Trade Names:Clozapine- Tablets 12.5 mg- Tablets 50 mg- Tablets 200 mg
Trade Names:Clozaril- Tablets 25 mg- Tablets 100 mg
Trade Names:FazaClo- Tablets, orally disintegrating 12.5 mg- Tablets, orally disintegrating 25 mg- Tablets, orally disintegrating 100 mgApo-Clozapine (Canada)Gen-Clozapine (Canada)
Interferes with dopamine binding at D 1 , D 2 , D 3 , and D 5 receptors in the CNS; has high affinity for the D 4 receptor; antagonizes adrenergic, cholinergic, histaminergic, and serotonergic neurotransmission.
C max is about 319 ng/mL (at steady state for tablets) and 413 ng/mL (at steady state for orally disintegrating tablets). T max is about 2.5 h (tablets) and 2.3 h (orally disintegrating tablets).
About 97% protein bound.
The half-life is about 8 h (single dose) and about 12 h (steady state). About 50% is excreted in urine and 30% in feces as metabolites.
Management of severely 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.
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.
PO 12.5 mg daily or twice daily; increase by 25 to 50 mg daily up to 300 to 450 mg daily by the end of 2 wk. May then increase dose in increments not to exceed 100 mg once or twice per week (max, 900 mg daily).
Store between 59° and 86°F. Protect orally disintegrating tablets from moisture.
Risk or severity of bone marrow suppression may be increased.Alcohol, CNS depressants, general anesthesia
Use with caution because of CNS effects of clozapine.Anticholinergics
Anticholinergic effects may be potentiated.Antihypertensives
Hypotensive effects may be potentiated.Barbituates (eg, phenobarbital)
May decrease concentrations and pharmacologic effects of clozapine.Benzodiazepines, psychotropic drugs (eg, haloperidol)
Consider the possibility of occurrence of orthostatic hypotension if clozapine therapy is initiated in a patient receiving agents from one of these classes.CYP2D6 substrates (eg, antidepressants, phenothiazines)
Use with caution.CYP-450 inducers (eg, carbamazepine, nicotine, phenytoin, rifampin)
May reduce clozapine plasma levels, decreasing the effectiveness.CYP-450 inhibitors (eg, caffeine, cimetidine, ciprofloxacin, citalopram, erythromycin, ketoconazole, modafinil, nefazodone, risperidone, ritonavir, SSRIs)
May elevate clozapine plasma levels, increasing the risk of adverse reactions. Concurrent use with ritonavir is contraindicated.Drugs metabolized by CYP2D6 (eg, amitriptyline, flecainide, vinblastine)
Clozapine may inhibit CYP2D6 activity and make individuals with normal CYP2D6 metabolic activity resemble poor metabolizers. Coadminister clozapine with agents metabolized by this enzyme with caution.Tramadol
Increased risk of seizures may occur during coadministration.Type 1C antiarrhythmics (eg, flecainide, propafenone)
Use with caution.
None well documented.
Tachycardia (25%); hypotension (9%); syncope (6%); hypertension (4%); chest pain/angina, ECG change/cardiac abnormality (1%); atrial or ventricular fibrillation, cardiomyopathy, deep vein thrombosis, myocarditis (postmarketing).
Somnolence (46%); drowsiness/sedation (39%); dizziness (27%); insomnia (20%); vertigo (19%); headache (7%); tremor (6%); agitation, disturbed sleep/nightmares, hypokinesia/akinesia, restlessness (4%); akathisia, confusion, rigidity, seizures (3%); fatigue (2%); anxiety, ataxia, depression, hyperkinesia, lethargy, slurred speech, weakness (1%); abnormal EEG, delirium, exacerbation of psychosis, mild cataplexy, myoclonus, paresthesia, status epilepticus (postmarketing).
Rash (2%); erythema multiforme, Stevens-Johnson syndrome (postmarketing).
Visual disturbances (5%); nasal congestion, throat discomfort (1%); narrow-angle glaucoma, periorbital edema (postmarketing).
Salivary hypersecretion (48%); salivation (31%); constipation (25%); nausea, vomiting (17%); dyspepsia (14%); dry mouth (6%); abdominal discomfort/heartburn (4%); nausea/vomiting (3%); diarrhea (2%); anorexia (1%); acute pancreatitis, dysphagia, fecal impaction, intestinal obstruction/paralytic ileus, salivary gland swelling (postmarketing).
Urinary abnormalities (2%); abnormal ejaculation, incontinence, urinary retention, urinary urgency/frequency (1%); acute interstitial nephritis, priapism (postmarketing).
Leukopenia/decreased WBC/neutropenia (3%); agranulocytosis, eosinophilia (1%); elevated hemoglobin/hematocrit, erythrocyte sedimentation rate increase, sepsis, thrombocytopenia, thrombocytosis (postmarketing).
Liver test abnormalities (1%); cholestasis, hepatitis, jaundice (postmarketing).
Weight increase (31%); hypercholesterolemia, hyperglycemia, hypertriglyceridemia, hyperuricemia, hyponatremia, weight loss (postmarketing).
Back pain, leg or neck pain, muscle pain or ache, muscle spasm, muscle weakness (1%); dystonia, myasthenic syndrome, rhabdomyolysis (postmarketing).
Dyspnea (1%); aspiration, pleural effusion, pulmonary embolism (postmarketing).
Sweating (6%); fever (5%); tongue numb/sore (1%); CPK elevation, hypersensitivity reactions, photosensitivity, overdose, sepsis, vasculitis (postmarketing).
Life-threatening agranulocytosis can occur. Baseline WBC and ANC should be done before initiation of treatment, during treatment, and for at least 4 wk after discontinuing treatment.Seizures
Use of clozapine has been associated with seizures. There is a greater likelihood at higher doses. Administer with caution to patients with a history of seizures or other predisposing factors.Myocarditis
There is an increased risk of fatal myocarditis, especially during, but not limited to, the first month of therapy. Promptly discontinue clozapine if myocarditis is suspected.CV and respiratory effects
Orthostatic 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 when clozapine is started in patients taking a benzodiazepine or other psychotropic agent because cardiac arrest, collapse, and respiratory arrest have occurred.Increased mortality
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared with placebo. Although the causes of death were varied, most of the deaths appeared to be either CV (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Clozapine is not approved for the treatment of dementia-related psychosis.
Baseline WBC and ANC should be done before initiation of treatment, during treatment, and for at least 4 wk after discontinuing treatment. The frequency of hematologic monitoring should be based on various stages of therapy (eg, initiation of therapy) or results from WBC count and ANC monitoring tests (eg, moderate leukopenia). Consult the manufacturer's information for additional details regarding the treatment of patients under the various conditions (eg, severe leukopenia). Regularly monitor patients with an established diagnosis of diabetes mellitus who are started on clozapine for worsening of glucose control. Patients with risk factors for diabetes mellitus (eg, family history of diabetes, obesity) who are started on treatment should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Monitor any patient being treated for symptoms of hypoglycemia, including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose testing. Monitor patients for signs and symptoms of tardive dyskinesia (eg, involuntary, dyskinetic movements) and infection. Monitor patients for signs and symptoms of cardiomyopathy (especially exertional dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea, and peripheral edema). Perform LFTs immediately in patients who develop nausea, vomiting, and/or anorexia.
Category B .
Safety and efficacy not established.
Approach dose selection with caution, taking into consideration decreased renal, hepatic, and cardiac function, and other concomitant disease and drug therapy.
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.
Use great caution in patients with renal or cardiac disease, narrow-angle glaucoma, pulmonary disease, enlarged prostate, or history of seizures; seizures are more likely at higher doses.
Has been reported. In clozapine-treated patients who developed cardiomyopathy, approximately 80% were younger than 50 yr of age and the duration of treatment was more than 6 mo in 65% of reports.
Because of initial sedation, mental and/or physical abilities may be impaired, especially during the first few days of therapy.
Some patients experience ECG repolarization changes during treatment. Several have experienced significant cardiac events, including ischemic changes, MI, nonfatal arrhythmias, and sudden, unexplained death.
May experience transient temperature elevations above 100.4°F, with peak incidence within first 3 wk of treatment.
Because of the CNS effects of clozapine, caution is advised in patients receiving general anesthesia.
Varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, fecal impaction, and paralytic ileus, have been associated with clozapine use.
Severe hyperglycemia, possibly leading to ketoacidosis, has been reported.
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.
Orally disintegrating tablets contain phenylalanine, a component of aspartame; use with caution in patients with phenylketonuria.
Consider the possibility in patients who present with deep vein thrombosis, acute dyspnea, chest pain, or other respiratory signs or symptoms.
At least 2 yr of treatment is recommended to maintain a reduction of risk for suicidal behavior. After 2 yr, assess the patient's risk of suicidal behavior. If the health care provider's assessment indicates that a significant risk of suicidal behavior is still present, treatment should be continued. If the health care provider's assessment is that the patient is no longer at risk of suicidal behavior, treatment may be discontinued and treatment with an antipsychotic medication to which the patient previously responded may be resumed.
This syndrome of potentially irreversible, involuntary dyskinetic movements has occurred with other antipsychotic agents. Incidence is highest among elderly patients, especially women.
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).
Aspiration pneumonia, cardiac arrhythmias, coma, delirium, drowsiness, excessive salivation, hypotension, respiratory depression or failure, seizures, tachycardia.
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