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Indications and Important Selected Safety Information About CLOZARIL® (clozapine)

indications:

CLOZARIL® (clozapine) is an atypical antipsychotic indicated for:

Treatment-resistant schizophrenia.
The treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment.
Reduction in the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder.

WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

See full prescribing information for complete boxed warning.

Severe Neutropenia: Clozapine can cause severe neutropenia, which can lead to serious and fatal infections. Patients initiating and continuing treatment with clozapine must have a baseline blood absolute neutrophil count (ANC) measured before treatment initiation and regular ANC monitoring during treatment.
Clozapine is available only through a restricted program called the Clozapine Risk Evaluation and Mitigation Strategy (REMS) program. https://www.newclozapinerems.com (888) 586-0758.
Orthostatic Hypotension, Bradycardia, and Syncope: Risk is dose-related. Starting dose is 12.5 mg. Titrate gradually and use divided dosages.
Seizure: Risk is dose-related. Titrate gradually and use divided doses. Use with caution in patients with history of seizure or risk factors for seizure.
Myocarditis, Cardiomyopathy and Mitral Valve Incompetence: Can be fatal. Discontinue and obtain cardiac evaluation if findings suggest these cardiac reactions.
Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Clozapine is not approved for this condition.

contraindications:

Known serious hypersensitivity to clozapine or any other component of clozapine.

drug interactions:

Concomitant use of Strong CYP1A2 Inhibitors: Reduce clozapine dose to one third when co-administered with strong CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin, enoxacin).
Concomitant use of Strong CYP3A4 Inducers is not recommended.
Discontinuation of CYP1A2 or CYP3A4 Inducers: Consider reducing clozapine dose when CYP1A2 (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued.
Anticholinergic drugs: Concomitant use may increase the risk for anticholinergic toxicity.

adverse reactions:

Most common adverse reactions (≥5%) were: CNS reactions (sedation, dizziness/vertigo, headache, and tremor); cardiovascular reactions (tachycardia, hypotension, and syncope); autonomic nervous system reactions (hypersalivation, sweating, dry mouth, and visual disturbances); gastrointestinal reactions (constipation and nausea); and fever.

To report SUSPECTED ADVERSE REACTIONS, contact HLS at (844) 457-8721; or FDA at (800) FDA-1088 or https://www.fda.gov/medwatch.

dosing and administration:

Required Laboratory Testing Prior to Initiation and During Therapy

Prior to initiating treatment with clozapine, a baseline ANC must be obtained. The baseline ANC must be at least 1500/µL for the general population, and at least 1000/µL for patients with documented Benign Ethnic Neutropenia (BEN).
To continue treatment, the ANC must be monitored regularly.

Initiating Treatment

Starting Dose: 12.5 mg once daily or twice daily.
The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to achieve a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased once weekly or twice weekly, in increments of up to 100 mg.
The maximum dose is 900 mg per day. To minimize the risk of orthostatic hypotension, bradycardia, and syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided dosages.

Discontinuing Treatment

Method of treatment discontinuation will vary depending on the patient’s last ANC count:
See package insert for appropriate ANC monitoring based on the level of neutropenia if abrupt treatment discontinuation is necessary because of moderate to severe neutropenia.
Reduce the dose gradually over a period of 1 to 2 weeks if termination of clozapine therapy is planned and there is no evidence of moderate to severe neutropenia.
For abrupt clozapine discontinuation for a reason unrelated to neutropenia, continuation of the existing ANC monitoring is recommended for general population patients until their ANC is ≥1500/µL and for BEN patients until their ANC is ≥1000/µL or above their baseline.
Additional ANC monitoring is required for any patient reporting onset of fever (temperature of 38.5°C or 101.3°F or greater) during the 2 weeks after discontinuation.
Monitor all patients carefully for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea.

Re-Initiation of Treatment
When restarting clozapine in patients who have had even a brief interruption in treatment with clozapine dosage must be reduced. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions.] If one day’s dosing has been missed, resume treatment at 40% to 50% of the established dose. If two days dosing have been missed, resume dose at approximately 25% of the established dosage. For longer interruptions, re-initiate at a dosage of 12.5 mg once daily or twice daily. If these dosages are well tolerated, the dosage may be increased to the previous dosage more quickly than recommended for initial treatment.

Warnings and precautions:

Anticholinergic Toxicity – When possible, avoid use with other anticholinergic drugs and use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions.

Cognitive and Motor Performance (Interference) – Advise caution when operating machinery, including automobiles.

Eosinophilia – Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis). Discontinue if these occur.

Fever – Evaluate for infection and for neutropenia, or NMS.

Gastrointestinal Hypomotility with Severe Complications: – Severe gastrointestinal adverse reactions have occurred with the use of CLOZARIL. If constipation is identified, close monitoring and prompt treatment is advised.

Fever – Evaluate for infection and for neutropenia, NMS.

Hepatotoxicity – Can be fatal. Monitor for hepatotoxicity. Discontinue treatment if hepatitis or transaminase elevations combined with other symptoms occur.

Metabolic Changes – Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include:

Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with
diabetes or at risk for diabetes.
Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics.
Weight Gain: Significant weight gain has occurred. Monitor weight gain.

Neuroleptic Malignant Syndrome (NMS) – Immediately discontinue and monitor closely. Assess for co-morbid conditions.

Pulmonary Embolism (PE) – Consider PE if respiratory distress, chest pain, or deep vein thrombosis occur.

QT Interval Prolongation – Can be fatal. Consider additional risk factors for prolonged QT interval (disorders and drugs).

use in specific populations:

Nursing Mothers: Discontinue drug or discontinue nursing, taking into consideration importance of drug to mother.

PHARMACOKINETICS - SPECIFIC POPULATIONS:

Pneumonia and other Inflammatory Conditions – Published case reports describe examples where pneumonia or other inflammatory conditions may increase clozapine concentrations. The clinical significance, the impact of treatments to modulate this inflammation, and mechanism of this potential increase in clozapine concentrations have not been fully characterized but may involve reduced cytochrome P450 1A2 activity.

For additional safety information, please see full Prescribing Information, including Boxed WARNING, which can be found at clozaril.com or www.clozapinerems.com.

For more information please contact:

HLS Therapeutics (USA), Inc.
(844) 457-8721

MLR: 2023HER002