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Clozapine


Pronunciation

 (KLOE za peen)


U.S. Brand Names

 Clozaril®; Fazaclo™


Generic Available

 Yes


Canadian Brand Names

 Clozaril®; Gen-Clozapine; Rhoxal-clozapine


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


Restrictions

 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, are encouraged to verify the patient's hematological status and qualification to receive clozapine with all existing registries.


Pregnancy Risk Factor

 B


Pregnancy Implications

 Teratogenic effects were not seen in animal studies; however, there are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if clearly needed.


Lactation

 Enters breast milk/not recommended (AAP rates "of concern")


Contraindications

 Hypersensitivity to clozapine or any component of the formulation; history of agranulocytosis or granulocytopenia with clozapine; uncontrolled epilepsy; severe central nervous system depression or comatose state; myeloproliferative disorders or use with other agents which have a well-known risk of agranulocytosis or bone marrow suppression

In patients with WBC 3500 cells/mm 3 before therapy; if WBC falls to <3000 cells/mm 3 during therapy the drug should be withheld until signs and symptoms of infection disappear and WBC rises to >3000 cells/mm 3


Warnings/Precautions

 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). Elderly patients are more susceptible to adverse effects (including agranulocytosis, cardiovascular, anticholinergic, and tardive dyskinesia).

Significant risk of agranulocytosis, potentially life-threatening. WBC testing should occur weekly for the first 6 months of therapy; thereafter, if acceptable WBC counts are maintained (WBC 3000/mm 3 , ANC 1500/mm 3 ) then WBC counts can be monitored every other week. WBCs must be monitored weekly for the first 4 weeks after therapy discontinuation. Use with caution in patients receiving other marrow suppressive agents. Eosinophilia has been reported to occur with clozapine and may require temporary or permanent interruption of therapy.

Cognitive and/or motor impairment (sedation) is common with clozapine, resulting in impaired performance of tasks requiring alertness (eg, operating machinery or driving). 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. Has been associated with benign, self-limiting fever (<100.4°F, usually within first 3 weeks). However, clozapine may also be associated with severe febrile reactions, including neuroleptic malignant syndrome (NMS). Clozapine's potential for extrapyramidal symptoms appears to be extremely low.

May cause anticholinergic effects; use with caution in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, xerostomia, visual problems, constipation, or history of bowel obstruction. May cause 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. Use with caution in patients with hepatic disease or impairment; hepatitis has been reported as a consequence of therapy.

May cause orthostatic hypotension and tachycardia; use with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). Concurrent use of psychotropics and benzodiazepines may increase the risk of severe cardiopulmonary reactions.

Myocarditis, pericarditis, pericardial effusion, cardiomyopathy, and CHF have also been associated with clozapine. 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 cardiomyopathy in clozapine-treated patients is similar to that in the general population. The majority of patients were over 50 years of age and were taking clozapine for >6 months. Clozapine should be discontinued in patients with confirmed cardiomyopathy unless benefit clearly outweighs risk. Rare cases of thromboembolism, including pulmonary embolism and stroke resulting in fatalities, have been associated with clozapine.


Adverse Reactions

>10%:

Cardiovascular: Tachycardia

Central nervous system: Drowsiness, dizziness

Gastrointestinal: Constipation, weight gain, sialorrhea

Genitourinary: Urinary incontinence

1% to 10%:

Cardiovascular: Angina, ECG changes, hyper-/hypotension, syncope

Central nervous system: Akathisia, seizure, headache, nightmares, akinesia, confusion, insomnia, fatigue, myoclonic jerks, restlessness, agitation, lethargy, ataxia, slurred speech, depression, anxiety

Dermatologic: Rash

Gastrointestinal: Abdominal discomfort, anorexia, diarrhea, heartburn, xerostomia, nausea, vomiting

Hematologic: Eosinophilia, leukopenia, leukocytosis

Hepatic: Liver function tests abnormal

Neuromuscular & skeletal: Tremor, rigidity, hyperkinesia, weakness

Ocular: Visual disturbances

Respiratory: Rhinorrhea

Miscellaneous: Diaphoresis (increased), fever

<1% (Limited to important or life-threatening): Agranulocytosis, arrhythmia, blurred vision, cardiomyopathy (usually dilated), CHF, diabetes mellitus, difficult urination, granulocytopenia, hyperglycemia, impotence, MI, myocarditis, neuroleptic malignant syndrome, pericardial effusion, pericarditis, rigidity, tardive dyskinesia, thrombocytopenia, thromboembolism, pulmonary embolism, stroke

Postmarketing and/or case reports: Aspiration, cholestasis, ESR increased, fecal impaction, hepatitis, intestinal obstruction, jaundice, narrow-angle glaucoma, paralytic ileus, photosensitivity, salivary gland swelling, status epilepticus


Overdosage/Toxicology

 Symptoms of overdose include altered states of consciousness, tachycardia, hypotension, hypersalivation, and respiratory depression. Following initiation of essential overdose management, toxic symptom treatment and supportive treatment should be initiated.


Drug Interactions

 Substrate of CYP1A2 (major), 2A6 (minor), 2C8/9 (minor), 2C19 (minor), 2D6 (minor), 3A4 (minor); Inhibits CYP1A2 (weak), 2C8/9 (weak), 2C19 (weak), 2D6 (moderate), 2E1 (weak), 3A4 (weak)

Anticholinergics: Clozapine has potent anticholinergic effects. May potentiate the effects of anticholinergic agents.

Antihypertensives: Clozapine may potentiate the hypotensive effects of antihypertensive agents.

Benzodiazepines: In combination with clozapine may produce respiratory depression and hypotension, especially during the first few weeks of therapy; monitor for altered response

Carbamazepine: A case of neuroleptic malignant syndrome has been reported in combination with clozapine; in addition, carbamazepine may alter clozapine levels (see enzyme inducers); monitor

CYP1A2 inducers: May decrease the levels/effects of clozapine. Example inducers include aminoglutethimide, carbamazepine, phenobarbital, and rifampin.

CYP1A2 inhibitors: May increase the levels/effects of clozapine. Example inhibitors include amiodarone, ciprofloxacin, fluvoxamine, ketoconazole, norfloxacin, ofloxacin, and rofecoxib.

CYP2D6 substrates: Clozapine may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Clozapine may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

Epinephrine: Clozapine may reverse the pressor effect of epinephrine; use should be avoided in the treatment of drug-induced hypotension.

Metoclopramide: May increase extrapyramidal symptoms (EPS) or risk.

Risperidone: Effects and/or toxicity may be increased when combined with clozapine; monitor

Valproic acid: May cause reductions in clozapine concentrations; monitor for altered response


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Herb/Nutraceutical: St John's wort may decrease clozapine levels. Avoid kava kava, gotu kola, valerian, St John's wort (may increase CNS depression).


Stability

 Dispensed in "clozapine patient system" packaging.


Mechanism of Action

 Clozapine (dibenzodiazepine antipsychotic) is a weak dopamine1 and dopamine2 receptor blocker, but blocks D1-D5 receptors; in addition, it blocks the serotonin2, alpha-adrenergic, histamine H1, and cholinergic receptors


Pharmacodynamics/Kinetics

Protein binding: 97% to serum proteins

Metabolism: Extensively hepatic

Bioavailability: 12% to 81%

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

Time to peak: 2.5 hours

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


Dosage

 Oral: 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.

Children and Adolescents: Childhood psychosis (unlabeled use): Initial: 25 mg/day; increase to a target dose of 25-400 mg/day

Adults: Schizophrenia or to reduce risk of suicidal behavior: 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 2-4 weeks, may require doses as high as 600-900 mg/day for the treatment of schizophrenia; median dose to reduce risk of suicidal behavior is ~300 mg/day (range 12.5-900 mg)

Elderly: Schizophrenia: Dose selection and titration should be cautious

Note: 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).


Administration

 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

 Mental status, ECG, WBC, vital signs, fasting lipid profile and fasting blood glucose/Hgb A1c (prior to treatment, at 3 months, then annually); BMI, personal/family history of obesity; waist circumference; blood pressure; abnormal involuntary movement scale (AIMS). WBC should be obtained at baseline and at least weekly for the first 6 months of continuous treatment. If WBC counts remain acceptable (WBC 3000/mm 3 , ANC 1500/mm 3 ) during this time period, then WBC counts may be monitored every other week thereafter. If clozapine is discontinued, a weekly WBC should be completed for an additional 4 weeks. If clozapine therapy is interrupted, 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 full prescribing information for determination of appropriate WBC-monitoring interval. 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.


Dietary Considerations

 May be taken without regard to food. FazaClo™ contains phenylalanine 1.75 mg per 25 mg tablet and phenylalanine 6.96 mg per 100 mg tablet.


Patient Education

 Use exactly as directed; do not increase dose or frequency. Do not discontinue without consulting prescriber. Avoid alcohol or caffeine and other prescription or OTC medications not approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. If you have diabetes, monitor blood glucose levels frequently. You may experience headache, excess drowsiness, dizziness, or blurred vision (use caution driving or when engaging in tasks requiring alertness until response to drug is known); dry mouth, constipation, diarrhea; nausea, vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); or postural hypotension (use caution climbing stairs or when changing position from lying or sitting to standing). Report persistent CNS effects (insomnia, depression, altered consciousness); palpitations, rapid heartbeat, severe dizziness; vision changes; hypersalivation, tearing, sweating; respiratory difficulty; or worsening of condition. Report seizures, flu-like symptoms, chest pain, shortness of breath, or excessive fatigue. Breast-feeding precaution: Breast-feeding is not recommended.


Nursing Implications

 Benign, self-limiting temperature elevations sometimes occur during the first 3 weeks of treatment, weekly CBC mandatory for first 6 months


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 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.

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.


Dosage Forms

Tablet: 12.5 mg, 25 mg, 100 mg

Clozaril®: 25 mg, 100 mg

Tablet, orally-disintegrating (FazaClo™): 25 mg [contains phenylalanine 1.75 mg; mint flavor], 100 mg [contains phenylalanine 6.96 mg; mint flavor]


References

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International Brand Names

 Cloment® (ZA); Clopine® (AU); Clopsine® (MX); Clozapin 1A Pharma® (DE); Clozapina Chiesi® (IT); Clozapina Fabra® (AR); Clozapin beta® (DE); Clozapin Destin® (CZ); Clozapine Alpharma® (FI, SE); Clozapine Dumex-Alpharma® (DK); Clozapine® (NO, PL); Clozapin Hexal® (DE); Clozapin-neuraxpharm® (DE); Clozaril® (AU, CA, GB, HK, ID, IE, NZ, SG, TH); Elcrit® (DE); Froidir® (FI); Gen-Clozapine (CA); Klozapol® (PL); Lanolept® (AT); Lapenax® (AR); Leponex® (AT, BE, BG, BR, CH, CL, CO, CR, CZ, DE, DK, DO, ES, FI, FR, GT, HN, HR, HU, IL, IT, LK, LU, MX, NL, NO, PA, PL, PT, RO, RU, SE, SI, SV, TR, YU, ZA); Lozapine® (IL); Rhoxal-clozapine (CA); SBPA Clozapine® (AU); Sensipin® (BD); Sizopin® (BD, IN); Zapen® (CO)


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