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Clozapine (clozapine)

BOXED WARNING

May cause agranulocytosis that can lead to serious infection and death. Absolute neutrophil count (ANC) must be ≥2000/mm3 and WBC count must be ≥3500/mm3 for a patient to begin treatment. D/C and do not rechallenge if ANC is <1000/mm3 or WBC count is <2000mm3. Available only through a restricted program. Orthostatic hypotension, bradycardia, syncope, and cardiac arrest may occur and the risk is highest during initial titration period, particularly with rapid dose escalation; caution with cardiovascular (CV)/cerebrovascular disease or conditions predisposing to hypotension (eg, dehydration, use of antihypertensives). Seizures may occur and risk is dose-related; caution with history or other predisposing risk factors for seizure (eg, CNS pathology, medications that lower seizure threshold, alcohol abuse). Caution about engaging in any activity where sudden loss of consciousness could cause serious risk to patient or others. Fatal myocarditis and cardiomyopathy reported; d/c and obtain cardiac evaluation upon suspicion of these reactions. Do not rechallenge in patients with clozapine-related myocarditis or cardiomyopathy. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk for death. Not approved for use in patients with dementia-related psychosis.

View FDA-Approved Full Prescribing Information for Clozaril

OTHER BRAND NAMES

Clozaril

THERAPEUTIC CLASS

Atypical antipsychotic

DEA CLASS

RX

INDICATIONS

Treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Reduction in risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for reexperiencing suicidal behavior, based on history and recent clinical state.

ADULT DOSAGE

Schizophrenia

Treatment of severely ill patients who fail to respond adequately to standard antipsychotic treatment. Reduction in risk of recurrent suicidal behavior in patients w/ schizophrenia or schizoaffective disorder who are judged to be at chronic risk for reexperiencing suicidal behavior

Initial: 12.5mg qd or bid
Titrate: May increase total daily dose in increments of 25-50mg/day, if well-tolerated
Target Dose: 300-450mg/day by the end of 2 weeks
Subsequent Dosing: May increase in increments of up to 100mg, once or twice weekly
Max: 900mg/day
Maint: Continue on the effective dose beyond the acute episode

Reinitiation (≥2 Days Since Last Dose):
Reinitiate w/ 12.5mg qd or bid; if well-tolerated, may increase to previous therapeutic dose more quickly than recommended for initial treatment

DOSING CONSIDERATIONS

Concomitant Medications
Strong CYP1A2 Inhibitors (eg, Fluvoxamine, Ciprofloxacin, Enoxacin):
During coadministration, use 1/3 of clozapine dose; when discontinuing comedication, increase clozapine dose based on clinical response

Moderate or Weak CYP1A2 Inhibitors (eg, Oral Contraceptives, Caffeine) or CYP2D6/CYP3A4 Inhibitors (eg, Cimetidine, Escitalopram, Erythromycin):
During coadministration, monitor for adverse reactions and consider reducing clozapine dose if necessary; when discontinuing comedication, monitor for lack of effectiveness and increase clozapine dose if necessary

Strong CYP3A4 Inducers (eg, Phenytoin, Carbamazepine, St. John's Wort, Rifampin):
Concomitant use is not recommended; if the inducer is necessary, may need to increase clozapine dose and monitor for decreased effectiveness
When discontinuing comedication, reduce clozapine dose based on clinical response

Moderate or Weak CYP1A2 or CYP3A4 Inducers:
During coadministration, monitor for decreased effectiveness and consider increasing clozapine dose if necessary; when discontinuing comedication, monitor for adverse reactions and consider reducing clozapine dose if necessary

Renal Impairment
May need to reduce dose w/ significant renal impairment

Hepatic Impairment
May need to reduce dose w/ significant hepatic impairment

Discontinuation
Reduce gradually over 1-2 weeks

Other Important Considerations
CYP2D6 Poor Metabolizers:
May need to reduce dose

ADMINISTRATION

Oral route

Administer in divided doses
Take w/ or w/o food

HOW SUPPLIED

Tab: 50mg*, 200mg*; (Clozaril) 25mg*, 100mg* *scored

CONTRAINDICATIONS

History of clozapine-induced agranulocytosis or severe granulocytopenia.

WARNINGS/PRECAUTIONS

Eosinophilia reported and may be associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. Evaluate promptly for signs/symptoms of systemic reactions if eosinophilia develops and d/c immediately if clozapine-related systemic disease is suspected. QT prolongation, torsades de pointes, and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death reported. D/C if QTc interval exceeds 500msec or symptoms consistent with torsades de pointes or other arrhythmias develop. Caution in patients at risk for significant electrolyte disturbance, particularly hypokalemia; correct electrolyte abnormalities before initiating treatment. Associated with metabolic changes (eg, hyperglycemia sometimes associated with ketoacidosis or hyperosmolar coma, dyslipidemia, weight gain) that may increase CV and cerebrovascular risk. Neuroleptic malignant syndrome (NMS) reported; d/c therapy immediately and institute symptomatic treatment. Transient fever may occur and may necessitate discontinuing treatment; rule out agranulocytosis, infection, or NMS. Pulmonary embolism (PE), deep vein thrombosis (DVT), and tardive dyskinesia (TD) reported; consider discontinuation if TD occurs. Has potent anticholinergic effects. Treatment can result in CNS and peripheral anticholinergic toxicity; caution in the presence of narrow-angle glaucoma, prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions. May result in GI adverse reactions; ensure adequate hydration and use of ancillary therapy (eg, bulk laxatives) if constipation occurs. Consider dose reduction if sedation, or impairment of cognitive/motor performance occurs. Caution in patients with risk factors for cerebrovascular adverse reactions. If abrupt discontinuation is necessary, monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound. Refer to PI for frequency of monitoring based on stage of therapy, WBC count, and ANC. Caution in elderly.

ADVERSE REACTIONS

Agranulocytosis, seizure, myocarditis, cardiomyopathy, orthostatic hypotension, hypersalivation, somnolence, sedation, syncope, dizziness/vertigo, constipation, bradycardia, N/V, tachycardia, sweating, visual disturbance, fever.

DRUG INTERACTIONS

See Boxed Warning and Dose Modifications. Not recommended with strong CYP3A4 inducers (eg, carbamazepine, phenytoin, St. John's wort). Caution with medications that prolong the QT interval (eg, ziprasidone, erythromycin, quinidine). CYP1A2, CYP2D6, or CYP3A4 inhibitors may increase levels and lead to adverse reactions. CYP3A4 or CYP1A2 inducers (eg, tobacco) may decrease levels, resulting in decreased effectiveness of therapy. May increase levels of drugs metabolized by CYP2D6 (eg, phenothiazines, carbamazepine, propafenone). Caution with anticholinergics. NMS reported with CNS-active medications (eg, lithium).

PREGNANCY AND LACTATION

Category B, not for use in nursing.

MECHANISM OF ACTION

Atypical antipsychotic; tricyclic dibenzodiazepine derivative. Has not been established. Efficacy may be mediated through antagonism of the dopamine type 2 and the serotonin type 2A receptors. Also acts as an antagonist at adrenergic, cholinergic, histaminergic, and other dopaminergic and serotonergic receptors.

PHARMACOKINETICS

Absorption: (100mg bid) Cmax=319ng/mL; Tmax=2.5 hrs. Distribution: Plasma protein binding (97%); found in breast milk. Metabolism: CYP1A2, CYP2D6, CYP3A4; demethylation, hydroxylation, N-oxidation. Norclozapine (active metabolite). Elimination: Urine (50%), feces (30%); T1/2=8 hrs (75mg single dose), 12 hrs (100mg bid).

ASSESSMENT

Assess for history of clozapine-induced agranulocytosis or severe granulocytopenia, previous hypersensitivity to the drug, history of seizures or other predisposing factors for seizure, renal/hepatic impairment, pregnancy/nursing status, possible drug interactions, and other conditions where treatment is cautioned. Obtain baseline CBC with differential (WBC count, ANC), FPG, lipid evaluations, ECG, and electrolytes (serum K+ and Mg2+ levels).

MONITORING

Monitor for signs/symptoms of agranulocytosis, myocarditis, cardiomyopathy, orthostatic hypotension, bradycardia, syncope, seizures, cognitive/motor impairment, eosinophilia, NMS, recurrence of psychosis and cholinergic rebound after abrupt discontinuation, metabolic changes (hyperglycemia, diabetes mellitus [DM], dyslipidemia, weight gain), QT interval prolongation, fever, PE, DVT, TD, cerebrovascular adverse reactions, and other adverse reactions. Monitor serum electrolyte levels, glucose control in patients with DM and periodic FPG levels if at risk for hyperglycemia. Monitor WBC count and ANC regularly; refer to PI for frequency of monitoring based on stage of therapy, WBC count, and ANC.

PATIENT COUNSELING

Counsel about the significant risks of developing agranulocytosis. Advise to report immediately the appearance of signs or symptoms consistent with agranulocytosis or infection. Inform that drug is available only through a special program designed to ensure the required blood monitoring. Inform about the risk of orthostatic hypotension and syncope, especially during the period of initial dose titration; instruct to strictly follow the instructions of the physician for dosage and administration. Inform about the significant risk of seizure during treatment; caution about driving and any other potentially hazardous activity while on treatment. Advise to contact physician immediately if patient feels faint, loses consciousness, or has signs/symptoms suggestive of bradycardia or arrhythmia. Counsel about the risk of metabolic changes and the need for specific monitoring. If dose was missed for >2 days, instruct not to restart medication at same dose but to contact physician for dosing instructions. Instruct to notify physician if pregnant/intending to become pregnant during therapy. Advise not to breastfeed if taking the drug. Instruct to notify physician if taking/planning to take any prescription or OTC drugs.

STORAGE

20-25°C (68-77°F). (Clozaril) Should not exceed 30°C (86°F).

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