Data from FDA - Curated by EPG Health - Last updated 05 July 2018

Indication(s)

1 INDICATIONS AND USAGE VERSACLOZ is an atypical antipsychotic indicated for: •Treatment-resistant schizophrenia. Efficacy was established in an active-controlled study (1.1, 14.1). •Reducing suicidal behavior in patients with schizophrenia or schizoaffective disorder. Efficacy was established in an active-controlled study (1.2, 14.2). 1.1 Treatment-Resistant Schizophrenia VERSACLOZ is 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, VERSACLOZ 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)]. 1.2 Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorders VERSACLOZ is 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)].

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Advisory information

contraindications
4 CONTRAINDICATIONS •Known hypersensitivity to clozapine or any other component of VERSACLOZ (4.1). 4.1 Hypersensitivity VERSACLOZ is 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 VERSACLOZ [see Adverse Reactions (6.2)].
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: •Severe Neutropenia [see Warnings and Precautions (5.1)]. •Orthostatic Hypotension, Bradycardia, and Syncope [see Warnings and Precautions (5.3)]. •Falls [see Warnings and Precautions (5.4)] •Seizures [see Warnings and Precautions (5.5) ]. •Myocarditis and Cardiomyopathy [see Warnings and Precautions (5.6) ]. •Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.7) ]. •Eosinophilia [see Warnings and Precautions (5.8) ]. •QT Interval Prolongation [see Warnings and Precautions (5.9) ]. •Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.10) ]. •Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.11) ]. •Hepatotoxicity [see Warnings and Precautions (5.12)]. •Fever [see Warnings and Precautions (5.13) ]. •Pulmonary Embolism [see Warnings and Precautions (5.14) ]. •Anticholinergic Toxicity [see Warnings and Precautions (5.15) ]. •Interference with Cognitive and Motor Performance [see Warnings and Precautions (5.16) ]. •Tardive Dyskinesia [see Warnings and Precautions (5.17) ]. •Cerebrovascular Adverse Reactions [see Warnings and Precautions (5.18) ]. •Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see Warnings and Precautions (5.19) ]. 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 (6.1). To report SUSPECTED ADVERSE REACTIONS, contact TruPharma, LLC, at 1-877-541-5504 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The most commonly reported adverse reactions (>5%) across clozapine clinical trials were: CNS reactions, including sedation, dizziness/vertigo, headache, and tremor; cardiovascular reactions, including tachycardia, hypotension, and syncope; autonomic nervous system reactions, including hypersalivation, sweating, dry mouth, and visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever. Table 9 summarizes the most commonly reported adverse reactions (>5%) in clozapine-treated patients (compared to chlorpromazine-treated patients) in the pivotal, 6-week, controlled trial in treatment-resistant schizophrenia. Table 9: Common Adverse Reactions (≥5%) in the 6-Week, Randomized, Chlorpromazine-controlled Trial in Treatment-Resistant Schizophrenia Adverse Reaction Clozapine (N=126) (%) Chlorpromazine (N=142) (%) Sedation Tachycardia Constipation Dizziness Hypotension Fever (hyperthermia) Hypersalivation Hypertension Headache Nausea/vomiting Dry mouth 21 17 16 14 13 13 13 12 10 10 5 13 11 12 16 38 4 1 5 10 12 20 Table 10 summarizes the adverse reactions reported in clozapine-treated patients at a frequency of 2% or greater across all clozapine studies (excluding the 2-year InterSePT™ Study). These rates are not adjusted for duration of exposure. Table 10: Adverse Reactions (≥2%) Reported in Clozapine-treated Patients (N=842) across all Clozapine Studies (excluding the 2-year InterSePT™ Study) Body System Adverse Reaction Clozapine N=842 Percentage of Patients Central Nervous System Drowsiness/Sedation Dizziness/Vertigo Headache Tremor 39 19 7 6 Syncope Disturbed Sleep/Nightmares Restlessness Hypokinesia/Akinesia 6 4 4 4 Agitation Seizures (convulsions) Rigidity Akathisia Confusion Fatigue Insomnia 4 3† 3 3 3 2 2 Cardiovascular Tachycardia Hypotension Hypertension 25† 9 4 Gastrointestinal Constipation Nausea Abdominal Discomfort/Heartburn Nausea/Vomiting Vomiting Diarrhea 14 5 4 3 3 2 Urogenital Urinary Abnormalities 2 Autonomic Nervous System Salivation Sweating Dry Mouth Visual Disturbances 31 6 6 5 Skin Rash 2 Hemic/Lymphatic Leukopenia/Decreased WBC/Neutropenia 3 Miscellaneous Fever Weight Gain 5 4 † Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine. Table 11 summarizes the most commonly reported adverse reactions (>10% of the clozapine or olanzapine group) in the InterSePT™ Study. This was an adequate and well-controlled, two-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder. The rates are not adjusted for duration of exposure. Table 11: Incidence of Adverse Reactions in Patients Treated with Clozapine or Olanzapine in the InterSePT™ Study (≥10% in the clozapine or olanzapine group) Adverse Reactions Clozapine N=479 % Reporting Olanzapine N=477 % Reporting Salivary hypersecretion 48% 6% Somnolence 46% 25% Weight increased 31% 56% Dizziness (excluding vertigo) 27% 12% Constipation 25% 10% Insomnia 20% 33% Nausea 17% 10% Vomiting 17% 9% Dyspepsia 14% 8% Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Central Nervous System Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, and post-discontinuation cholinergic rebound adverse reactions. Cardiovascular System Atrial or ventricular fibrillation, ventricular tachycardia, QT interval prolongation, Torsades de Pointes, myocardial infarction, cardiac arrest, and periorbital edema. Endocrine System Pseudopheochromocytoma. Gastrointestinal System Acute pancreatitis, dysphagia, salivary gland swelling. Hepatobiliary System Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure. Immune System Disorders Angioedema, leukocytoclastic vasculitis. Urogenital System Acute interstitial nephritis, nocturnal enuresis, priapism, and renal failure. Skin and Subcutaneous Tissue Disorders Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens-Johnson Syndrome. Musculoskeletal System and Connective Tissue Disorders Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus. Respiratory System Aspiration, pleural effusion, pneumonia, lower respiratory tract infection. Hemic and Lymphatic System Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia. Vision Disorders Narrow-angle glaucoma. Miscellaneous Creatine phosphokinase elevation, hyperuricemia, hyponatremia, and weight loss.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION •Starting Dose: 12.5 mg once daily or twice daily (2.2). •Use cautious titration and divided dosage schedule (2.2, 5.3). •Titration: increase the total daily dosage in increments of 25 mg to 50 mg per day, if well-tolerated (2.2). •Target dose: 300 mg to 450 mg per day, in divided doses, by the end of 2 weeks (2.2). •Subsequent increases: increase in increments of 100 mg or less, once or twice weekly (2.2). •Maximum daily dose: 900 mg (2.2). •Administer orally using syringe provided (2.3). •Shake bottle for 10 seconds prior to withdrawing suspension from bottle; use oral syringes and syringe adaptor provided (2.3). 2.1 Required Laboratory Testing Prior to Initiation and During Therapy Prior to initiating treatment with VERSACLOZ, 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 [see Warnings and Precautions (5.1)]. 2.2 Dosing Information The starting dose is 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 [see Warnings and Precautions (5.3) ]. 2.3 Important Administration Instructions VERSACLOZ Oral Suspension is administered to the mouth by the oral syringes provided (1 mL or 9 mL). After shaking the bottle for 10 seconds prior to each use, the syringe adaptor is pressed on top of the bottle. The oral syringe (1 mL or 9 mL) is filled with air, and inserted into the adaptor. The air is dispelled into the bottle and then the bottle is turned upside down. The prescribed amount of the suspension is drawn from the bottle and dispensed directly to the mouth. The prescribed dose should be administered immediately after it is prepared. Do not draw a dose and store it in the syringe for later use. After use, the oral syringe may be washed with warm water and dried for next use. The bottle may be closed with the same cap without removing the bottle adaptor. Educate patients and caregivers on the steps to administer VERSACLOZ as described in the Patient Instructions for Use. VERSACLOZ can be taken with or without food [see Pharmacokinetics (12.3)]. 2.4 Maintenance Treatment Generally, patients responding to VERSACLOZ should continue maintenance treatment on their effective dose beyond the acute episode. 2.5 Discontinuation of Treatment Method of treatment discontinuation will vary depending on the patient's last ANC: •See Tables 2 or 3 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 VERSACLOZ 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 [see Warnings and Precautions (5.1) ]. •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. 2.6 Re-Initiation of Treatment When restarting VERSACLOZ in patients who have discontinued VERSACLOZ (i.e., 2 days or more since the last dose), re-initiate with 12.5 mg once daily or twice daily. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions (5.3)]. If that dose is well tolerated, the dose may be increased to the previously therapeutic dose more quickly than recommended for initial treatment. 2.7 Dosage Adjustments with Concomitant use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2, CYP3A4 Inducers Dose adjustments may be necessary in patients with concomitant use of: strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin); moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine); CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline); CYP3A4 inducers (e.g., phenytoin, carbamazepine, St. John’s wort, and rifampin); or CYP1A2 inducers (e.g., tobacco smoking) (Table 1) [see Drug Interactions (7)]. Table 1: Dose Adjustment in Patients Taking Concomitant Medications Co-medications Scenarios Initiating VERSACLOZ while taking a co-medication Adding a co-medication while taking VERSACLOZ Discontinuing a co-medication while continuing VERSACLOZ Strong CYP1A2 Inhibitors Use one third of the VERSACLOZ dose. Increase VERSACLOZ dose based on clinical response. Moderate or Weak CYP1A2 Inhibitors Monitor for adverse reactions. Consider reducing the VERSACLOZ dose if necessary. Monitor for lack of effectiveness. Consider increasing VERSACLOZ dose if necessary. CYP2D6 or CYP3A4 Inhibitors Strong CYP3A4 Inducers Concomitant use is not recommended. However, if the inducer is necessary, it may be necessary to increase the VERSACLOZ dose. Monitor for decreased effectiveness. Reduce VERSACLOZ dose based on clinical response. Moderate or weak CYP1A2 or CYP3A4 Inducers Monitor for decreased effectiveness. Consider increasing the VERSACLOZ dose if necessary. Monitor for adverse reactions. Consider reducing the VERSACLOZ dose if necessary. 2.8 Renal or Hepatic Impairment, or CYP2D6 Poor Metabolizers It may be necessary to reduce the VERSACLOZ dose in patients with significant renal or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations (8.6, 8.7) ].
Use in special populations
8 USE IN SPECIFIC POPULATIONS • Nursing Mothers: Discontinue drug or discontinue nursing, taking into consideration importance of drug to mother (8.3). 8.1 Pregnancy Pregnancy Category B Risk Summary 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/m2 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, VERSACLOZ should be used during pregnancy only if clearly needed. Clinical Considerations 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 (5.10) ]. 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. Animal Data 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/m2 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/m2 body surface area basis. 8.3 Nursing Mothers VERSACLOZ is present in human milk. Because of the potential for serious adverse reactions in nursing infants from VERSACLOZ, 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. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in clinical studies utilizing VERSACLOZ to determine whether those over 65 years of age differ from younger subjects in their response to VERSACLOZ. Orthostatic hypotension and tachycardia can occur with clozapine treatment [see Boxed Warning and 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 (5.15) ]. Carefully select VERSACLOZ 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 (5.17) ]. 8.6 Patients with Renal or Hepatic Impairment 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), Clinical Pharmacology (12.3)]. 8.7 CYP2D6 Poor Metabolizers 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), Clinical Pharmacology (12.3)]. 8.8 Hospice Patients 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.
Pregnancy and lactation
8.3 Nursing Mothers VERSACLOZ is present in human milk. Because of the potential for serious adverse reactions in nursing infants from VERSACLOZ, 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.

Interactions

7 DRUG INTERACTIONS •Concomitant use of Strong CYP1A2 Inhibitors: Reduce VERSACLOZ dose to one third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin) (2.7, 7.1). •Concomitant use of Strong CYP3A4 Inducers is not recommended (2.7, 7.1). • Discontinuation of CYP1A2 or CYP3A4 Inducers: Consider reducing VERSACLOZ dose when CYP1A2 (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued (2.7, 7.1). 7.1 Potential for Other Drugs to Affect VERSACLOZ Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering VERSACLOZ concomitantly with drugs that are inducers or inhibitors of these enzymes. CYP1A2 Inhibitors Concomitant use of VERSACLOZ and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the VERSACLOZ dose to one third of the original dose when VERSACLOZ is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The VERSACLOZ dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration (2.7), Clinical Pharmacology (12.3)]. Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when VERSACLOZ is coadministered with these inhibitors. Consider reducing the VERSACLOZ dosage if necessary [see Dosage and Administration (2.7)]. CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with VERSACLOZ and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline) can increase clozapine levels and lead to adverse reactions [see Clinical Pharmacology (12.3)]. Use caution and monitor patients closely when using such inhibitors. Consider reducing the VERSACLOZ dose [see Dosage and Administration (2.7)]. CYP1A2 and CYP3A4 Inducers Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of VERSACLOZ. Tobacco smoke is a moderate inducer of CYP1A2. Strong CYP3A4 inducers include carbamazepine, phenytoin, St. John’s wort, and rifampin. It may be necessary to increase the VERSACLOZ dose if used concomitantly with inducers of these enzymes. However, concomitant use of VERSACLOZ and strong CYP3A4 inducers is not recommended [see Dosage and Administration (2.7)]. Consider reducing the VERSACLOZ dosage when discontinuing coadministered enzyme inducers, because discontinuation of inducers can result in increased clozapine plasma levels and an increased risk of adverse reactions [see Dosage and Administration (2.7)]. Drugs that Cause QT Interval Prolongation Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of VERSACLOZ. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Warnings and Precautions (5.9) ]. 7.2 Potential for VERSACLOZ to Affect Other Drugs Concomitant use of VERSACLOZ with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering VERSACLOZ with other drugs that are metabolized by CYP2D6. It may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide).

More information

Category Value
Authorisation number NDA203479
Agency product number J60AR2IKIC
Orphan designation No
Product NDC 52817-601
Date Last Revised 31-01-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1369825
Marketing authorisation holder TruPharma, LLC
Warnings WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Severe Neutropenia Clozapine treatment has caused severe neutropenia, defined as an absolute neutrophil count (ANC) less than 500/µL. Severe neutropenia can lead to serious infection and death. Prior to initiating treatment with VERSACLOZ a baseline ANC must be at least 1500/µL for the general population, and must be at least 1000/µL for patients with documented Benign Ethnic Neutropenia (BEN). During treatment, patients must have regular ANC monitoring. Advise patients to immediately report symptoms consistent with severe neutropenia or infection (e.g., fever, weakness, lethargy, or sore throat) [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)]. Because of the risk of severe neutropenia, VERSACLOZ is available only through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program [see Warnings and Precautions (5.2)]. Orthostatic Hypotension, Bradycardia, Syncope Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine 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 VERSACLOZ cautiously in patients with cardiovascular/cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications) [see Dosage and Administration (2.2, 2.6) and Warnings and Precautions (5.3)]. Seizures Seizures have occurred with clozapine treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering VERSACLOZ 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 [see Dosage and Administration (2.2) and Warnings and Precautions (5.5) ]. Myocarditis and Cardiomyopathy Fatal myocarditis and cardiomyopathy have occurred with clozapine treatment. Discontinue VERSACLOZ and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with VERSACLOZ-related myocarditis or cardiomyopathy should not be rechallenged with VERSACLOZ. Consider the possibility of myocarditis or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur [see Warnings and Precautions (5.6) ]. 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. VERSACLOZ is not approved for use in patients with dementia-related psychosis [see Warnings and Precautions (5.7) ]. 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 VERSACLOZ must have a baseline blood absolute neutrophil count (ANC) measured before treatment initiation and regular ANC monitoring during treatment (2.1, 5.1). • VERSACLOZ is 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 (2.2, 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 (2.2, 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: VERSACLOZ is not approved for this condition ( 5.7 ).