prior antipsychotic therapy after gradually tapering off clozapine over 1-2 weeks.
Elderly:
Schizophrenia: Experience in the elderly is limited; initial dose should be 12.5-25 mg/day; increase as tolerated by 25 mg/day to desired response. Elderly may require slower titration and daily increases may not be tolerated.
Psychosis/agitation related to Alzheimer's dementia (unlabeled use): Initial: 12.5 mg/day; if necessary, gradually increase as tolerated not to exceed 75-100 mg/day (Rabins, 2007)
Termination of therapy: If dosing is interrupted for ≥48 hours, therapy must be reinitiated at 12.5-25 mg/day; may be increased more rapidly than with initial titration, unless cardiopulmonary arrest occurred during initial titration.
In the event of planned termination of clozapine, gradual reduction in dose over a 1- to 2-week period is recommended. If conditions warrant abrupt discontinuation (leukopenia), monitor patient for psychosis and cholinergic rebound (headache, nausea, vomiting, diarrhea).
Dosage adjustment for toxicity:
Eosinophilia:
U.S. labeling: Interrupt therapy for eosinophil count >4000/mm3; may resume therapy when eosinophil count <3000/mm3
Canadian labeling: Interrupt therapy for eosinophil count >3000/mm3; may resume therapy when eosinophil count <1000/ mm3
Moderate leukopenia or granulocytopenia (WBC <3000/mm3 and/or ANC <1500/mm3): Discontinue therapy; may rechallenge patient when WBC is >3500/mm3 and ANC is >2000/mm3. Note: Patient is at greater risk for developing agranulocytosis.
Severe leukopenia or granulocytopenia (WBC <2000/mm3 and/or ANC <1000/mm3 [U.S. labeling] or ANC <1500/mm3 [Canadian labeling]): Discontinue therapy and do not rechallenge patient.
Platelets <50,000/mm3: Canadian labeling recommends discontinuing therapy
Administration: Oral
May be taken without regard to food. Total daily dose may be divided into uneven doses with larger dose administered at bedtime.
Canadian labeling: Maintenance dosing ≤200 mg/day may be administered as single dose in the evening.
Orally-disintegrating tablet: Should be removed from foil blister by peeling apart (do not push tablet through the foil). Remove immediately prior to use. Place tablet in mouth and allow to dissolve; swallow with saliva. If dosing requires splitting tablet, throw unused portion away.
Monitoring Parameters
Note: The Canadian labeling recommends initiating treatment in an inpatient setting or an outpatient setting with medical supervision and monitoring of vital signs for at least 6-8 hours after the first few doses.
Mental status, ECG, WBC (see below), vital signs, fasting lipid profile and fasting blood glucose/Hgb A1c (prior to treatment, at 3 months, then annually; liver function tests; BMI, personal/family history of obesity; waist circumference (weight should be assessed prior to treatment, at 4 weeks, 8 weeks, 12 weeks, and then at quarterly intervals. Consider titrating to a different antipsychotic agent for a weight gain ≥5% of the initial weight); blood pressure; abnormal involuntary movement scale (AIMS).
WBC and ANC should be obtained at baseline and at least weekly for the first 6 months (26 weeks) of continuous treatment. If counts remain acceptable (WBC ≥3500/mm3, ANC ≥2000/mm3) during this time period, then they may be monitored every other week for the next 6 months (26 weeks). If WBC/ANC continue to remain within these acceptable limits after the second 6 months (26 weeks) of therapy, monitoring can be decreased to every 4 weeks. If clozapine is discontinued, a weekly WBC should be conducted for an additional 4 weeks or until WBC is ≥3500/mm3 and ANC is ≥2000/mm3. If clozapine therapy is interrupted due to moderate leukopenia, weekly WBC/ANC monitoring is required for 12 months in patients restarted on clozapine treatment. (Note: When therapy is interrupted for >3 days, the Canadian labeling recommends weekly hematologic testing for an additional 6 weeks). If therapy is interrupted for reasons other than leukopenia/granulocytopenia, the 6-month time period for initiation of biweekly WBCs may need to be reset. This determination depends upon the treatment duration, the length of the break in therapy, and whether or not an abnormal blood event occurred.
Consult manufacturer prescribing information for determination of appropriate WBC/ANC monitoring interval.
Dietary Considerations
May be taken without regard to food. Some products may contain phenylalanine.
Patient Education
Avoid alcohol. Maintain adequate hydration. If you have diabetes, monitor blood glucose levels frequently. You may experience headache, excess drowsiness, dizziness, or blurred vision; constipation; dry mouth, nausea, or vomiting; or postural hypotension. You may be prone to infections; report fever, sore throat, or other possible signs of infection. Report persistent CNS effects (insomnia, depression, altered consciousness); palpitations, rapid heartbeat, or severe dizziness; vision changes; hypersalivation, tearing, or sweating; seizures; chest pain or shortness of breath; excessive fatigue; or worsening of condition.
Geriatric Considerations
Not recommended for use in nonpsychotic patients (eg, dimentia-related psychotic symptoms). Studies in subjects >65 years of age have not been done. Orthostatic hypotension and sustained tachycardia have been noted in up to 25% of patients taking clozapine; therefore, elderly with cardiovascular disease may be at risk. The anticholinergic effects of clozapine may be prominent in elderly (eg, constipation, confusion, urinary retention).
This medication is considered to be potentially inappropriate in this patient population (Beers Criteria: Quality of evidence - moderate; Strength of recommendation - strong).
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Sialorrhea and xerostomia (normal salivary flow resumes upon discontinuation). Many patients may experience orthostatic hypotension with clozapine; precautions should be taken; do not use atropine-like drugs for xerostomia in patients taking clozapine due to significant potentiation.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Most pharmacology textbooks state that in presence of phenothiazines, systemic doses of epinephrine paradoxically decrease the blood pressure. This is the so called “epinephrine reversal” phenomenon. This has never been observed when epinephrine is given by infiltration as part of the local anesthesia procedure.
Mental Health: Child/Adolescent Considerations
Eleven adolescents with childhood-onset schizophrenia who failed a 6-week trial of haloperidol were treated with clozapine (mean 6-week daily dose: 370 mg) (Frazier, 1994). Twenty-one patients (mean age: 14 ± 2.3 years) with schizophrenia (DSM-III-R) who had been nonresponsive to typical antipsychotics received clozapine 176 ± 149 mg/day (final dose) (Kumra, 1996). Clozapine was evaluated in 11 neuroleptic-resistant children (<13 years of age) mean dosage: 227 mg/day (Turetz, 1997). A 15-year old boy with severe treatment-refractory bipolar disorder type I was treated successfully with clozapine 300 mg/day (Masi, 1998).
Frazier JA, Gordon CT, McKenna K, et al, “An Open Trial of Clozapine in 11 Adolescents With Childhood-Onset Schizophrenia,” J Am Acad Child Adolesc Psychiatry, 1994, 33(5):658-63.
Kumra S, Frazier JA, Jacobsen LK, et al, “Childhood-Onset Schizophrenia. A Double-Blind Clozapine-Haloperidol Comparison,” Arch Gen Psychiatry, 1996, 53(12):1090-7.
Kumra S, Oberstar JV, Sikich L, et al, “Efficacy and Tolerability of Second-Generation Antipsychotics in Children and Adolescents With Schizophrenia,” Schizophr Bull, 2008, 34(1):60-71.
Masi G and Milone A, “Clozapine Treatment in an Adolescent With Bipolar Disorder,” Panminerva Med, 1998, 40(3):254-7.
Turetz M, Mozes T, Toren P, et al, “An Open Trial of Clozapine in Neuroleptic-Resistant Childhood-Onset Schizophrenia,” Br J Psychiatry, 1997, 170:507-10.
Mental Health: Comment
Clozapine is the prototype drug from the antipsychotic class often referred to as atypical. It should be noted that the definition of the term “atypical” is not universally agreed upon. Some prefer to describe antipsychotics based on their pharmacological properties. A common feature of all definitions used to describe “atypical” antipsychotics is the lack of significant acute or subacute EPS, at dosages generally associated with antipsychotic actions. Other experts have included definitions of atypicality that include a) failure to increase serum prolactin levels; b) superior efficacy for positive, negative, and cognitive symptoms; and c) lack of evidence of tardive dyskinesia or dystonia following chronic administration. Clozapine meets all of these criteria and therefore is considered the standard by which other atypical antipsychotics should be compared.
Recently, questions have been raised about its ability (as well as other atypical antipsychotics) to differentiate itself on negative symptom improvement. However, clozapine is considered the drug of choice for treating refractory schizophrenia. Refractory illness is often defined by “Kane” criteria in which patients have failed to respond to at least two antipsychotics from different chemical classes at 1000 mg of chlorpromazine or its equivalent (Kane, 1988).
In a recent trial, clozapine therapy demonstrated superiority over olanzapine therapy in preventing suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide (Meltzer, 2003). The authors concluded that the use of clozapine for 2 years in this population should lead to a significant reduction in suicidal behavior.
Tardive dyskinesia (TD) secondary to typical antipsychotics has an estimated incidence of 3% to 5% per year for the first 5 years of treatment. The incidence of TD associated with the atypical antipsychotics is estimated to be 0.5% to 1%. It is not clear if this estimate represents a risk associated with mental illness or to what extent drug therapy can be implicated. Clozapine appears less likely to cause tardive dyskinesia than typical antipsychotics (fluphenazine, haloperidol), but is generally associated with more weight gain and metabolic abnormalities such as diabetes.
Dose-dependent side effects associated with clozapine include seizures, tachycardia, and sedation.
Coadministration of two or more antipsychotics does not generally improve clinical response and may increase the potential for adverse effects.
In 2008, the FDA issued a warning regarding increased mortality risk with typical and atypical antipsychotic drugs when used in elderly patients with dementia-related psychosis.
Kane J, Honigfeld G, Singer J, et al, “Clozapine for the Treatment-Resistant Schizophrenic. A Double-Blind Comparison With Chlorpromazine,” Arch Gen Psychiatry, 1988, 45(9):789-96.
Meltzer HY, Alphs L, Green AI, et al, “Clozapine Treatment for Suicidality in Schizophrenia: International Suicide Prevention Trial (InterSePT),” Arch Gen Psychiatry, 2003, 60(1):82-91.
Nursing: Physical Assessment/Monitoring
Initiate at lower doses and taper dosage slowly when discontinuing. Instruct patients with diabetes to monitor blood glucose levels closely; may cause hyperglycemia. Be alert to the potential for cardiac abnormalities. Monitor weight prior to treatment and at least monthly. Consider titrating to a different antipsychotic agent for a weight gain ≥5% of initial weight. Review ophthalmic exam periodically and assess results of weekly laboratory tests.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 25 mg, 50 mg, 100 mg, 200 mg
Clozaril®: 25 mg, 100 mg [scored]
Tablet, orally disintegrating, oral:
FazaClo®: 12.5 mg [contains phenylalanine 0.87 mg/tablet; mint flavor]
FazaClo®: 25 mg [contains phenylalanine 1.74 mg/tablet; mint flavor]
FazaClo®: 100 mg [contains phenylalanine 6.96 mg/tablet; mint flavor]
FazaClo®: 150 mg [contains phenylalanine 10.44 mg/tablet; mint flavor]
FazaClo®: 200 mg [contains phenylalanine 13.92 mg/tablet; mint flavor]
Pricing: U.S. (www.drugstore.com)
Tablets (Clozaril)
25 mg (100): $242.17
References
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International Brand Names
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Last full review/revision April 2012
Content last modified April 2012
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