Adult Dosing
Treatment resistant schizophrenia
- 150-300 mg PO bid
- Start: 12.5 mg PO daily-bid; then continue with daily dosage increments of 25-50 mg/day, if well tolerated, to achieve a target dose of 300-450 mg/day by the end of 2 wks.
- Max: 900 mg/day
Notes- Gradually taper dose over 1-2wk for discontinuation of therapy
- Make subsequent dosage increments not >once or twice weekly, in increments not to exceed 100 mg
- Reinitiation of treatment in patients previously discontinued:
- Start: 12.5 mg PO daily-bid
- If well tolerated, it is feasible to titrate patients back to a therapeutic dose more quickly than is recommended for initial treatment
Schizophrenia-associated suicide prevention
- 150-300 mg PO bid
- Start: 12.5 mg PO daily-bid; then continue with daily dosage increments of 25-50 mg/day, if well tolerated, to achieve a target dose of 300-450 mg/day by the end of 2 wks.
- Max: 900 mg/day
Notes- Gradually taper dose over 1-2wk for discontinuation of therapy
- Make subsequent dosage increments not >once or twice weekly, in increments not to exceed 100 mg
- For chronic risk patients having prior history of suicidal behavior reassess suicide risk q2 yrs
- Reinitiation of treatment in patients previously discontinued:
- Start: 12.5 mg PO daily-bid
- If well tolerated, it is feasible to titrate patients back to a therapeutic dose more quickly than is recommended for initial treatment
Pediatric Dosing
- Safety and efficacy in pediatrics have not been established
[Outline]
See Supplemental Patient Information
- Elderly patients with dementia-related psychosis are at an increased risk of death when treated with antipsychotic drugs [US Black Box Warning]
- This drug is not approved for the treatment of patients with dementia-related psychosis [US Black Box Warning]
- Potential for occurrence of life-threatening agranulocytosis exists; reserve use of this drug in severely ill patients with schizophrenia failing to show an acceptable response to adequate courses of standard antipsychotic drug therapy or for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are at risk of reexperiencing suicidal behavior [US Black Box Warning]
- Administer patients at least 2 trials, each with a different standard drug product for schizophrenia, at an adequate dose and for an adequate duration before initiating therapy with clozapine
- This drug is available only through a distribution system that ensures monitoring of WBC counts and ANCs according to the schedule [US Black Box Warning]
- Determine baseline WBC count and ANC before initiation of therapy. Also determine WBC count and ANC qwk for the first 6 months. Thereafter, if WBC counts and ANCs (WBC count
3500/mm3 and ANC 2000/mm3 are maintain during the first 6 months of continuous therapy monitor WBC counts and ANCs q2 wks for the next 6 months. Thereafter, if WBC counts and ANCs (WBC count 3500/mm3 and ANC 2000/mm3 are maintain during the second 6 months of continuous therapy monitor WBC counts and ANCs q4 wks - On discontinuation of treatment monitor WBC count and ANC for at least 4 wks from the day of discontinuation or until WBC count 3500/mm3 and ANC 2000/mm3
- If agranulocytosis is not detected early and therapy is not interrupted it could prove fatal. Increased incidence of agranulocytosis may occur on reduction in the frequency of monitoring of WBC counts
- Patients who have developed agranulocytosis during treatment are at increased risk of development of subsequent episodes of agranulocytosis. Patients having an initial episode of moderate leukopenia (3000/mm3 >WBC count 2000/mm3 are at an increased risk of subsequent episodes of agranulocytosis
- Women, the elderly, and patients who are cachectic or having serious underlying medical illness are at higher risk for agranulocytosis
- If the total WBC count falls below 2000/mm3 or the ANC falls below 1000/mm3, consider bone-marrow aspiration to ascertain granulopoietic status and avoid rechallenging such patients with this drug
- Protective isolation with close observation may be necessary if granulopoiesis is determined to be deficient. On evidence of infection perform appropriate cultures and institute an appropriate antibiotic regimen
- Patients discontinued from clozapine therapy due to significant granulopoietic suppression may develop agranulocytosis upon rechallenge with a shorter latency on reexposure
- Although therapy may be resumed if no symptoms of infection develop and when the WBC count rises >3500/mm3 and the ANC rises above 2000/mm3 it is strongly advised to consider whether the benefit of continuing therapy outweighs the increased risk of agranulocytosis
- Patients with an initial episode of moderate leukopenia (3000/mm3WBC count=2000/mm 3) posses up to a 12-fold increased risk of having a subsequent episode of agranulocytosis when rechallenged as compared to the full cohort of patients treated with this drug
- Although therapy may be restarted if no symptoms of infection occur and when the WBC count rises above 3500/mm3 and the ANC rises above 2000/mm3 it is strongly advised to consider whether the benefit of continuing therapy outweighs the increased risk of agranulocytosis
- Weekly determine WBC count and monitor ANC for one year following recovery from an episode of moderate leukopenia and/or moderate granulocytopenia
- If a differential count reveals a total eosinophil count > 4000/mm3 interrupt therapy until the eosinophil count falls below 3000/mm3
- Seizure may occur in association with therapy with this drug. Advise patients to avoid engaging in any activities requiring mental alertness as sudden loss of consciousness may lead to serious risk to themselves or others
- Myocarditis may occur in association with treatment. Incidence of fatal myocarditis is highest during the first month of therapy
- Consider the possibility of myocarditis in patients with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs or symptoms of heart failure, or electrocardiographic findings such as ST-T wave abnormalities or arrhythmias. Tachycardia observed during the first month of therapy warrants close monitoring for other signs of myocarditis. On suspicion of myocarditis promptly discontinue treatment with this drug. Avoid rechallenging patients with clozapine-related myocarditis with clozapine
- Orthostatic hypotension with or without syncope may occur. Rare occasions of collapse can be intense and may be accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension may occur mostly during initial titration in association with rapid dose escalation. Start therapy with 12.5 mg once or twice daily in patients who have had even a brief interval off clozapine (i.e., 2 or more days since the last dose)
- Cases of collapse/respiratory arrest/cardiac arrest may occur in patients
- Exercise caution when clozapine is initiated in patients having a benzodiazepine or any other psychotropic drug
- Tachycardia or hypotension may occur which poses a serious risk for an individual with compromised cardiovascular function
- ECG repolarization changes including S-T segment depression and flattening or inversion of T-waves may occur. Cardiac events, including ischemic changes, myocardial infarction, arrhythmias, and sudden death may occur in patients. CHF, pericarditis, and pericardial effusions have been reported on post marketing surveillance
- Exercise caution in patients having history of cardiovascular and/or pulmonary disease and carefully observe the recommendation for gradual titration of dose
- Potentially fatal symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) has occurred in association with administration of antipsychotic drugs. Manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. Additional signs including elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure have occurred
- Immediately discontinue antipsychotic drugs and other drugs not essential for concomitant therapy, provide intensive symptomatic treatment, carefully monitor patients and provide treatment for concomitant serious medical problems for management of NMS
- Carefully consider potential reintroduction of drug therapy in patients recovered from NMS as recurrences of NMS can occur
- Risk of developing irreversible tardive dyskinesia increases as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increases. Elderly women are more prone to syndrome of potentially irreversible, involuntary, dyskinetic movements. Syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn
- Prescribe this drug in a manner that is most likely to minimize the risk of tardive dyskinesia. Discontinue therapy on occurrence of signs and symptoms of tardive dyskinesia. Periodically reassessed need for continued treatment
- Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death have occurred in patients treated with atypical antipsychotics
- Regularly monitor patients treated with atypical antipsychotics for worsening of glucose control. Perform fasting blood glucose test at the beginning of treatment and periodically thereafter during treatment. Monitor patients treated with atypical antipsychotics for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness
- Monitor fasting blood glucose in patients who develop symptoms of hyperglycemia during therapy
- As risk of agranulocytosis and seizure increases over time, avoid the extended treatment in patients failing to show an acceptable level of clinical response. Periodically reevaluate the need for continuous treatment in patients exhibiting beneficial clinical responses
- Risk for development of cardiomyopathy exists. On development of signs and symptoms suggestive of cardiomyopathy perform further investigations. If cardiomyopathy is confirmed discontinue this drug unless the benefit to the patient clearly outweighs the risk
- Transient temperature elevations >100.4 degree F may occur with the peak incidence within the first 3 weeks of therapy; it may be essential for discontinuing patients from therapy. Carefully evaluate patients with fever to rule out the possibility of an underlying infectious process or for the development of agranulocytosis. Consider possibility of NMS in presence of high fever
- Consider possibility of pulmonary embolism in patients receiving this drug present with deep-vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms
- Inform phenylketonuric patients that clozapine contains phenylalanine (a component of aspartame)
- Immediately perform LFTs in patients who develop nausea, vomiting, and/or anorexia during treatment. Discontinue therapy if the elevation of these values is clinically significant or if symptoms of jaundice occur
- Take utmost care in using this drug in the presence of narrow-angle glaucoma
- Varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, fecal impaction, and paralytic ileus may occur. These manifestations may be fatal on rare occasions. Treat constipation by ensuring adequate hydration and use of ancillary therapy such as bulk laxatives. Consultation with a gastroenterologist is advisable in serious cases
- Take utmost care in using this drug in the presence of prostatic enlargement
- This drug interferes with cognitive and motor performance. Carefully adhere to the recommendations for gradual-dose escalation and caution patients about activities requiring alertness
- An increased risk of cerebrovascular adverse events exists in the dementia population with some atypical antipsychotics
Cautions: Use cautiously in
- Renal impairment
- Hepatic impairment
- Concurrent hepatic disease
- Cardiac disease
- Risk factors for stroke
- Diabetes mellitus
- Risk factors for diabetes mellitus
- Hypotension
- Hypovolemia
- Seizure disorder
- History of neuroleptic malignant syndrome
- Dementia
- Myelosuppression
- Prostatic hypertrophy
- PKU (phenylalanine-containing forms)
- Patients being administered general anesthesia
- Changes in smoking habits
- Geriatrics
Supplemental Patient Information
- Advise patients to immediately report the appearance of lethargy, weakness, fever, sore throat, or any other signs of infection occurring at any time during therapy. Promptly perform WBC count and ANC in such patients
- Advise patients to avoid driving and any other potentially hazardous activity while taking this drug
- Advise patients to notify their physician if they become pregnant or having intend to become pregnant during therapy
Pregnancy Category:B
Breastfeeding: Possibly unsafe; As there is little published data about clozapine during breastfeeding prefer other agents. Closely monitor infant for excessive sedation and periodically monitor infants WBC count if breastfeeding is undertaken by a mother who is taking clozapine. This information is based upon LactMed database (available at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT last accessed 1 April 2011). According to manufacturer's data women receiving this drug should not breastfeed.
