Save up to 80% by drug discount in your pharmacy with "Pharmacy Near Me - National Drug Discount Card"
You can scan QR Code(just open camera on your phone/scan by application) from the image on prescription drug discount card to save it to your mobile phone. Or just click on image if you're on mobile phone.
| Product NDC Code | 0093-5377 | ||||||
|---|---|---|---|---|---|---|---|
| Drug Name | Clozapine |
||||||
| Type | Generic | ||||||
| Pharm Class | Atypical Antipsychotic [EPC] | ||||||
| Active Ingredients |
|
||||||
| Route | ORAL | ||||||
| Dosage Form | TABLET, ORALLY DISINTEGRATING | ||||||
| RxCUI drug identifier | 476177, 476179, 721773, 996921, 1006801 |
||||||
| Application Number | ANDA090308 | ||||||
| Labeler Name | Teva Pharmaceuticals USA, Inc. | ||||||
| Packages |
|
||||||
| Check if available Online | Get Medication Prices online with Discount |
Overdosage of Clozapine
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE 10.1 Overdosage Experience The most commonly reported signs and symptoms associated with Clozapine ODT overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g. 10.2 Management of Overdosage There are no specific antidotes for Clozapine ODT overdose. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222).
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.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 ( 5.2 )] Falls [see Warnings and Precautions ( 5.3 )] Seizures [see Warnings and Precautions ( 5.4 )] Myocarditis, Pericarditis, and Cardiomyopathy and Mitral Valve Incompetence [see Warnings and Precautions ( 5.5 )] Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.6 )] Gastrointestinal Hypomotility with Severe Complications [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 )] Patients with Phenylketonuria [ see Warnings and Precautions ( 5.18 )] Cerebrovascular Adverse Reactions [see Warnings and Precautions ( 5.19 )] Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see Warnings and Precautions ( 5.20 )] 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 Teva at 1-888-838-2872 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 Clozapine Chlorpromazine Adverse Reaction (N=126) (N=142) (%) (%) Sedation 21 13 Tachycardia 17 11 Constipation 16 12 Dizziness 14 16 Hypotension 13 38 Fever (hyperthermia) 13 4 Hypersalivation 13 1 Hypertension 12 5 Headache 10 10 Nausea/vomiting 10 12 Dry mouth 5 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 Clozapine Adverse Reaction N=842 Percentage of Patients Central Nervous System Drowsiness/Sedation 39 Dizziness/Vertigo 19 Headache 7 Tremor 6 Syncope 6 Disturbed Sleep/Nightmares 4 Restlessness 4 Hypokinesia/Akinesia 4 Agitation 4 Seizures (convulsions) 3 † Rigidity 3 Akathisia 3 Confusion 3 Fatigue 2 Insomnia 2 Cardiovascular Tachycardia 25 † Hypotension 9 Hypertension 4 Gastrointestinal Constipation 14 Nausea 5 Abdominal Discomfort/Heartburn 4 Nausea/Vomiting 3 Vomiting 3 Diarrhea 2 Urogenital Urinary abnormalities 2 Autonomic Nervous System Salivation 31 Sweating 6 Dry mouth 6 Visual disturbances 5 Skin Rash 2 Hemic/Lymphatic Leukopenia/Decreased WBC/Neutropenia 3 Miscellaneous Fever 5 Weight Gain 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) Clozapine Olanzapine N=479 N=477 Adverse Reactions % Reporting % 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, pericarditis, and periorbital edema. Endocrine System Pseudopheochromocytoma. Gastrointestinal System Acute pancreatitis, dysphagia, salivary gland swelling, megacolon, fecal incontinence, and intestinal ischemia, infarction, perforation, ulceration or necrosis. 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.
Clozapine Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS Concomitant use of Strong CYP1A2 Inhibitors : Reduce Clozapine ODT 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 Clozapine ODT dose when CYP1A2 (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued. (2.7, 7.1 ) Anticholinergic drugs: Concomitant use may increase the risk for anticholinergic toxicity. (5.7, 5.15, 7.1 ) 7.1 Potential for Other Drugs to Affect Clozapine ODT Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering Clozapine ODT concomitantly with drugs that are inducers or inhibitors of these enzymes. CYP1A2 Inhibitors Concomitant use of Clozapine ODT and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the Clozapine ODT dose to one third of the original dose when Clozapine ODT is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The Clozapine ODT 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 Clozapine ODT is coadministered with these inhibitors. Consider reducing the Clozapine ODT dosage if necessary [see Dosage and Administration ( 2.7 )]. CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with Clozapine ODT 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 Clozapine ODT 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 Clozapine ODT. 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 Clozapine ODT dose if used concomitantly with inducers of these enzymes. However, concomitant use of Clozapine ODT and strong CYP3A4 inducers is not recommended [see Dosage and Administration ( 2.7 )]. Consider reducing the Clozapine ODT 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 )]. Anticholinergic Drugs Concomitant treatment with Clozapine ODT and other drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) can increase the risk for anticholinergic toxicity and severe gastrointestinal adverse reactions related to hypomotility. Avoid concomitant use of Clozapine ODT with anticholinergic drugs when possible [see Warnings and Precautions ( 5.7 , 5.15 )] . Drugs that Cause QT Interval Prolongation Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. 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 Clozapine ODT to Affect Other Drugs Concomitant use of Clozapine ODT with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering Clozapine ODT 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).
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of Clozapine ODT in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors. 12.2 Pharmacodynamics Clozapine demonstrated binding affinity to the following receptors: histamine H 1 (K i 1.1 nM), adrenergic α 1A (K i 1.6 nM), serotonin 5-HT 6 (K i 4 nM ) , serotonin 5-HT 2A (K i 5.4 nM), muscarinic M 1 (K i 6.2 nM), serotonin 5-HT 7 (K i 6.3 nM), serotonin 5-HT 2C (K i 9.4 nM), dopamine D 4 (K i 24 nM), adrenergic α 2A (K i 90 nM), serotonin 5-HT 3 (K i 95 nM), serotonin 5-HT 1A (K i 120 nM), dopamine D 2 (K i 160 nM), dopamine D 1 (K i 270 nM), dopamine D 5 (K i 454 nM), and dopamine D 3 (K i 555 nM). Clozapine causes little or no prolactin elevation. Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs. Sharp wave activity and spike and wave complexes may also develop. Patients have reported an intensification of dream activity during clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep. 12.3 Pharmacokinetics Absorption In humans Clozapine ODT (25 mg and 100 mg) is equally bioavailable relative to a clozapine oral solution. Clozapine ODT is bioequivalent to Clozaril ® (clozapine) tablets, a registered trademark of Novartis Pharmaceuticals Corporation. Following a dosage of 100 mg twice daily, the average steady-state peak plasma concentration was 413 ng/mL (range: 132 to 854 ng/mL), occurring at the average of 2.3 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady-state was 168 ng/mL (range: 45 to 574 ng/mL), after 100 mg b.i.d. dosing. A comparative bioequivalence/bioavailability study was conducted in 32 patients (with schizophrenia or schizoaffective disorder) comparing Clozapine ODT 200 mg to 2 × Clozapine ODT 100 mg (the approved reference product) under fasted conditions. The study also evaluated the effect of food and chewing on the pharmacokinetics of the 200 mg tablet. Under fasted conditions, the mean AUC ss and C min,ss of clozapine for the 200 mg oral disintegrating tablets were equivalent to those of the 2 x 100 mg tablets. The mean C max,ss of clozapine for Clozapine ODT 200 mg was 85% that for 2 x 100 mg Clozapine ODT. This decrease in C max,ss for Clozapine ODT 200 mg is not clinically significant. For Clozapine ODT 200 mg, food significantly increased the C min,ss of clozapine by 21%. However, this increase is not clinically significant. The mean AUC ss and C max,ss of clozapine under fed conditions were equivalent to those under fasted conditions. Food delayed clozapine absorption by 1.5 hours, from a median T max of 2.5 hours under fasted conditions to 4 hours under fed conditions. The mean C max,ss of clozapine under chewed conditions for Clozapine ODT 200 mg was about 86% that for 2 x 100 mg Clozapine ODT under non-chewed conditions, while the AUC ss and C min,ss values were similar between the chewed and non-chewed conditions. In a food-effect study, a single dose of Clozapine ODT 12.5 mg was administered to healthy volunteers under fasting conditions and after a high-fat meal. When Clozapine ODT were administered after a high-fat meal, the C max of both clozapine and its active metabolite, desmethylclozapine, were decreased by approximately 20%, compared to administration under fasting conditions, while the AUC values were unchanged. This decrease in C max is not clinically significant. Therefore, Clozapine ODT can be taken without regard to meals. Distribution Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important [see Drug Interactions ( 7 )]. Metabolism and Excretion Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N -oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N -oxide derivatives were inactive. The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving steady state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of Clozapine ODT demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady state, approximately dose-proportional changes with respect to AUC (area under the curve), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg twice daily. Drug-Drug Interaction Studies Fluvoxamine: A pharmacokinetic study was conducted in 16 patients with schizophrenia who received clozapine under steady-state conditions. After coadministration of fluvoxamine for 14 days, mean trough concentrations of clozapine and its metabolites, N -desmethylclozapine and clozapine N -oxide, were elevated about three-fold compared to baseline steady state concentrations. Paroxetine, Fluoxetine, and Sertraline: In a study of patients with schizophrenia (n=14) who received clozapine under steady-state conditions, coadministration of paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Specific Population Studies Renal or Hepatic Impairment: No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with significant renal or hepatic impairment when given usual doses. CYP2D6 Poor Metabolizers: A subset (3% to 10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. Patients with 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.
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of Clozapine ODT in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Clozapine demonstrated binding affinity to the following receptors: histamine H 1 (K i 1.1 nM), adrenergic α 1A (K i 1.6 nM), serotonin 5-HT 6 (K i 4 nM ) , serotonin 5-HT 2A (K i 5.4 nM), muscarinic M 1 (K i 6.2 nM), serotonin 5-HT 7 (K i 6.3 nM), serotonin 5-HT 2C (K i 9.4 nM), dopamine D 4 (K i 24 nM), adrenergic α 2A (K i 90 nM), serotonin 5-HT 3 (K i 95 nM), serotonin 5-HT 1A (K i 120 nM), dopamine D 2 (K i 160 nM), dopamine D 1 (K i 270 nM), dopamine D 5 (K i 454 nM), and dopamine D 3 (K i 555 nM). Clozapine causes little or no prolactin elevation. Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs. Sharp wave activity and spike and wave complexes may also develop. Patients have reported an intensification of dream activity during clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Absorption In humans Clozapine ODT (25 mg and 100 mg) is equally bioavailable relative to a clozapine oral solution. Clozapine ODT is bioequivalent to Clozaril ® (clozapine) tablets, a registered trademark of Novartis Pharmaceuticals Corporation. Following a dosage of 100 mg twice daily, the average steady-state peak plasma concentration was 413 ng/mL (range: 132 to 854 ng/mL), occurring at the average of 2.3 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady-state was 168 ng/mL (range: 45 to 574 ng/mL), after 100 mg b.i.d. dosing. A comparative bioequivalence/bioavailability study was conducted in 32 patients (with schizophrenia or schizoaffective disorder) comparing Clozapine ODT 200 mg to 2 × Clozapine ODT 100 mg (the approved reference product) under fasted conditions. The study also evaluated the effect of food and chewing on the pharmacokinetics of the 200 mg tablet. Under fasted conditions, the mean AUC ss and C min,ss of clozapine for the 200 mg oral disintegrating tablets were equivalent to those of the 2 x 100 mg tablets. The mean C max,ss of clozapine for Clozapine ODT 200 mg was 85% that for 2 x 100 mg Clozapine ODT. This decrease in C max,ss for Clozapine ODT 200 mg is not clinically significant. For Clozapine ODT 200 mg, food significantly increased the C min,ss of clozapine by 21%. However, this increase is not clinically significant. The mean AUC ss and C max,ss of clozapine under fed conditions were equivalent to those under fasted conditions. Food delayed clozapine absorption by 1.5 hours, from a median T max of 2.5 hours under fasted conditions to 4 hours under fed conditions. The mean C max,ss of clozapine under chewed conditions for Clozapine ODT 200 mg was about 86% that for 2 x 100 mg Clozapine ODT under non-chewed conditions, while the AUC ss and C min,ss values were similar between the chewed and non-chewed conditions. In a food-effect study, a single dose of Clozapine ODT 12.5 mg was administered to healthy volunteers under fasting conditions and after a high-fat meal. When Clozapine ODT were administered after a high-fat meal, the C max of both clozapine and its active metabolite, desmethylclozapine, were decreased by approximately 20%, compared to administration under fasting conditions, while the AUC values were unchanged. This decrease in C max is not clinically significant. Therefore, Clozapine ODT can be taken without regard to meals. Distribution Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important [see Drug Interactions ( 7 )]. Metabolism and Excretion Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N -oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N -oxide derivatives were inactive. The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving steady state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of Clozapine ODT demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady state, approximately dose-proportional changes with respect to AUC (area under the curve), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg twice daily. Drug-Drug Interaction Studies Fluvoxamine: A pharmacokinetic study was conducted in 16 patients with schizophrenia who received clozapine under steady-state conditions. After coadministration of fluvoxamine for 14 days, mean trough concentrations of clozapine and its metabolites, N -desmethylclozapine and clozapine N -oxide, were elevated about three-fold compared to baseline steady state concentrations. Paroxetine, Fluoxetine, and Sertraline: In a study of patients with schizophrenia (n=14) who received clozapine under steady-state conditions, coadministration of paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Specific Population Studies Renal or Hepatic Impairment: No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with significant renal or hepatic impairment when given usual doses. CYP2D6 Poor Metabolizers: A subset (3% to 10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. Patients with 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.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS Clozapine ODT 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 Clozapine ODT [see Adverse Reactions ( 6.2 )] . Known hypersensitivity to clozapine or any other component of Clozapine ODT ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION Clozapine, USP an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5 H -dibenzo [ b , e ] [1,4] diazepine. The structural formula is: C 18 H 19 CIN 4 M.W. 326.82 Clozapine Orally Disintegrating Tablets (referred to as Clozapine ODT) is available as yellow, orally disintegrating tablets of 12.5 mg, 25 mg, 100 mg, 150 mg, and 200 mg for oral administration without water. Clozapine Orally Disintegrating Tablets may be chewed. Each orally disintegrating tablet contains clozapine, USP, equivalent to 12.5 mg, 25 mg, 100 mg, 150 mg, and 200 mg. The active component of Clozapine Orally Disintegrating Tablets is clozapine, USP. Inactive ingredients include aspartame powder, colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, peppermint flavor, sodium stearyl fumarate and xylitol. Clozapine ODT contains aspartame [ see Warnings and Precautions (5.18)] . Phenylalanine is a component of aspartame. Each 12.5 mg, orally disintegrating tablet contains 2.5 mg aspartame, thus, 1.4 mg phenylalanine. Each 25 mg, orally disintegrating tablet contains 5 mg aspartame, thus, 2.8 mg phenylalanine. Each 100 mg, orally disintegrating tablet contains 20 mg aspartame, thus, 11.2 mg phenylalanine. Each 150 mg, orally disintegrating tablet contains 30 mg aspartame, thus, 16.8 mg phenylalanine. Each 200 mg, orally disintegrating tablet contains 40 mg aspartame, thus, 22.4 mg phenylalanine. 1
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION Recommended starting oral dosage is 12.5 mg once daily or twice daily. ( 2.2 ) If well-tolerated, increase the total daily dosage in increments of 25 mg to 50 mg per day at target dosage of 150 mg to 225 mg twice per day by the end of two weeks ( 2.2 ) Subsequently may increase the dosage in increments up to 100 mg, once or twice weekly. ( 2.2 ) Maximum daily dosage is 450 mg twice daily. ( 2.2 ) Administer with or without food. Clozapine ODT may be allowed to disintegrate or chewed, and may be taken with or without water. See additional administration instructions in full prescribing information ( 2.2 ). See dosage modification based on ANC results ( 2.3 , 2.4 ) See recommendations for discontinuing Clozapine ODT treatment ( 2.5 ), restarting Clozapine ODT after interrupting dosing ( 2.6 ), dosage modifications for drug interactions ( 2.7 ), dosage recommendations in patients with renal or hepatic impairment and CYP2D6 poor metabolizers ( 2.8 ) in the full prescribing information. Tablets rapidly disintegrate after placement in the mouth and may be chewed if desired. No water is needed ( 2.3 ). 2.1 Absolute Neutrophil Count Testing Prior to Clozapine ODT Initiation Prior to initiating Clozapine ODT treatment, obtain a baseline absolute neutrophil count (ANC). Clozapine ODT initiation is not recommended in patients with an ANC less than 1500/µL [see Warnings and Precautions ( 5.1 )] . For patients with documented Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count)), obtain at least two baseline ANC levels. Clozapine ODT initiation is not recommended in patients with BEN with an ANC less than 1000/µL [see Warnings and Precautions ( 5.1 )] . For dosage modifications based on ANC results, see Dosage and Administration ( 2.4 , 2.5 ). 2.2 Recommended Dosage and Administration Recommended Dosage To reduce the risk of orthostatic hypotension, bradycardia, and syncope, the recommended starting dosage is much lower than the target dosage [see Warnings and Precautions ( 5.3 )] . The recommended starting oral dosage of Clozapine ODT is 12.5 mg once or twice daily. If well-tolerated, increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly. The maximum recommended Clozapine ODT oral dosage is 450 mg twice daily. Administration Instructions Clozapine ODT can be taken with or without food, may be allowed to disintegrate or chewed, and may be taken with or without water [see Clinical Pharmacology ( 12.3 )]. Just prior to use, peel the foil from the blister and gently remove the orally disintegrating tablet (ODT). Do not push the ODT through the foil, because this could damage the ODT. After removing Clozapine ODT from the blister pack or bottle, immediately place in the mouth. 2.3 Dosage Modifications Based on ANC Results Table 1 provides recommended Clozapine ODT dosage modifications based on ANC results [see Warnings and Precautions ( 5.1 )] . For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2 [see Dosage and Administration ( 2.5 )]. Table 1: Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing Recommended Dosage Modification Recommended Frequency of ANC Testing During Clozapine ODT Treatment ANC Within Normal Range (≥ 1500/µL) No dosage modification; continue treatment Day 1 to Month 6: Weekly Month 7 to Month 12: Every 2 weeks Month 13 and thereafter: Every month If Clozapine ODT treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now has a normal ANC level) for: < 30 days, continue the previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients who initiate treatment Mild Neutropenia (ANC between 1000 to 1499/µL) 1 No dosage modification; continue treatment Three times weekly Once ANC ≥ 1500/µL, recommend returning to the patient’s last Normal Range ANC testing frequency Moderate Neutropenia (ANC between 500 to 999/µL) 1 Interrupt treatment and recommend hematology consultation Resume treatment once ANC ≥1000/µL Daily Once ANC ≥ 1000/µL, three times weekly Once ANC ≥ 1500/µL, test weekly for 4 weeks. If ANC ≥ 1500/µL after monitoring weekly for 4 weeks, return to the patient’s last Normal Range ANC testing frequency Severe Neutropenia (ANC less than 500/µL) 1 Discontinue treatment and recommend hematology consultation Daily Once ANC ≥ 1000/µL, three times weekly Once ANC ≥ 1500/µL, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients who initiate treatment 1 Confirm all initial reports of ANC less than 1500/µL with a repeat ANC measurement within 24 hours 2.4 Dosage Modifications Based on ANC Results for Patients with Benign Ethnic Neutropenia Table 2 provides recommended Clozapine ODT dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count). [see Warnings and Precautions ( 5.1 )] . For dosage modifications based on ANC results for patients without BEN, see Table 1 [see Dosage and Administration ( 2.4 )]. Table 2: Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing in Patients with Benign Ethnic Neutropenia 1 Recommended Dosage Modification Recommended Frequency of ANC Testing During Clozapine ODT Treatment in Patients with BEN ANC Within the Normal Range for Patients with BEN (≥ 1000/µL ) No dosage modification; continue treatment Day 1 to Month 6: Weekly Month 7 to Month 12: Every 2 weeks Month 13 and thereafter: Monthly If Clozapine ODT treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now their ANC (≥ 1000/µL and ≥ the patient’s ANC baseline prior to treatment) for: < 30 days, continue previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients with BEN who initiate treatment Neutropenia in Patients with BEN (ANC level between 500 to 999/µL) 2 Recommend hematology consultation No dosage modification; continue treatment Three times weekly Once ANC ≥ 1000/µL and ≥ the patient’s ANC baseline, obtain ANC tests weekly for 4 weeks If ANC ≥ 1000/µL and ≥ the patient’s baseline after monitoring for 4 weeks, return to the patient’s last Normal ANC Range testing frequency for patients with BEN. Severe Neutropenia in Patients with BEN (ANC level less than 500/µL) 2 Discontinue treatment and recommend hematology consultation Daily Once ANC ≥ 500/µL, obtain ANC three times weekly Once ANC ≥ 1000/µL and ≥ the patient’s baseline, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients with BEN who initiate treatment 1 Benign Ethnic Neutropenia (BEN) is also known as Duffy-null associated neutrophil count. 2 Confirm all initial reports of ANC less than 1500/µL with a repeat ANC measurement within 24 hours 2.5 Discontinuation of Clozapine ODT Treatment If discontinuing Clozapine ODT in patients with: Moderate or severe neutropenia, see Table 1 [see Dosage and Administration ( 2.4 )]. Normal or mild neutropenia, reduce the dosage gradually over a period of 1 to 2 weeks, and continue monitoring ANC levels until their ANC is ≥1500/µL. If discontinuing Clozapine ODT in patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) with: Neutropenia, see Table 2 [see Dosage and Administration ( 2.5 )]. ANC within their normal range of ANC reduce the dosage gradually over a period of 1 to 2 weeks. When discontinuing Clozapine ODT, monitor patients for the symptoms related to psychotic recurrence and cholinergic rebound (e.g., profuse sweating, headache, nausea, vomiting, diarrhea). 2.6 Restarting Clozapine ODT Treatment After Interrupting Clozapine ODT When restarting Clozapine ODT in patients who have interrupted Clozapine ODT treatment, use a lower dosage to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions ( 5.3 )] . If one day’s dosage is missed, resume Clozapine ODT treatment at 40% to 50% of the previous dosage. If two days of dosing is missed, resume Clozapine ODT treatment at approximately 25% of the previous dosage. For longer interruptions, restart Clozapine ODT treatment with a dosage of 12.5 mg once or twice daily. If this dosage is well-tolerated, may increase the dosage to the previous dosage more quickly than recommended than for initial Clozapine ODT treatment. 2.7 Dosage Modifications for Drug Interactions See Table 3 for recommended dosage modifications to reduce the risk of Clozapine ODT-associated adverse reactions or reduce the risk of lower effectiveness [see Drug Interactions ( 7 )] . Table 3: Clozapine ODT Dosage Modifications for Drug Interactions Strong CYP1A2 Inhibitors Administer one third of the Clozapine ODT dosage. Moderate or Weak CYP1A2 Inhibitors Consider reducing the Clozapine ODT dosage if necessary. CYP2D6 or CYP3A4 Inhibitors Strong CYP3A4 Inducers Concomitant use is not recommended. However, if concomitant use is necessary, it may be necessary to increase the Clozapine ODT dosage. Monitor for decreased effectiveness. Moderate or weak CYP1A2 or CYP3A4 Inducers Consider increasing the Clozapine ODT dosage if necessary. 2.8 Dosage Recommendations in Patients with Renal or Hepatic Impairment, or CYP2D6 Poor Metabolizers It may be necessary to reduce the Clozapine ODT dosage in patients with significant renal impairment or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations ( 8.6 , 8.7 )] .
| |
| |
| |
|
|
| |
| |
| |
|
|
| |
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Clozapine Orally Disintegrating Tablets are available as 12.5 mg, 25 mg, 100 mg, 150 mg and 200 mg round, yellow, orally disintegrating tablets. Orally disintegrating tablets: 12.5 mg, 25 mg, 100 mg, 150 mg and 200 mg ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE Clozapine orally disintegrating tablets (Clozapine ODT) is an atypical antipsychotic indicated for: 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 ODT should be used only in patients who have failed to respond adequately to standard antipsychotic treatment ( 1.1 ) 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 ( 1.2 ) 1.1 Treatment-resistant Schizophrenia Clozapine Orally Disintegrating Tablets (Clozapine ODT) 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 their use, Clozapine ODT should be used only in patients who have failed to respond adequately to standard antipsychotic treatment [see Warnings and Precautions ( 5.1 , 5.4 )]. The effectiveness of Clozapine ODT in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing Clozapine ODT 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 Disorder Clozapine ODT 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 ODT 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 )] .
Spl product data elements
Usually a list of ingredients in a drug product.Clozapine Clozapine CLOZAPINE CLOZAPINE ASPARTAME SILICON DIOXIDE CROSPOVIDONE (15 MPA.S AT 5%) MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE PEPPERMINT SODIUM STEARYL FUMARATE XYLITOL I3 Clozapine Clozapine CLOZAPINE CLOZAPINE ASPARTAME SILICON DIOXIDE CROSPOVIDONE (15 MPA.S AT 5%) MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE PEPPERMINT SODIUM STEARYL FUMARATE XYLITOL I7 Clozapine Clozapine CLOZAPINE CLOZAPINE ASPARTAME SILICON DIOXIDE CROSPOVIDONE (15 MPA.S AT 5%) MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE PEPPERMINT SODIUM STEARYL FUMARATE XYLITOL I2 Clozapine Clozapine CLOZAPINE CLOZAPINE I1 Clozapine Clozapine CLOZAPINE CLOZAPINE L1
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m 2 body surface area basis. Mutagenesis Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes, or the in vivo micronucleus assay in mice. Impairment of Fertility Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight, or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m 2 body surface area basis.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m 2 body surface area basis. Mutagenesis Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes, or the in vivo micronucleus assay in mice. Impairment of Fertility Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight, or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m 2 body surface area basis.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.Package/Label Display Panel NDC 0093-5416-01 Clozapine Orally Disintegrating Tablets 12.5 mg Phenylketonurics: Contains phenylalanine 1.4 mg per each 12.5 mg orally disintegrating tablet. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Rx only 100 Tablets 1
Package/Label Display Panel NDC 0093-5417-01 Clozapine Orally Disintegrating Tablets 25 mg Phenylketonurics: Contains phenylalanine 2.8 mg per each 25 mg orally disintegrating tablet. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Rx only 100 Tablets 2
Package/Label Display Panel NDC 0093-5419-01 Clozapine Orally Disintegrating Tablets 100 mg Phenylketonurics: Contains phenylalanine 11.2 mg per each 100 mg orally disintegrating tablet. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Rx only 100 Tablets 3
Package/Label Display panel NDC 0093-5376-01 Clozapine Orally Disintegrating Tablets 150 mg Phenylketonurics: Contains phenylalanine 16.8 mg per each 150 mg orally disintegrating tablet. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Rx only 100 Tablets 4
Package/Label Display panel NDC 0093-5377-01 Clozapine Orally Disintegrating Tablets 200 mg Phenylketonurics: Contains phenylalanine 22.4 mg per each 200 mg orally disintegrating tablet. PHARMACIST: Dispense the accompanying Medication Guide to each patient. Rx only 100 Tablets 5
Clozapine: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Discuss the following issues with patients and caregivers: Severe Neutropenia: Instruct patients (and caregivers) [see Warnings and Precautions ( 5.1 )]: - About the risk of developing severe neutropenia and infection with Clozapine ODT treatment. - To immediately report to their health care provider any symptom or sign of infection during Clozapine ODT treatment - About the importance of having frequent ANC testing Orthostatic Hypotension, Bradycardia, and Syncope: Inform patients and caregivers about the risk of orthostatic hypotension and syncope, especially during the period of initial dose titration. Instruct them to strictly follow the clinician’s instructions for dosage and administration [see Dosage and Administration ( 2.3 , 2.6 )] . Advise patients to consult their clinician immediately if they feel faint, lose consciousness, or have signs or symptoms suggestive of bradycardia or arrhythmia [see Warnings and Precautions ( 5.2 )]. Falls: Inform patients of the risk of falls, which may lead to fractures or other injuries [see Warnings and Precautions ( 5.3 )]. Seizures: Inform patients and caregivers about the significant risk of seizure during Clozapine ODT treatment. Caution them about driving and any other potentially hazardous activity while taking Clozapine ODT [see Warnings and Precautions ( 5.4 )]. Gastrointestinal Hypomotility with Severe Complications: Educate patients and caregivers on the risks, prevention, and treatment of Clozapine ODT-induced constipation, including medications to avoid when possible (e.g., drugs with anticholinergic activity). Encourage appropriate hydration, physical activity, and fiber intake and emphasize that prompt attention and treatment to the development of constipation or other gastrointestinal symptoms is critical in preventing severe complications. Advise patients and caregivers to contact their health care provider if they experience symptoms of constipation (e.g., difficulty passing stools, incomplete passage of stool, decreased bowel movement frequency) or other symptoms associated with gastrointestinal hypomotility (e.g., nausea, abdominal distension or pain, vomiting) [see Warnings and Precautions ( 5.8 ), Drug Interactions ( 7.1 )] . QT Interval Prolongation : Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of arrhythmia. Instruct patients to not take Clozapine ODT with other drugs that cause QT interval prolongation. Instruct patients to inform their clinicians that they are taking Clozapine ODT before any new drug [see Warnings and Precautions ( 5.9 ) and Drug Interactions ( 7.1 )]. Metabolic Changes (hyperglycemia and diabetes mellitus, dyslipidemia, weight gain): Educate patients and caregivers about the risk of metabolic changes and the need for specific monitoring. The risks include hyperglycemia and diabetes mellitus, dyslipidemia, weight gain, and cardiovascular reactions. Educate patients and caregivers about the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus (e.g., polydipsia, polyuria, polyphagia, and weakness). Monitor all patients for these symptoms. Patients who are diagnosed with diabetes or have risk factors for diabetes (obesity, family history of diabetes) should have their fasting blood glucose monitored before beginning treatment and periodically during treatment. Patients who develop symptoms of hyperglycemia should have assessments of fasting glucose. Clinical monitoring of weight is recommended [see Warnings and Precautions ( 5.10 )] . Patients with Phenylketonuria: Inform patients and caregivers that Clozapine ODT contain phenylalanine (a component of aspartame) [see Warnings and Precautions ( 5.18 )]. Interference with Cognitive and Motor Performance: Because Clozapine ODT may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Clozapine ODT therapy does not affect them adversely [see Warnings and Precautions ( 5.16 )] . Hepatotoxicity: Instruct patients to immediately report to their physician any symptom or sign of potential liver injury (e.g fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy) [see Warnings and Precautions ( 5.12 )]. Missed Doses and Re-Initiating Treatment: Inform patients and caregivers that if the patient misses taking Clozapine ODT for 1 day or more, they should not restart their medication at the same dosage but should contact their physician for dosing instructions [see Dosage and Administration ( 2.5 ) and Warnings and Precautions ( 5.1 , 5.2 )]. Pregnancy: Patients and caregivers should notify the clinician if the patient becomes pregnant or intends to become pregnant during therapy [see Use in Specific Populations ( 8.1 )]. Nursing: Advise patients and caregivers that the patient should not breast feed an infant if they are taking Clozapine ODT [see Use in Specific Populations ( 8.3 )] . Concomitant Medication: Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter drugs; there is a potential for significant drug-drug interactions [see Dosage and Administration ( 2.6 ), Drug Interactions ( 7.1 )] . Administration: Patients should be advised that Clozapine ODT should remain in the original package until immediately before use [see Dosage and Administration ( 2.2 )] . Brands listed are the trademarks of their respective owners. Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. I 6/2025
Spl medguide
Information about the patient medication guide that accompanies the drug product. Certain drugs must be dispensed with an accompanying medication guide. This field may contain information about when to consult the medication guide and the contents of the medication guide.MEDICATION GUIDE CLOZAPINE ORAL DISINTEGRATING TABLETS (CLOZAPINE ODT) (kloe′ za peen) for oral use What is the most important information I should know about CLOZAPINE ODT? CLOZAPINE ODT can cause serious side effects including: Severe neutropenia (low white blood cell (WBC) counts) that can lead to serious infections and death. Your healthcare provider will do WBC blood tests before starting treatment with Clozapine ODT and weekly for the first 6 months. After your first 6 months of treatment, your healthcare provider will determine how frequent you will have blood tests. If you have symptoms of severe neutropenia or an infection, your healthcare provider will do more frequent WBC blood test(s) to check if Clozapine ODT is causing your symptoms and may send you to see a blood specialist (hematologist). Tell your health care provider right away if you have any of the following symptoms or signs of neutropenia or infection: feel like you have the flu fever or chills feel extremely tired or weak sores or ulcers inside your mouth, gums, or on your skin sores or pain in or around your rectal area wounds that take a long time heal skin, throat, vaginal, urinary tract, or lung infection pain or burning while peeing unusual vaginal discharge or itching abdominal pain or bloating Orthostatic hypotension (decreased blood pressure), bradycardia (slow heart rate), or syncope (fainting) that can lead to death . You may feel lightheaded or faint when you rise too quickly from a sitting or lying position. Tell your healthcare provider right away if you feel dizzy or pass out. Seizures. See “ What should I avoid while taking Clozapine ODT?” Myocarditis (heart muscle inflammation), pericarditis (inflammation of outer layer of the heart) and cardiomyopathy (heart muscle weakness) that can lead to death. Symptoms of myocarditis, pericarditis, and cardiomyopathy include: chest pain fast heartbeat or palpitations shortness of breath fever flu-like symptoms feel tired or faint swollen legs, ankles, or feet Increased risk of death in elderly people with dementia-related psychosis. Medicines like Clozapine ODT can increase the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and dementia. Clozapine ODT is not for treatment of elderly people with dementia-related psychosis. What is Clozapine ODT? Clozapine ODT is a prescription antipsychotic medicine used to treat people: Who are severely ill with schizophrenia not helped by other schizophrenia medicines With schizophrenia or schizoaffective disorder who have been suicidal and may be at risk of suicidal behavior again It is not known if Clozapine ODT is safe and effective in children. Who should not take Clozapine ODT? Do not take Clozapine ODT if you: are allergic to clozapine or any of the ingredients in Clozapine ODT. See the end of this Medication Guide for a complete list of ingredients in Clozapine ODT. Before taking Clozapine ODT, tell your healthcare provider about all your medical conditions, including if you: have or have had heart problems or a family history of heart problems including heart attack, heart failure, abnormal heart rhythm or long QT syndrome, or stroke have or have had low or high blood pressure have or have had kidney or liver problems have or have had seizures (convulsions) have or have had stomach or intestinal problems including constipation, slow emptying of your stomach, or diarrhea have or have had low levels of potassium or magnesium in your blood have or have had diabetes or high blood sugar in you or your family have or have had high levels of total cholesterol, “bad” cholesterol (LDL-C) which causes plaque build-up in arteries, or triglycerides, or low levels of “good” cholesterol (HDL-C) which helps remove excess cholesterol from the arteries have increased pressure in your eyes (glaucoma), an enlarged prostate, or problems passing urine have or have had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia) smoke tobacco plan to stop smoking tobacco while taking Clozapine ODT use products containing caffeine are pregnant or plan to become pregnant. Talk to your healthcare provider if you become pregnant while taking Clozapine ODT. If you become pregnant while receiving Clozapine ODT, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research- programs/pregnancyregistry/ are breast feeding or plan to breast feed. Clozapine ODT can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take Clozapine ODT. Tell your healthcare provider about all the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements. Clozapine ODT and other medicines may affect each other causing side effects. Your healthcare provider can tell you if it is safe to take Clozapine ODT with your other medicines. Do not start or stop any medicines while taking Clozapine ODT without talking to your healthcare provider first. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take Clozapine ODT? Take Clozapine ODT exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking Clozapine ODT unless your healthcare provider tells you to. Talk to your healthcare provider or pharmacist if you are not sure how to take Clozapine ODT. If you miss taking Clozapine ODT for 1 day or more, call your healthcare provider right away. Do not take 2 doses at the same time unless your healthcare provider tells you to. Take Clozapine ODT with or without food. See the detailed Instructions for Use at the end of this Medication Guide for information on how to take Clozapine ODT. If you take too much (overdose) Clozapine ODT, call your healthcare provider or the Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. Symptoms of Clozapine ODT overdose can include: feeling sleepy confusion coma fast or irregular heartbeat low blood pressure shallow or difficult breathing having a lot of saliva in your mouth seizures What should I avoid while taking Clozapine ODT? You should not drink alcohol while taking Clozapine ODT because it can increase your chances of getting serious side effects. Do not drive, operate machinery, swim, climb, or do dangerous activities until you know how Clozapine ODT affects you. What are the possible side effects of Clozapine ODT? Clozapine ODT can cause serious side effects, including: See "What is the most important information I should know about Clozapine ODT?" falls. Clozapine ODT may make you sleepy, dizzy, may cause a decrease in your blood pressure when changing positions, and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries. slow emptying of your stomach and intestines (decreased gastric motility). Severe constipation and bowel problems can happen and can lead to hospitalization, surgery, and death. You may not feel or be aware of constipation symptoms. Your healthcare provider will examine you for possible bowel problems. Tell your healthcare provider if you get any signs and symptoms of decreased gastrointestinal motility during treatment with Clozapine ODT, including: having bowel movements less than normal hard or dry stools difficulty passing gas stomach bloating or pain nausea or vomiting Staying well hydrated, increasing physical activity, and taking fiber during treatment with Clozapine ODT can help prevent constipation and other bowel problems. Your healthcare provider may prescribe medicines to prevent severe problems. high count of a certain white blood cell (eosinophilia). Clozapine ODT can cause a high count of eosinophils in some people and can be serious. This is a different risk than the risk of Clozapine ODT causing an abnormally low white blood cell count (neutropenia). Your health care provider may send you to see an internal medicine specialist (internist) or blood specialist (hematologist). Tell your healthcare provider right away if you have any of these symptoms: feeling very tired or weak fever rash swelling joint pain coughing and wheezing nausea, vomiting, or diarrhea night sweats confusion difficulty swallowing serious heart rhythm problems (QTc Interval Prolongation) that can cause death . Your healthcare provider will do a physical exam and may obtain blood tests and an electrocardiogram before starting you on treatment with Clozapine ODT. Tell your healthcare provider right away if you have any of these symptoms: passing out or feeling like you will pass out dizziness feeling as if your heart is pounding or missing beats problems with your metabolism such as: high blood sugar (hyperglycemia) or diabetes. Increases in blood sugar can happen in some people who take Clozapine ODT. Extremely high blood sugar can lead to coma and death. If you have diabetes or risk factors for diabetes (such as being overweight), your health care provider should check your blood sugar before you start Clozapine ODT and during treatment. Tell your healthcare provider if you have any of these symptoms of high blood sugar while taking Clozapine ODT: feel very thirsty need to urinate more than usual feel very hungry feel weak or tired feel sick to your stomach feel confused, or your breath smells fruity increased fat levels (cholesterol and triglycerides) in your blood (dyslipidemia). Your healthcare provider should check the fat levels in your blood before you start and during treatment with Clozapine ODT. weight gain. You and your healthcare provider should check your weight regularly. neuroleptic malignant syndrome (NMS). NMS is a rare but serious condition that can lead to death and must be treated in a hospital. Tell your healthcare provider right away if you become severely ill and have any of these symptoms: high fever stiff muscles confusion changes in breathing, heartbeat, and blood pressure increased sweating liver problems . Clozapine ODT can cause serious life-threatening liver problems that can lead to death. Tell your healthcare provider right away if you have any of these symptoms: feeling tired loss of appetite nausea and vomiting yellowing of your skin or whites of your eyes pain on the right side of your stomach (abdomen) elevated bilirubin levels fever. Some people may have a fever while they take Clozapine ODT. If you have a fever, your healthcare provider will do blood tests to check for neutropenia or an infection. Your healthcare provider may also send you to see a blood specialist (hematologist). Tell your healthcare provider if you have a fever. blood clot in your lung (pulmonary embolism) or in the veins of your legs (deep vein thrombosis). Get emergency help right away if you have symptoms of a blood clot including: chest pain and shortness of breath swelling or pain in your leg, ankle or foot warm feeling in the skin of your affected leg changes in your skin color such as turning pale or blue a problem that includes dry mouth, increased sweating, increased pulse rate, constipation, and urinary retention (anticholinergic toxicity). problems thinking clearly and moving your body. See What should I avoid while taking Clozapine ODT?” uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia) . Tardive dyskinesia may not go away, even if you stop Clozapine ODT. Tardive dyskinesia may also start after you stop taking Clozapine ODT. stroke (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death. The most common side effects of Clozapine ODT include: sleepiness or drowsiness dizziness heart and blood vessel problems fast heartbeat passing out (syncope) increased sweating vision problems headache shaking movements (tremors) low blood pressure having a lot of saliva in your mouth dry mouth constipation and nausea fever These are not all the possible side effects of Clozapine ODT. Your healthcare provider may lower your dose or temporarily or permanently stop treatment with Clozapine ODT if you have certain symptoms or if your WBC count is low. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. You may report side effects to FDA at 1-800-FDA-1088. How should I store Clozapine ODT? Store Clozapine ODT at room temperature between 68°F to 77°F (20°C to 25°C). Keep Clozapine ODT bottle in a sealed blister until time of use. Keep Clozapine ODT and all medicines out of the reach of children. General information about the safe and effective use of Clozapine ODT. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Clozapine ODT for a condition for which it was not prescribed. Do not give Clozapine ODT to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider (including pharmacist) for information about Clozapine ODT that is written for health professionals. What are the ingredients in Clozapine ODT? Active ingredient: clozapine Inactive ingredients: aspartame powder, colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, peppermint flavor, sodium stearyl fumarate and xylitol Manufactured For: Teva Pharmaceuticals, Parsippany, NJ 07054 This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. B 6/2025
| |||
|
| ||
| |||
|
| ||
| |||
| |||
| |||
| |||
| |||
|
|
| |
| |||
| |||
|
| ||
| | |||
| |||
|
| ||
| |||
|
|
| |
| |||
|
|
| |
| |||
|
|
| |
| |||
| |||
|
| ||
| |||
| |||
| This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. B 6/2025 | |||
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 14.1 Treatment-resistant Schizophrenia The efficacy of clozapine in treatment-resistant schizophrenia was established in a multicenter, randomized, double-blind, active-controlled (chlorpromazine) study in patients with a DSM-III diagnosis of schizophrenia who had inadequate responses to at least 3 different antipsychotics (from at least 2 different chemical classes) during the preceding 5 years. The antipsychotic trials must have been judged adequate; the antipsychotic dosages must have been equivalent to or greater than 1000 mg per day of chlorpromazine for a period of at least 6 weeks, each without significant reduction of symptoms. There must have been no period of good functioning within the preceding 5 years. Patients must have had a baseline score of at least 45 on the investigator-rated Brief Psychiatric Rating Scale (BPRS). On the 18-item BPRS, 1 indicates the absence of symptoms, and 7 indicates severe symptoms; the maximum potential total BPRS score is 126. At baseline, the mean BPRS score was 61. In addition, patients must have had a score of at least 4 on at least two of the following four individual BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content. Patients must have had a Clinical Global Impressions – Severity Scale score of at least 4 (moderately ill). In the prospective, lead-in phase of the trial, all patients (N=305) initially received single-blind treatment with haloperidol (the mean dose was 61 mg per day) for 6 weeks. More than 80% of patients completed the 6-week trial. Patients with an inadequate response to haloperidol (n=268) were randomized to double-blind treatment with clozapine (N=126) or chlorpromazine (N=142). The maximum daily clozapine dose was 900 mg; the mean daily dose was >600 mg. The maximum daily chlorpromazine dose was 1800 mg; the mean daily dose was >1200 mg. The primary endpoint was treatment response, predefined as a decrease in BPRS score of at least 20% and either (1) a CGI-S score of ≤3 (mildly ill), or (2) a BPRS score of ≤35, at the end of 6 weeks of treatment. Approximately 88% of patients from the clozapine and chlorpromazine groups completed the 6-week trial. At the end of six weeks, 30% of the clozapine group responded to treatment, and 4% of the chlorpromazine group responded to treatment. The difference was statistically significant (p<0.001). The mean change in total BPRS score was -16 and -5 in the clozapine and chlorpromazine group, respectively; the mean change in the 4 key BPRS item scores was -5 and -2 in the clozapine and chlorpromazine group, respectively; and the mean change in CGI-S score was -1.2 and -0.4, in the clozapine and chlorpromazine group, respectively. These changes in the clozapine group were statistically significantly greater than in the chlorpromazine group (p<0.001 in each analysis). 14.2 Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT ™ , a trademark of Novartis Pharmaceuticals Corporation). This was a prospective, randomized, open-label, active-controlled, multicenter, international, parallel-group comparison of clozapine (Clozaril ® ) versus olanzapine (Zyprexa ® , a registered trademark of Eli Lilly and Company) in 956 patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for recurrent suicidal behavior. Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment. To enter the trial, patients must have met one of the following criteria: They had attempted suicide within the three years prior to their baseline evaluation. They had been hospitalized to prevent a suicide attempt within the three years prior to their baseline evaluation. They demonstrated moderate-to-severe suicidal ideation with a depressive component within one week prior to their baseline evaluation. They demonstrated moderate-to-severe suicidal ideation accompanied by command hallucinations to do self-harm within one week prior to their baseline evaluation. Dosing regimens for each treatment group were determined by individual investigators and were individualized by patient. Dosing was flexible, with a dose range of 200 to 900 mg/day for clozapine and 5 to 20 mg/day for olanzapine. For the 956 patients who received clozapine or olanzapine in this study, there was extensive use of concomitant psychotropics: 84% with antipsychotics, 65% with anxiolytics, 53% with antidepressants, and 28% with mood stabilizers. There was significantly greater use of concomitant psychotropic medications among the patients in the olanzapine group. The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide; (2) hospitalization due to imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized; or (3) worsening of suicidality severity as demonstrated by “much worsening” or “very much worsening” from baseline in the Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist (CGI-SS-BP) scale. A determination of whether or not a reported event met criterion 1 or 2 above was made by the Suicide Monitoring Board (SMB), a group of experts blinded to patient data. A total of 980 patients were randomized to the study and 956 received study medication. Sixty-two percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective disorder. Only about one-fourth of the total patient population (27%) was identified as “treatment-resistant” at baseline. There were more males than females in the study (61% of all patients were male). The mean age of patients entering the study was 37 years of age (range 18 to 69). Most patients were Caucasian (71%), 15% were Black, 1% were Asian, and 13% were classified as being of “other” races. Patients treated with clozapine had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine. This result should be interpreted only as evidence of the effectiveness of clozapine in delaying time to recurrent suicidal behavior and not a demonstration of the superior efficacy of clozapine over olanzapine. The probability of experiencing (1) a significant suicide attempt, including a completed suicide, or (2) hospitalization because of imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized, was lower for clozapine patients than for olanzapine patients at Week 104: clozapine 24% versus olanzapine 32%; 95% CI of the difference: 2%, 14% (Figure 1). Figure 1. Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide in Patients with Schizophrenia or Schizoaffective Disorder at High Risk of Suicidality 2
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in clinical studies utilizing clozapine to determine whether those over 65 years of age differ from younger subjects in their response to clozapine. Orthostatic hypotension and tachycardia can occur with Clozapine ODT treatment [see Boxed Warning and Warnings and Precautions ( 5.2 )]. 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 ODT, such as urinary retention and constipation [see Warnings and Precautions ( 5.15 )]. Carefully select Clozapine ODT 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 )].
Nursing mothers
Information about excretion of the drug in human milk and effects on the nursing infant, including pertinent adverse effects observed in animal offspring.8.2 Lactation Risk Summary Clozapine is present in human milk. There is one case report of sedation and a report of agranulocytosis in an infant exposed to clozapine through human milk (see Clinical Considerations) . There is no information on the effects of clozapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Clozapine ODT and any potential adverse effects on the breastfed child from Clozapine ODT or from the underlying maternal condition. Clinical Considerations Infants exposed to Clozapine ODT should be monitored for excess sedation and neutropenia.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use Safety and effectiveness of clozapine in pediatric patients have not been established.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including Clozapine ODT, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Atypical Antipsychotics at1-866-961-2388 or visiting http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including Clozapine ODT, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery ( see Clinical Considerations ). Available data from published epidemiologic studies over decades of use with clozapine during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes ( see Data ). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including Clozapine ODT, during pregnancy ( see Clinical Considerations ). In animal reproduction studies, no adverse developmental effects were observed when clozapine was administered orally to pregnant rats or rabbits during the period of organogenesis, or to pregnant rats during pregnancy and lactation, at doses up to approximately 0.4 and 0.9 times the maximum recommended human dose (MRHD) of 900 mg/day, for rats and rabbits respectively, based on mg/m 2 body surface area ( see Data ). The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who have been exposed to antipsychotic drugs, including Clozapine ODT, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data 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/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.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Lactation : Infants exposed to Clozapine ODT through breast milk should be monitored for excess sedation and neutropenia. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including Clozapine ODT, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Atypical Antipsychotics at1-866-961-2388 or visiting http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including Clozapine ODT, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery ( see Clinical Considerations ). Available data from published epidemiologic studies over decades of use with clozapine during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes ( see Data ). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including Clozapine ODT, during pregnancy ( see Clinical Considerations ). In animal reproduction studies, no adverse developmental effects were observed when clozapine was administered orally to pregnant rats or rabbits during the period of organogenesis, or to pregnant rats during pregnancy and lactation, at doses up to approximately 0.4 and 0.9 times the maximum recommended human dose (MRHD) of 900 mg/day, for rats and rabbits respectively, based on mg/m 2 body surface area ( see Data ). The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who have been exposed to antipsychotic drugs, including Clozapine ODT, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data 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/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. 8.2 Lactation Risk Summary Clozapine is present in human milk. There is one case report of sedation and a report of agranulocytosis in an infant exposed to clozapine through human milk (see Clinical Considerations) . There is no information on the effects of clozapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Clozapine ODT and any potential adverse effects on the breastfed child from Clozapine ODT or from the underlying maternal condition. Clinical Considerations Infants exposed to Clozapine ODT should be monitored for excess sedation and neutropenia. 8.4 Pediatric Use Safety and effectiveness of clozapine in pediatric patients have not been established. 8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in clinical studies utilizing clozapine to determine whether those over 65 years of age differ from younger subjects in their response to clozapine. Orthostatic hypotension and tachycardia can occur with Clozapine ODT treatment [see Boxed Warning and Warnings and Precautions ( 5.2 )]. 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 ODT, such as urinary retention and constipation [see Warnings and Precautions ( 5.15 )]. Carefully select Clozapine ODT 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 )].
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 12.5 mg Yellow, round, flat-faced, beveled-edge, unscored tablet. Debossed with I3 on one side and plain on the other side. Available in bottles of 100 (NDC 0093-5416-01). 25 mg Yellow, round, flat-faced, beveled-edge, unscored tablet. Debossed with I7 on one side and plain on the other side. Available in bottles of 100 (NDC 0093-5417-01) and cartons of 48 tablets for Institutional Use Only (8x6 blister cards) (NDC 0093-5417-84). 100 mg Yellow, round, flat-faced, beveled-edge, unscored tablet. Debossed with I2 on one side and plain on the other side. Available in bottles of 100 (NDC 0093-5419-01) and cartons of 48 tablets for Institutional Use Only (8x6 blister cards) (NDC 0093-5419-84). 150 mg Yellow, round, flat-faced, beveled-edge, unscored tablet. Debossed with I1 on one side and plain on the other side. Available in bottles of 100 (NDC 0093-5376-01) and cartons of 48 tablets for Institutional Use Only (8x6 blister cards) (NDC 0093-5376-84). 200 mg Yellow, round, flat-faced, beveled-edge, unscored tablet. Debossed with L1 on one side and plain on the other side. Available in bottles of 100 (NDC 0093-5377-01) and cartons of 48 tablets for Institutional Use Only (8x6 blister cards) (NDC 0093-5377-84). 16.2 Storage and Handling Store Clozapine Orally Disintegrating Tablets (referred to as Clozapine ODT) at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture. Keep in a sealed blister until time of use. This unit-dose package is non child-resistant. Keep Clozapine ODT in the original package until used by the patient. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). The quantity of Clozapine ODT depends on the ANC testing results [see Warnings and Precautions ( 5.1 )]. If a patient is eligible for ANC testing: Every week, then a 1-week supply of Clozapine ODT can be dispensed. Every 2 weeks, then a 2-week supply of Clozapine ODT can be dispensed. Every 4 weeks, then a 4-week supply of Clozapine ODT can be dispensed.
16.1 How Supplied 12.5 mg Yellow, round, flat-faced, beveled-edge, unscored tablet. Debossed with I3 on one side and plain on the other side. Available in bottles of 100 (NDC 0093-5416-01). 25 mg Yellow, round, flat-faced, beveled-edge, unscored tablet. Debossed with I7 on one side and plain on the other side. Available in bottles of 100 (NDC 0093-5417-01) and cartons of 48 tablets for Institutional Use Only (8x6 blister cards) (NDC 0093-5417-84). 100 mg Yellow, round, flat-faced, beveled-edge, unscored tablet. Debossed with I2 on one side and plain on the other side. Available in bottles of 100 (NDC 0093-5419-01) and cartons of 48 tablets for Institutional Use Only (8x6 blister cards) (NDC 0093-5419-84). 150 mg Yellow, round, flat-faced, beveled-edge, unscored tablet. Debossed with I1 on one side and plain on the other side. Available in bottles of 100 (NDC 0093-5376-01) and cartons of 48 tablets for Institutional Use Only (8x6 blister cards) (NDC 0093-5376-84). 200 mg Yellow, round, flat-faced, beveled-edge, unscored tablet. Debossed with L1 on one side and plain on the other side. Available in bottles of 100 (NDC 0093-5377-01) and cartons of 48 tablets for Institutional Use Only (8x6 blister cards) (NDC 0093-5377-84).
Storage and handling
Information about safe storage and handling of the drug product.16.2 Storage and Handling Store Clozapine Orally Disintegrating Tablets (referred to as Clozapine ODT) at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture. Keep in a sealed blister until time of use. This unit-dose package is non child-resistant. Keep Clozapine ODT in the original package until used by the patient. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). The quantity of Clozapine ODT depends on the ANC testing results [see Warnings and Precautions ( 5.1 )]. If a patient is eligible for ANC testing: Every week, then a 1-week supply of Clozapine ODT can be dispensed. Every 2 weeks, then a 2-week supply of Clozapine ODT can be dispensed. Every 4 weeks, then a 4-week supply of Clozapine ODT can be dispensed.
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS, AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Severe Neutropenia Clozapine Orally Disintegrating Tablets (Clozapine ODT) has caused severe neutropenia which is associated with an increased risk of serious and potentially fatal infections. Prior to initiating Clozapine ODT treatment, obtain baseline ANC(s). Clozapine ODT initiation is not recommended in patients with a baseline ANC less than 1500/µL (less than 1000/µL for those with Benign Ethnic Neutropenia (also known as Duffy-null associated neutrophil count)). See recommendations for dosage modifications based on ANC levels during Clozapine ODT treatment [see Dosage and Administration ( 2.4 , 2.5 )]. Consider a hematology consultation before initiating Clozapine ODT or during Clozapine ODT treatment [see Warnings and Precautions ( 5.1 )]. 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, or when restarting patients who have had even a brief interruption in treatment with Clozapine ODT. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages to minimize risk. Use Clozapine ODT cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications) [see Dosage and Administration ( 2.3 , 2.6 ), Warnings and Precautions ( 5.2 )] . 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 Clozapine ODT 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 ( 2.3 ), Warnings and Precautions ( 5.4 )] . Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence Fatal myocarditis and cardiomyopathy have occurred with clozapine treatment. Discontinue Clozapine ODT and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with clozapine-related myocarditis or cardiomyopathy should not be rechallenged with Clozapine ODT. Consider the possibility of myocarditis, pericarditis, or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur [see Warnings and Precautions ( 5.5 )] . 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. Clozapine ODT is not approved for use in patients with dementia-related psychosis [see Warnings and Precautions ( 5.6 )] . WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS, AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Severe Neutropenia: Clozapine has caused severe neutropenia, which is associated with an increased risk of serious and fatal infections. Prior to initiating Clozapine Orally Disintegrating Tablets (Clozapine ODT) treatment, obtain baseline ANC(s). Clozapine ODT initiation is not recommended in patients with a baseline ANC less than 1500/µL (less than 1000/µL for those with Benign Ethnic Neutropenia (also known as Duffy-null associated neutrophil count)). See recommendations for dosage modifications based on ANC levels during Clozapine ODT treatment ( 2.1 , 2.3 , 2.4 , 5.1 ). Orthostatic Hypotension, Bradycardia, and Syncope: Risk is dose-related. Starting dose is 12.5 mg. Titrate gradually and use divided dosages. ( 2.2 , 5.2 ) 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. ( 5.4 ) Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence: Can be fatal. Discontinue and obtain cardiac evaluation if findings suggest these cardiac reactions. ( 5.5 ) Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Clozapine ODT is not approved for this condition. ( 5.6 )
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API