Applies to the following strength(s): 25 mg ; 100 mg ; 12.5 mg ; 150 mg ; 200 mg ; 50 mg ; 50 mg/mL
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Usual Adult Dose for:
Additional dosage information:
Usual Adult Dose for Schizophrenia
Initial dose: 12.5 mg orally once or twice a day
Titration and Maintenance: May increase total daily dose in increments of 25 mg to 50 mg per day to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of week 2. Subsequent dose increases can be in increments of up to 100 mg once or twice weekly.
Maximum dose: 900 mg per day
-The absolute neutrophil count (ANC) must be 2000/mm3 or greater and WBC count 3500 mm3 or greater, prior to initiating treatment; the ANC and WBC must be monitored regularly during therapy.
-A low starting dose, gradual titration, and divided doses are necessary to minimize the risk of orthostatic hypotension, bradycardia, and syncope.
-When therapy is interrupted for 2 or more days, re-initiate with 12.5 mg once or twice a day; based on tolerability, a dose that is restarted may be increased to a previously therapeutic dose more quickly than it was for initial treatment.
-For the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment.
-To reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder, who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state.
Renal Dose Adjustments
Use with caution; dose reduction may be necessary in patients with significant renal impairment
Liver Dose Adjustments
Use with caution; dose reduction may be necessary in patients with significant hepatic impairment
Elderly Patients: Dosing should be conservative taking into account the greater frequency of decreased renal, hepatic, or cardiac function, as well as other concomitant disease and other drug therapy.
Poor CYP450 2D6 Metabolizers: Dose reduction may be necessary
-In the event of planned discontinuation, reduce the dose gradually over a period of 1 to 2 weeks.
-In the event of neutropenia or agranulocytosis, treatment may need to be immediately discontinued.
Concomitant Strong CYP450 1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin, enoxacin):
-Upon initiating therapy or adding a strong CYP450 1A2 inhibitor to clozapine therapy, reduce clozapine dose to one-third.
-When discontinuing a strong CYP450 1A2 inhibitor and continuing clozapine, increase clozapine dose based on clinical response.
Concomitant Moderate or Weak CYP450 1A2 Inhibitors (e.g. oral contraceptive, caffeine) or CYP450 2D6/3A4 Inhibitors (cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, sertraline):
-Upon initiating clozapine therapy or adding a moderate or weak CYP450 1A2 inhibitor, a CYP450 2D6 inhibitor or a CYP450 3A4 inhibitor to clozapine therapy, monitor for adverse reactions and reduce clozapine dose if needed.
-When discontinuing a moderate or weak CYP450 1A2 inhibitor or a CYP450 2D6 or 3A4 inhibitor, and continuing clozapine, monitor for lack of effectiveness and consider increasing clozapine dose if necessary.
Concomitant Strong CYP450 3A4 Inducers (e.g. phenytoin, carbamazepine, St. John's wort, and rifampin):
-Concomitant use of clozapine is not recommended, however, if strong CYP450 3A4 inducers is necessary, a dose increase of clozapine dose may be needed; monitor for decreased effectiveness.
-When discontinuing a strong CYP450 3A4 inducer and continuing clozapine, reduce clozapine dose based on clinical response.
Concomitant Moderate or Weak CYP450 1A2 (e.g. tobacco smoking) or CYP450 3A4 Inducer:
-Upon initiating clozapine therapy or adding a moderate or weak CYP450 1A2 or CYP450 3A4 inducer to clozapine therapy, monitor for decreased effectiveness and consider increasing clozapine dose if needed.
-When discontinuing a moderate or weak CYP450 1A2 or CYP450 3A4 inducer and continuing clozapine, monitor for adverse reactions and consider reducing the clozapine dose if needed.
The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for clozapine (Versacloz(R)) suspension. It includes elements to assure safe use, and an implementation system. For additional information: www.fda.gov/REMS
US BOXED WARNINGS:
AGRANULOCYTOSIS: Treatment has caused agranulocytosis, defined as an absolute neutrophil count (ANC) less than 500/mm3. Agranulocytosis can lead to serious infection and death. Prior to initiating treatment, obtain a baseline white blood cell (WBC) count and ANC. The ANC must be greater than or equal to 2000/mm3 and the WBC must be greater than or equal to 3500/mm3 for a patient to begin treatment. During treatment, patients must have regular monitoring of ANC and WBC. Discontinue and do not rechallenge if the ANC is less than 1000/mm3 or the WBC is less than 2000/mm3. Advise patients to immediately report symptoms consistent with agranulocytosis or infection (e.g. fever, weakness, lethargy, or sore throat).
-Because of the risk of agranulocytosis, this drug is only available through a restricted program called the CLOZARIL National Registry. Under the registry, prescribers, patients, and pharmacies must enroll in the program.
ORTHOSTATIC HYPOTENSION, BRADYCARDIA, SYNCOPE, and cardiac arrest have occurred with treatment. The risk is highest during the initial titration period, particularly with rapid dose escalation. These reactions can occur with the first dose, with doses as low as 12.5 mg per day. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages. Use cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g. dehydration, use of antihypertensive medications).
SEIZURES have occurred with treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering to patients with a history of seizures or other predisposing risk factors for seizure (CNS pathology, medications that lower the seizure threshold, alcohol abuse). Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others.
MYOCARDITIS AND CARDIOMYOPATHY, including fatalities, have occurred with treatment. Discontinue this drug and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with drug-related myocarditis or cardiomyopathy should not be rechallenged. Consider the possibility of myocarditis or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur.
INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. This drug is not approved for use in patients with dementia-related psychosis.
Safety and efficacy have not been established in patients younger than 18 years.
Consult WARNINGS section for additional precautions.
Data not available
-May be taken with or without food
-If a dose is missed for more than 2 days; patients should be restarted at 12.5 mg once or twice a day
Oral Disintegrating Tablets (ODT):
-Do not remove from blister until time of use; peel foil from blister and remove tablet; do not push tablet through foil as it may damage tablet.
-Place tablet in mouth and allow to disintegrate; swallow with saliva; tablet may be chewed
-ODT tablets contain phenylalanine
-Use appropriate enclosed oral syringe; 1 mL syringe for doses of 50 mg or less; 9 mL syringe for doses greater than 50 mg
-Prior to use, shake bottle for 10 seconds; on first use, remove cap and press syringe adaptor into bottle opening.
-Fill oral syringe with air; insert syringe into bottle neck adapter and push air into bottle.
-Draw out prescribed dose into oral syringe; administer dose directly from the oral syringe into the mouth.
-Measured dose should be used immediately; do not store suspension in the syringe.
-Syringe should be washed with warm water after each use; the bottle cap may be closed without removing the syringe adaptor.
-Do not refrigerate or freeze
-Protect from light
-Stable for 100 days after initial bottle opening
Oral Disintegrating Tablets:
-Tablets must remain in original package until use by patient
-Because of the risk of agranulocytosis, this drug is available only through a restricted program; the CLOZARIL National Registry enrolls prescribers, patients, pharmacies, and distributors; further information is available at http://www.clozarilregistry.com or 1-888-669-6682.
-Blood monitoring is required in order to reduce the risk of developing agranulocytosis; weekly blood tests are required for the first 6 months; if WBC counts and ANC are acceptable and maintained, blood tests will be every 2 weeks for the next 6 months; thereafter, blood tests can be every 4 weeks; if abnormalities are detected, changes in therapy or laboratory monitoring may be necessary as prescribed by the CLOZARIL National Registry; WBC count and ANC must be monitored weekly for at least 4 weeks from the day of discontinuation or until WBC count is 3500/mm3 or greater and ANC is 2000/mm3 or greater.
-Electrolytes should be monitored to decrease the risk of QT prolongation
-Monitor cardiac status
-Monitor for increases in blood sugar, weight, and lipids
-Monitor for clinical worsening and suicidality
-Patients should be informed of the significant risk of developing agranulocytosis and that their participation in the CLOZARIL National Registry is designed to reduce this risk; patients will need to immediately report symptoms consistent with agranulocytosis or infection (e.g. fever, weakness, lethargy, or sore throat).
-Patients should be informed of the risk of orthostatic hypotension, bradycardia, and syncope, as well as the risk of QT interval prolongation; patients should discuss with their physician any new medications or use of over-the-counter medications or alcohol.
-This drug may impair judgment, thinking, or motor skills, and carries a risk of seizures; patients should be cautioned about engaging in activities that could cause serious risk to self or others if a sudden loss of consciousness were to occur.
-Patients should be advised to contact their health care professional if they miss taking their drug for more than 2 days.
-Advise patient to speak to physician or health care professional if pregnant, intend to become pregnant, or are breastfeeding.