Clozapine
Pronouncation: (KLOE-za-PEEN)Class: Dibenzapine derivative
Trade Names:
Clozapine
- Tablets 12.5 mg
Trade Names:
Clozaril
- Tablets 25 mg
- Tablets 100 mg
Trade Names:
FazaClo
- Tablets, orally disintegrating 25 mg
- Tablets, orally disintegrating 100 mg
Pharmacology
Feedback for Clozapine
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Interferes with dopamine binding at D 1 , D 2 , D 3 , and D 5 receptors in CNS; antagonizes adrenergic, cholinergic, histaminergic, and serotonergic neurotransmission.
Pharmacokinetics
Absorption
C max is about 319 ng/mL (at steady state). T max is about 2.5 h.
Distribution
About 97% protein bound.
Metabolism
Extensively metabolized.
Elimination
The t ½ is about 8 h (single dose) and about 12 h (steady state). About 50% is excreted in urine and 30% in feces as metabolites.
Indications and Usage
Management of severely and chronically mentally ill schizophrenic patients who have not responded to or cannot tolerate standard antipsychotic drug treatment; to reduce risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for reexperiencing suicidal behavior.
Contraindications
History of clozapine-induced agranulocytosis or severe granulocytopenia; myeloproliferative disorders; simultaneous administration with other agents known to cause bone marrow suppression; severe CNS depression or comatose states; uncontrolled epilepsy; paralytic ileus; hypersensitivity to product.
Dosage and Administration
Cautious titration and divided dosage schedules are recommended.
Adults Initial dosePO 12.5 mg daily or twice daily; increase by 25 to 50 mg daily up to 300 to 450 mg daily within 2 wk. May then increase dose in increments not to exceed 100 mg once or twice/wk.
Usual dosage300 to 600 mg daily (max, 900 mg daily).
General Advice
- Only available through a distribution system that ensures monitoring of WBC counts.
- If reinitiating treatment in patient who has been off clozapine (2 or more days since last dose), ensure that dose is retitrated, starting at 12.5 mg once or twice daily.
- Administer prescribed dose without regard to meals. Administer with food if GI upset occurs.
- Tablets, orally disintegrating
- Remove tablet from blister pack just prior to use. Do not push tablet through foil. Peel foil from blister and gently remove tablet from blister.
- Place tablet in mouth immediately after removing from blister pack and allow to disintegrate and swallow with saliva. No water is needed to take the tablet.
- Destroy half tablets. Do not save half tablets for future dosing.
Storage/Stability
Store tablets and orally disintegrating tablets at controlled room temperature (not exceeding 86°F). Protect orally disintegrating tablets from moisture.
Drug Interactions
Agents that suppress bone marrowRisk or severity of bone marrow suppression may be increased.
Alcohol and CNS drugs (eg, benzodiazepines, carbamazepine, tricyclic antidepressants)Use with caution because of CNS effects of clozapine.
AnticholinergicsAnticholinergic effects may be potentiated.
AntihypertensivesHypotensive effects may be potentiated.
Barbiturates (eg, phenobarbital), nicotine, phenytoin, rifampinMay decrease blood levels of clozapine.
Drugs known to induce CYP-450 enzymes (eg, phenytoin, rifampin)May reduce clozapine plasma levels, decreasing the effectiveness.
Drugs that inhibit CYP-450 (eg, caffeine, cimetidine, ciprofloxacin, erythromycin, fluoxetine, fluvoxamine, modafinil, nefazodone, risperidone, ritonavir)May elevate clozapine plasma levels, increasing the risk of adverse reactions.
Type 1C antiarrhythmics (eg, flecainide, propafenone)Use with caution.
Laboratory Test Interactions
None well documented.
Adverse Reactions
Cardiovascular
Tachycardia (25%); hypotension (9%); hypertension (4%); chest pain/angina, ECG change/cardiac abnormality (1%); atrial or ventricular fibrillation, cardiomyopathy, deep vein thrombosis, myocarditis (postmarketing).
CNS
Somnolence (46%); drowsiness/sedation (39%); dizziness (27%); insomnia (20%); vertigo (19%); headache (7%); syncope, tremor (6%); agitation, disturbed sleep/nightmares, hypokinesia/akinesia, restlessness (4%); akathisia, confusion, rigidity, seizures (3%); fatigue (2%); anxiety, ataxia, depression, epileptiform movements/myoclonic jerks, hyperkinesia, lethargy, slurred speech, weakness (1%); abnormal EEG, delirium, exacerbation of psychosis, mild cataplexy, myoclonus, paresthesia, status epilepticus (postmarketing).
Dermatologic
Rash (2%); erythema multiforme, Stevens-Johnson syndrome (postmarketing).
EENT
Visual disturbances (5%); nasal congestion, throat discomfort (1%); narrow-angle glaucoma, periorbital edema (postmarketing).
GI
Salivary hypersecretion (48%); salivation (31%); constipation (25%); nausea, vomiting (17%); dyspepsia (14%); dry mouth (6%); abdominal discomfort/heartburn (4%); diarrhea (2%); anorexia (1%); acute pancreatitis, dysphagia, fecal impaction, intestinal obstruction/paralytic ileus, salivary gland swelling (postmarketing).
Genitourinary
Urinary abnormalities (2%); abnormal ejaculation, incontinence, urinary retention, urinary urgency/frequency (1%); acute interstitial nephritis, priapism (postmarketing).
Hematologic
Leukopenia/decreased WBC/neutropenia (3%); agranulocytosis, eosinophilia (1%); elevated hemoglobin/hematocrit, erythrocyte sedimentation rate increase, sepsis, thrombocytopenia, thrombocytosis (postmarketing).
Hepatic
Liver test abnormalities (1%); cholestasis, hepatitis, jaundice (postmarketing).
Metabolic
Weight increase (31%); hyperglycemia, hyperuricemia, hyponatremia, weight loss (postmarketing).
Respiratory
Dyspnea (1%); aspiration, pleural effusion, pulmonary embolism (postmarketing).
Miscellaneous
Sweating (6%); fever (5%); pain (back, neck, legs), muscle spasm, muscle pain/ache, muscle weakness, tongue numb/sore (1%); CPK elevation, hypersensitivity reactions, myasthenic syndrome, photosensitivity, rhabdomyolysis, vasculitis (postmarketing).
Precautions
WarningsAgranulocytosisLife-threatening adverse reaction. Monitor WBC and differential count before initiation of treatment and at least weekly for the first 6 mo and for 4 wk after discontinuation of treatment. Do not initiate therapy if WBC is less than 3,500/mm 3 or if patient has a history of myeloproliferative disease. CV and respiratory effectsOrthostatic hypotension can occur. Rarely, collapse can be profound and accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur during initial dose titration in association with rapid dose escalation. Caution is advised with use of psychotropics or benzodiazepines because collapse, respiratory arrest, and cardiac arrest have been reported. DementiaElderly patients with dementia-related psychosis treated with atypical antipsychotic agents (eg, Clozaril ), compared with placebo, are at increased risk of death. MyocarditisIncreased risk of fatal myocarditis, especially during the first month of therapy. Promptly discontinue clozapine if myocarditis is suspected. SeizuresAssociated with therapy; use caution when administering to patients with a history of seizures or other predisposing factors. High clozapine dosage appears to be an important predictor of seizures. |
MonitorBlood glucoseEnsure fasting blood glucose is evaluated before starting therapy and periodically thereafter during therapy in patient with risk factors for diabetes mellitus (eg, obesity, family history of diabetes). Bone marrow aspirationEnsure WBC counts and differential are performed daily and bone marrow aspiration is considered if the total WBC count falls below 2,000/mm 3 or the absolute neutrophil count (ANC) falls below 1,000/mm 3 . CulturesEnsure appropriate cultures are obtained and appropriate antibiotics are started if patient develops signs or symptoms of infection. Hepatic transaminasesEnsure hepatic transaminases are evaluated in patient who develops nausea, vomiting, and/or appetite loss, or other signs of hepatitis. Be prepared to discontinue therapy if transaminases are significantly elevated or if jaundice develops. Neurologic statusAssess baseline neurologic status and, during treatment, observe for involuntary body and facial movements, drowsiness, agitation, anxiety, aggressive reaction, or seizure activity. Repeat WBC countRepeat WBC count and differential if, after initial treatment, the total WBC count has dropped below 3,500/mm 3 , or if it has dropped a substantial amount (single drop of 3,000 or more in the WBC count or a cumulative drop of 3,000 or more within 3 wk) from baseline, even if the WBC count is above 3,500/mm 3 , or if immature forms are present. If subsequent WBC counts are between 3,000 and 3,500/mm 3 , and the ANC is above 1,500/mm 3 , increase WBC and differential counts to twice weekly. Response to treatmentFrequently assess patient for response to treatment. Restarting therapyEnsure clozapine therapy is not restarted in patient whose total WBC count falls below 2,000/mm 3 or the ANC falls below 1,000/mm 3 . Review therapyEnsure therapy is periodically reviewed to determine if it needs to be continued without change or if a dose change (eg, increase, decrease, discontinuation) is indicated. Adverse reactionsAdvise patient to immediately report any of the following symptoms: chest pain, constipation, dizziness, dyspnea, excessive drowsiness, fever, palpitations, persistent nausea or vomiting, symptoms of hyperglycemia (polyuria, polydipsia, polyphagia), tachycardia, unexplained fatigue. WBC count decreaseWithhold therapy if WBC count falls below 3,000/mm 3 or the ANC falls below 1,500/mm 3 . Repeat WBC count and differential daily and closely monitor patient for symptoms of infection. Consider reinstituting clozapine if no symptoms of infection develop, and if the total WBC count returns to levels greater than 3,000/mm 3 and the ANC returns to levels above 1,500/mm 3 . Continue to monitor WBC counts and differential twice weekly until total WBC counts return to levels above 3,500/mm 3 . WBC scheduleEnsure WBC count and differential are determined prior to, weekly for the first 6 mo of treatment, and then every other week for duration of treatment. Determine WBC and differential weekly for 4 wk following discontinuation of treatment. |
Pregnancy
Category B .
Lactation
Undetermined.
Children
Safety and efficacy not established.
Elderly
Approach dose selection with caution, taking into consideration decreased renal, hepatic, and cardiac function, and other concomitant disease and drug therapy.
Hepatic Function
Use caution when administering clozapine to patients who have concurrent hepatic disease. Hepatitis has been reported in patients with normal and preexisting abnormalities in liver function.
Special Risk Patients
Use great caution in patients with renal or cardiac disease, narrow-angle glaucoma, enlarged prostate, or history of seizures; seizures are more likely at higher doses.
Cognitive and motor performance
Because of initial sedation, mental and/or physical abilities may be impaired, especially during the first few days of therapy.
Debilitated patients
Lower doses required; high risk for anticholinergic and hypotensive effects.
ECG changes
Some patients experience ECG repolarization changes during treatment. Several have experienced significant cardiac events, including ischemic changes, MI, nonfatal arrhythmias, and sudden, unexplained death.
Fever
May experience transient temperature elevations above 100.4°F with peak incidence within first 3 wk of treatment.
General anesthesia
Because of the CNS effects of clozapine, caution is advised in patients receiving general anesthesia.
GI
Varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction; fecal impaction and paralytic ileus have been associated with clozapine use.
Hyperglycemia and diabetes mellitus
Severe hyperglycemia, possibly leading to ketoacidosis, has been reported. Monitor patients with established diagnosis of diabetes mellitus regularly for worsening of glucose control.
Neuroleptic malignant syndrome (NMS)
This potentially fatal condition has been reported in association with antipsychotic drugs. Signs and symptoms include hyperpyrexia, muscle rigidity, altered mental status, irregular pulse or BP, tachycardia, diaphoresis, and cardiac arrhythmias.
Pulmonary embolism
Consider the possibility in patients who present with deep vein thrombosis, acute dyspnea, chest pain, or other respiratory signs or symptoms.
Tardive dyskinesia
This syndrome of potentially irreversible, involuntary dyskinetic movements has occurred with other antipsychotic agents. Incidence is highest among elderly patients, especially women.
Withdrawal of medication
For planned discontinuation of therapy, gradually reduce dosage over 1 to 2 wk. If abrupt discontinuation is required (eg, leukopenia), carefully observe the patient for recurrence of psychotic symptoms and symptoms of cholinergic rebound (eg, headache, nausea, vomiting).
Overdosage
Symptoms
Aspiration pneumonia, cardiac arrhythmias, coma, delirium, drowsiness, excessive salivation, hypotension, respiratory depression or failure, seizures, tachycardia.
Patient Information
- Explain name, dose, action, and potential adverse reactions of drug, including risk of developing agranulocytosis, seizures, myocarditis, and tardive dyskinesia.
- Ensure patient or caregiver understands that medication will only be provided in 1‐ or 2‐wk supplies, depending on frequency of WBC count monitoring. Ensure patient knows how to obtain refills so that therapy is continued without interruption.
- Instruct patient to take prescribed dose without regard to meals but to take with food if stomach upset occurs.
- Instruct patient using orally disintegrating tablet to keep tablet in unopened blister until just before use. Instruct patient to remove tablet by peeling the foil from the back of the blister and then to immediately place the tablet (or half tablet if ordered) in mouth, allow the tablet to disintegrate, and then swallow with saliva. Advise patient to destroy any half tablets and not to save for future use.
- Advise patient that dose will be started low and then increased until max benefit is obtained.
- Instruct patient not to change the dose or stop taking unless advised by health care provider.
- Advise patient to notify health care provider if condition does not appear to improve or worsens.
- Advise patient that if a dose is missed to take it as soon as possible and then return to the normal schedule. Instruct patient that if a dose is skipped not to double the dose to catch up. Caution patient that if medication has not been taken for more than 2 days not to restart medication but to contact health care provider for new dosing instructions.
- Advise patient that if medication needs to be discontinued, it will be slowly withdrawn over a period of 1 to 2 wk unless safety concerns (eg, low WBC count) require a more rapid withdrawal.
- Instruct patient not to stop taking clozapine when feeling better.
- Instruct diabetic patient to monitor blood glucose more frequently when drug is started or dose is changed and to inform health care provider of significant changes in readings.
- Tell patient to immediately report lethargy, weight gain, involuntary body or facial movements, change in personality or mood, weakness, fever, sore throat, general body discomfort, flu-like symptoms, mucus membrane sores or other signs of possible infection, muscle rigidity, altered mental status, rapid or irregular heartbeat, pounding in the chest, sweating, seizures, chest pain, unexplained fatigue, swelling of feet or ankles, rapid or difficult breathing, unexplained shortness of breath, unquenchable thirst, or frequent urination to health care provider.
- Advise patient to avoid strenuous activity during periods of high temperature or humidity.
- Instruct patient to avoid alcoholic beverages and sedatives (eg, diazepam) while taking clozapine.
- Instruct patient to get up slowly from lying or sitting position and to avoid sudden position changes to prevent postural hypotension. Advise patient to report dizziness with position changes to health care provider. Caution patient that hot tubs and hot showers or baths may make dizziness worse.
- Advise patient to take sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
- Advise patient taking antihypertensives to monitor BP at regular intervals.
- Advise patient with phenylketonuria that the orally disintegrating tablet contains phenylalanine.
- Advise patient that drug may impair judgment, thinking, or motor skills or cause drowsiness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
- Advise patient with history of seizures or factors predisposing to seizures that drug may cause seizures and not to engage in any activity in which sudden loss of consciousness could cause serious risk to patient or others (eg, driving, swimming, climbing).
- Advise patient that follow-up visits and weekly blood cell counts will be required to monitor therapy and to keep appointments.
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More Clozapine resources:
FazaClo Orally Disintegrating Tablets
Clozapine - Includes detailed dosage instructions.
