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Product Name
:
CLOZAPINE-ELSaad (tab)
Chemical Name
:
Clozapine
Therapeutic Category
:
Central nervous system drugs
Pharmacologic Category
:
Antipsychotic Agent, Atypical
Pharmaceutical Form
:
Tablets
Composition
:
Clozapine 100mg
Monitoring Parameters
Dosing
 
Dosing: Adult
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.
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).

Dosing: Pediatric

Children and Adolescents: Childhood psychosis (unlabeled use): Oral: Initial: 12.5-25 mg/day; increase to a target dose of 25-400 mg/day (Kumra, 2008; Turetz, 1997)

Dosing: Geriatric

Schizophrenia: Oral: 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): Oral: Initial: 12.5 mg/day; if necessary, gradually increase as tolerated not to exceed 75-100 mg/day (Rabins, 2007)
Dosing: 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
Use
 
Treatment-refractory schizophrenia; to reduce risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder
Use - Unlabeled/Investigational
Schizoaffective disorder, bipolar disorder, childhood psychosis, severe obsessive-compulsive disorder; psychosis/agitation related to Alzheimer’s dementia
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, 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, 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
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 Drug
 
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: 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).
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
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
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
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
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
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
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
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. 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
Macrolide Antibiotics: May decrease the metabolism of CloZAPine. Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin (Systemic); Spiramycin. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
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
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
Omeprazole: May decrease the serum concentration of CloZAPine. Omeprazole may increase the serum concentration of CloZAPine. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Phenytoin: May decrease the serum concentration of CloZAPine. Risk C: Monitor therapy
Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification
Quinagolide: Antipsychotics may diminish the therapeutic effect of Quinagolide. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of CloZAPine. Risk D: Consider therapy modification
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: May enhance the adverse/toxic effect of Antipsychotics. Risk C: Monitor therapy
Thioridazine: CYP2D6 Inhibitors may decrease the metabolism of Thioridazine. Risk X: Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Risk C: Monitor therapy
Pregnancy
 
B
Pregnancy Implications
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.
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
 
   
 
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