CLOZAPINE tablet, orally disintegrating

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

CLOZAPINE (UNII: J60AR2IKIC) (CLOZAPINE - UNII:J60AR2IKIC)

Available from:

Mylan Institutional Inc.

INN (International Name):

CLOZAPINE

Composition:

CLOZAPINE 25 mg

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Clozapine orally disintegrating tablets are indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, clozapine orally disintegrating tablets should be used only in patients who have failed to respond adequately to standard antipsychotic treatment [see Warnings and Precautions ( 5.1, 5.5)] . The effectiveness of clozapine in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing clozapine and chlorpromazine in patients who had failed other antipsychotics [see Clinical Studies (14.1)]. Clozapine orally disintegrating tablets are indicated for reducing 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. Suicidal behavior refers to actions by a patient that put him/herself at risk for death. The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT™ trial [see Clinical Studies (14.2)] . Clozapine orally disintegrating tablets are contraindicated in patients with a history of serious hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson Syndrome) or any other component of clozapine orally disintegrating tablets [see Adverse Reactions (6.2)] . There are no adequate or well-controlled studies of clozapine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 0.4 and 0.9 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m 2 body surface area basis. The studies revealed no evidence of impaired fertility or harm to the fetus due to clozapine. Because animal reproduction studies are not always predictive of human response, clozapine orally disintegrating tablets should be used during pregnancy only if clearly needed. Consider the risk of exacerbation of psychosis when discontinuing or changing treatment with antipsychotic medications during pregnancy and postpartum. Consider early screening for gestational diabetes for patients treated with antipsychotic medications [see Warnings and Precautions (5.11)] . Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Monitor neonates for symptoms of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. The severity of complications can vary from self-limited symptoms to some neonates requiring intensive care unit support and prolonged hospitalization. In embryofetal developmental studies, clozapine had no effects on maternal parameters, litter sizes, or fetal parameters when administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m 2 body surface area basis. In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum. Observations were made on fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual maturity and mated. Clozapine caused a decrease in maternal body weight but had no effects on litter size or body weights of either F1 or F2 generations at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m 2 body surface area basis. Clozapine is present in human milk. Because of the potential for serious adverse reactions in nursing infants from clozapine orally disintegrating tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Safety and effectiveness in pediatric patients have not been established. There have not been sufficient numbers of geriatric patients in clinical studies utilizing clozapine orally disintegrating tablets to determine whether those over 65 years of age differ from younger subjects in their response to clozapine orally disintegrating tablets. Orthostatic hypotension and tachycardia can occur with clozapine treatment [see Boxed Warningand Warnings and Precautions (5.3)] . Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects. Elderly patients may be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation [see Warnings and Precautions (5.16)] . Carefully select clozapine orally disintegrating tablets doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy. Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women [see Warnings and Precautions (5.18)] . Dose reduction may be necessary in patients with significant impairment of renal or hepatic function. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration (2.8)and Clinical Pharmacology (12.3)] . Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration (2.8)and Clinical Pharmacology (12.3)] . For hospice patients (i.e., terminally ill patients with an estimated life expectancy of 6 months or less), the prescriber may reduce the ANC monitoring frequency to once every 6 months, after a discussion with the patient and his/her caregiver. Individual treatment decisions should weigh the importance of monitoring ANC in the context of the need to control psychiatric symptoms and the patient’s terminal illness.

Product summary:

Clozapine Orally Disintegrating Tablets are available containing 100 mg of clozapine, USP. The 100 mg tablets are peach, round, unscored tablets debossed with C over 100 on one side of the tablet and blank on the other side. They are available as follows: NDC 51079-288-04 – Unit dose blister packages of 40 (5 cards of 8 tablets each). Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from moisture. Keep out of reach of children. Clozapine orally disintegrating tablets must remain in the original package until used by the patient. Drug dispensing should not ordinarily exceed a weekly supply. If a patient is eligible for ANC testing every 2 weeks, then a 2-week supply of clozapine orally disintegrating tablets can be dispensed. If a patient is eligible for ANC testing every 4 weeks, then a 4-week supply of clozapine orally disintegrating tablets can be dispensed. Dispensing should be contingent upon the ANC testing results.

Authorization status:

Abbreviated New Drug Application

Summary of Product characteristics

CLOZAPINE- CLOZAPINE TABLET, ORALLY DISINTEGRATING
MYLAN INSTITUTIONAL INC.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
CLOZAPINE ORALLY
DISINTEGRATING TABLETS SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING
INFORMATION FOR
CLOZAPINE ORALLY DISINTEGRATING TABLETS.
CLOZAPINE ORALLY DISINTEGRATING TABLETS, FOR ORAL USE
INITIAL U.S. APPROVAL: 1989
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 ORALLY DISINTEGRATING TABLETS MUST HAVE A BASELINE BLOOD
ABSOLUTE
NEUTROPHIL COUNT (ANC) MEASURED BEFORE TREATMENT INITIATION AND
REGULAR ANC
MONITORING DURING TREATMENT ( 2.1, 5.1).
CLOZAPINE ORALLY DISINTEGRATING TABLETS ARE AVAILABLE ONLY THROUGH A
RESTRICTED
PROGRAM CALLED THE CLOZAPINE REMS ( 5.2).
ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE: RISK IS
DOSE-RELATED. STARTING
DOSE IS 12.5 MG. TITRATE GRADUALLY AND USE DIVIDED DOSAGES ( 2.3, 2.6,
5.3).
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 ( 2.3, 5.5).
MYOCARDITIS AND CARDIOMYOPATHY: CAN BE FATAL. DISCONTINUE AND OBTAIN
CARDIAC
EVALUATION IF FINDINGS SUGGEST THESE CARDIAC REACTIONS ( 5.6).
INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED
PSYCHOSIS: CLOZAPINE
ORALLY DISINTEGRATING TABLETS ARE NOT APPROVED FOR THIS CONDITION (
5.7).
RECENT MAJOR CHANGES
1. Boxed Warning, Orthostatic Hypotension, Bradycardia, Syncope4/2023
Dosage and Administration, Re-Initiation of Treatment ( 2.6) 4/2023
Warnings and Precautions, Orthostatic Hypotension, Bradycardia, and
Syncope ( 5.3) 4/2023
Warnings and Precautions, Gastroi