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 | 52817-601 | ||||
|---|---|---|---|---|---|
| Drug Name | Versacloz |
||||
| Type | Brand | ||||
| Pharm Class | Atypical Antipsychotic [EPC] | ||||
| Active Ingredients |
|
||||
| Route | ORAL | ||||
| Dosage Form | SUSPENSION | ||||
| RxCUI drug identifier | 1369825, 1369831 |
||||
| Application Number | NDA203479 | ||||
| Labeler Name | TruPharma LLC | ||||
| Packages |
|
||||
| Check if available Online | Get Medication Prices online with Discount |
Overdosage of VERSACLOZ
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 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 VERSACLOZ. 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 (5.3) ]. • Falls [see Warnings and Precautions (5.4) ] • Seizures [see Warnings and Precautions (5.5) ]. • Myocarditis, Cardiomyopathy and Mitral Valve Incompetence [see Warnings and Precautions (5.6) ]. • Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.7) ]. • Gastrointestinal Hypomotility and Severe Complications [see Warnings and Precautions (5.8)]. • Eosinophilia [see Warnings and Precautions (5.9) ]. • QT Interval Prolongation [see Warnings and Precautions (5.10) ]. • Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.11) ]. • Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.12) ]. • Hepatotoxicity [see Warnings and Precautions (5.13) ]. • Fever [see Warnings and Precautions (5.14) ]. • Pulmonary Embolism [see Warnings and Precautions (5.15) ]. • Anticholinergic Toxicity [see Warnings and Precautions (5.16) ]. • Interference with Cognitive and Motor Performance [see Warnings and Precautions (5.17) ]. • Tardive Dyskinesia [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 TruPharma, LLC, at 1-877-541-5504 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The most commonly reported adverse reactions ( > 5%) across clozapine clinical trials were: CNS reactions, including sedation, dizziness/vertigo, headache, and tremor; cardiovascular reactions, including tachycardia, hypotension, and syncope; autonomic nervous system reactions, including hypersalivation, sweating, dry mouth, and visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever. Table 9 summarizes the most commonly reported adverse reactions ( > 5%) in clozapine-treated patients (compared to chlorpromazine-treated patients) in the pivotal, 6-week, controlled trial in treatment-resistant schizophrenia. Table 9: Common Adverse Reactions (≥5%) in the 6-Week, Randomized, Chlorpromazine-controlled Trial in Treatment-Resistant Schizophrenia Adverse Reaction Clozapine (N=126) (%) Chlorpromazine (N=142) (%) Sedation Tachycardia Constipation Dizziness Hypotension Fever (hyperthermia) Hypersalivation Hypertension Headache Nausea/vomiting Dry mouth 21 17 16 14 13 13 13 12 10 10 5 13 11 12 16 38 4 1 5 10 12 20 Table 10 summarizes the adverse reactions reported in clozapine-treated patients at a frequency of 2% or greater across all clozapine studies (excluding the 2-year InterSePT ™ Study). These rates are not adjusted for duration of exposure. Table 10: Adverse Reactions (≥2%) Reported in Clozapine-treated Patients (N=842) across all Clozapine Studies (excluding the 2-year InterSePT™ Study) Body System Adverse Reaction Clozapine N=842 Percentage of Patients Central Nervous System Drowsiness/Sedation Dizziness/Vertigo Headache Tremor 39 19 7 6 Syncope Disturbed Sleep/Nightmares Restlessness Hypokinesia/Akinesia 6 4 4 4 Agitation Seizures (convulsions) Rigidity Akathisia Confusion Fatigue Insomnia 4 3† 3 3 3 2 2 Cardiovascular Tachycardia Hypotension Hypertension 25† 9 4 Gastrointestinal Constipation Nausea Abdominal Discomfort/Heartburn Nausea/Vomiting Vomiting Diarrhea 14 5 4 3 3 2 Urogenital Urinary Abnormalities 2 Autonomic Nervous System Salivation Sweating Dry Mouth Visual Disturbances 31 6 6 5 Skin Rash 2 Hemic/Lymphatic Leukopenia/Decreased WBC/Neutropenia 3 Miscellaneous Fever Weight Gain 5 4 † Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine. Table 11 summarizes the most commonly reported adverse reactions ( > 10% of the clozapine or olanzapine group) in the InterSePT ™ Study. This was an adequate and well-controlled, two-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder. The rates are not adjusted for duration of exposure. Table 11: Incidence of Adverse Reactions in Patients Treated with Clozapine or Olanzapine in the InterSePT™ Study (≥10% in the clozapine or olanzapine group) Adverse Reactions Clozapine N=479 % Reporting Olanzapine N=477 % Reporting Salivary hypersecretion 48% 6% Somnolence 46% 25% Weight increased 31% 56% Dizziness (excluding vertigo) 27% 12% Constipation 25% 10% Insomnia 20% 33% Nausea 17% 10% Vomiting 17% 9% Dyspepsia 14% 8% Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Central Nervous System Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, and post-discontinuation cholinergic rebound adverse reactions. Cardiovascular System Atrial or ventricular fibrillation, ventricular tachycardia, palpitations, QT interval prolongation, Torsades de Pointes, mitral valve incompetence associated with clozapine-related cardiomyopathy, myocardial infarction, cardiac arrest, and periorbital edema. Endocrine System Pseudopheochromocytoma. Gastrointestinal System Acute pancreatitis, dysphagia, salivary gland swelling, megacolon, 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, renal failure and retrograde ejaculation. 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, sleep apnea. 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.
| | | |
| 21 17 16 14 13 13 13 12 10 10 5 | 13 11 12 16 38 4 1 5 10 12 20 |
| | |
| 39 19 7 6 | |
| Syncope Disturbed Sleep/Nightmares Restlessness Hypokinesia/Akinesia | 6 4 4 4 |
| Agitation Seizures (convulsions) Rigidity Akathisia Confusion Fatigue Insomnia | 4 3† 3 3 3 2 2 |
| 25† 9 4 | |
| 14 5 4 3 3 2 | |
| 2 | |
| 31 6 6 5 | |
| 2 | |
| 3 | |
| 5 4 | |
| † Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine. | |
| | | |
| 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% |
VERSACLOZ 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 VERSACLOZ dose to one third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin) ( 2.7 , 7.1 ). • Concomitant use of Strong CYP3A4 Inducers is not recommended ( 2.7 , 7.1 ). • Discontinuation of CYP1A2 or CYP3A4 Inducers : Consider reducing VERSACLOZ dose when CYP1A2 (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued ( 2.7 , 7.1 ). • Anticholinergic drugs: Concomitant use may increase the risk for anticholinergic toxicity ( 5.8 , 5.16 , 7.1 ). 7.1 Potential for Other Drugs to Affect VERSACLOZ Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering VERSACLOZ concomitantly with drugs that are inducers or inhibitors of these enzymes. CYP1A2 Inhibitors Concomitant use of VERSACLOZ and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the VERSACLOZ dose to one third of the original dose when VERSACLOZ is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The VERSACLOZ dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration (2.7) , Clinical Pharmacology (12.3) ]. Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when VERSACLOZ is coadministered with these inhibitors. Consider reducing the VERSACLOZ dosage if necessary [see Dosage and Administration (2.7) ] . CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with VERSACLOZ and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline) can increase clozapine levels and lead to adverse reactions [see Clinical Pharmacology (12.3) ] . Use caution and monitor patients closely when using such inhibitors. Consider reducing the VERSACLOZ dose [see Dosage and Administration (2.7) ] . CYP1A2 and CYP3A4 Inducers Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of VERSACLOZ. Tobacco smoke is a moderate inducer of CYP1A2. Strong CYP3A4 inducers include carbamazepine, phenytoin, St. John’s wort, and rifampin. It may be necessary to increase the VERSACLOZ dose if used concomitantly with inducers of these enzymes. However, concomitant use of VERSACLOZ and strong CYP3A4 inducers is not recommended [see Dosage and Administration (2.7) ]. Consider reducing the VERSACLOZ dosage when discontinuing coadministered enzyme inducers, because discontinuation of inducers can result in increased clozapine plasma levels and an increased risk of adverse reactions [see Dosage and Administration (2.7) ]. Anticholinergic Drugs Concomitant treatment with clozapine 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 VERSACLOZ with anticholinergic drugs when possible [see Warnings and Precautions ( 5.8 , 5.16 )]. Drugs that Cause QT Interval Prolongation Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of VERSACLOZ. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Warnings and Precautions (5.10) ] . 7.2 Potential for VERSACLOZ to Affect Other Drugs Concomitant use of VERSACLOZ with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering VERSACLOZ with other drugs that are metabolized by CYP2D6. It may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide).
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 in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. VERSACLOZ 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 sAbsorption In man, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. VERSACLOZ Oral Suspension is bioequivalent to clozapine marketed tablets. Following oral administration of 100 mg to 800 mg VERSACLOZ, once daily, the average steady-state peak plasma concentration was 275 ng/mL (range: 105 - 723 ng/mL), occurring at the average of 2.2 hours (range: 1 - 3.5 hours) after dosing. The average minimum concentration at steady-state was 75 ng/mL (range: 11 - 198 ng/mL). When VERSACLOZ was administered after a high fat meal there was no effect on the AUC ss or C min, ss , however C max was reduced about 20%, and there was a slight delay in T max of 0.5 hour from a median T max of 2.0 hours under fasted conditions to 2.5 hours under fed conditions. The decrease in C max is not considered clinically relevant. Therefore VERSACLOZ may 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 VERSACLOZ is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. VERSACLOZ 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: 4-12 hours), compared to a mean elimination half-life of 12 hours (range: 4-66 hours), after achieving steady-state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine 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 schizophrenic patients 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 schizophrenic patients (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 Populations 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%–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 in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. VERSACLOZ 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 sAbsorption In man, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. VERSACLOZ Oral Suspension is bioequivalent to clozapine marketed tablets. Following oral administration of 100 mg to 800 mg VERSACLOZ, once daily, the average steady-state peak plasma concentration was 275 ng/mL (range: 105 - 723 ng/mL), occurring at the average of 2.2 hours (range: 1 - 3.5 hours) after dosing. The average minimum concentration at steady-state was 75 ng/mL (range: 11 - 198 ng/mL). When VERSACLOZ was administered after a high fat meal there was no effect on the AUC ss or C min, ss , however C max was reduced about 20%, and there was a slight delay in T max of 0.5 hour from a median T max of 2.0 hours under fasted conditions to 2.5 hours under fed conditions. The decrease in C max is not considered clinically relevant. Therefore VERSACLOZ may 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 VERSACLOZ is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. VERSACLOZ 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: 4-12 hours), compared to a mean elimination half-life of 12 hours (range: 4-66 hours), after achieving steady-state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine 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 schizophrenic patients 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 schizophrenic patients (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 Populations 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%–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 VERSACLOZ is contraindicated in patients with a history of serious hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson Syndrome) or any other component of VERSACLOZ [see Adverse Reactions (6.2) ] . •Known hypersensitivity to clozapine or any other component of VERSACLOZ ( 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 VERSACLOZ, 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 is: VERSACLOZ is available as a free-flowing yellow suspension. Each mL contains 50 mg of clozapine. The active component of VERSACLOZ is clozapine. The remaining components are glycerin, sorbitol (crystallizing), sodium dihydrogen phosphate dihydrate, xanthan gum, sodium methylparaben, sodium propylparaben, povidone, water, and sodium hydroxide to adjust to a pH range of 6.5 – 7.0. structure
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 • Starting Dose: 12.5 mg once daily or twice daily ( 2.2 ). • Use cautious titration and divided dosage schedule ( 2.2 , 5.3 ). • Titration: increase the total daily dosage in increments of 25 mg to 50 mg per day, if well-tolerated ( 2.2 ). • Target dose: 300 mg to 450 mg per day, in divided doses, by the end of 2 weeks ( 2.2 ). • Subsequent increases: increase in increments of 100 mg or less, once or twice weekly ( 2.2 ). • Maximum daily dose: 900 mg ( 2.2 ). • Administer orally using syringe provided ( 2.3 ). • Shake bottle for 10 seconds prior to withdrawing suspension from bottle; use oral syringes and syringe adaptor provided ( 2.3 ). 2.1 Required Laboratory Testing Prior to Initiation and During Therapy Prior to initiating treatment with VERSACLOZ, a baseline ANC must be obtained. The baseline ANC must be at least 1500/µL for the general population, and at least 1000/µL for patients with documented Benign Ethnic Neutropenia (BEN). To continue treatment, the ANC must be monitored regularly [see Warnings and Precautions (5.1) ] . 2.2 Dosing Information The starting dose is 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to achieve a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased once weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. To minimize the risk of orthostatic hypotension, bradycardia, and syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided dosages [see Warnings and Precautions (5.3) ]. 2.3 Important Administration Instructions VERSACLOZ Oral Suspension is administered to the mouth by the oral syringes provided (1 mL or 9 mL). After shaking the bottle for 10 seconds prior to each use, the syringe adaptor is pressed on top of the bottle. The oral syringe (1 mL or 9 mL) is filled with air, and inserted into the adaptor. The air is dispelled into the bottle and then the bottle is turned upside down. The prescribed amount of the suspension is drawn from the bottle and dispensed directly to the mouth. The prescribed dose should be administered immediately after it is prepared. Do not draw a dose and store it in the syringe for later use. After use, the oral syringe may be washed with warm water and dried for next use. The bottle may be closed with the same cap without removing the bottle adaptor. Educate patients and caregivers on the steps to administer VERSACLOZ as described in the Patient Instructions for Use. VERSACLOZ can be taken with or without food [see Clinical Pharmacology (12.3 )]. 2.4 Maintenance Treatment Generally, patients responding to VERSACLOZ should continue maintenance treatment on their effective dose beyond the acute episode. 2.5 Discontinuation of Treatment Method of treatment discontinuation will vary depending on the patient's last ANC: • See Tables 2 or 3 for appropriate ANC monitoring based on the level of neutropenia if abrupt treatment discontinuation is necessary because of moderate to severe neutropenia. • Reduce the dose gradually over a period of 1 to 2 weeks if termination of VERSACLOZ therapy is planned and there is no evidence of moderate to severe neutropenia. • For abrupt clozapine discontinuation for a reason unrelated to neutropenia, continuation of the existing ANC monitoring is recommended for general population patients until their ANC is ≥1500/µL and for BEN patients until their ANC is ≥1000/µL or above their baseline. • Additional ANC monitoring is required for any patient reporting onset of fever (temperature of 38.5°C or 101.3°F, or greater) during the 2 weeks after discontinuation [see Warnings and Precautions (5.1) ] . • Monitor all patients carefully for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea. 2.6 Re-Initiation of Treatment When restarting VERSACLOZ in patients who have had even a brief interruption in treatment with VERSACLOZ, dosage must be reduced. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions (5.3) ] . If one day’s dosing has been missed, resume treatment at 40% to 50% of the established dose. If two days dosing has been missed, resume dosage at approximately 25% of the established dosage. For longer interruptions, re-initiate with a dosage of 12.5 mg once daily or twice daily. If these dosages are well tolerated, the dosages may be increased to the previous dosage more quickly than recommended for initial treatment. 2.7 Dosage Adjustments with Concomitant use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2, CYP3A4 Inducers Dose adjustments may be necessary in patients with concomitant use of: strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin); moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine); CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline); CYP3A4 inducers (e.g., phenytoin, carbamazepine, St. John’s wort, and rifampin); or CYP1A2 inducers (e.g., tobacco smoking) (Table 1) [see Drug Interactions (7) ] . Table 1: Dose Adjustment in Patients Taking Concomitant Medications Co-medications Scenarios Initiating VERSACLOZ while taking a co-medication Adding a co-medication while taking VERSACLOZ Discontinuing a co-medication while continuing VERSACLOZ Strong CYP1A2 Inhibitors Use one third of the VERSACLOZ dose. Increase VERSACLOZ dose based on clinical response. Moderate or Weak CYP1A2 Inhibitors Monitor for adverse reactions. Consider reducing the VERSACLOZ dose if necessary. Monitor for lack of effectiveness. Consider increasing VERSACLOZ dose if necessary. CYP2D6 or CYP3A4 Inhibitors Strong CYP3A4 Inducers Concomitant use is not recommended. However, if the inducer is necessary, it may be necessary to increase the VERSACLOZ dose. Monitor for decreased effectiveness. Reduce VERSACLOZ dose based on clinical response. Moderate or weak CYP1A2 or CYP3A4 Inducers Monitor for decreased effectiveness. Consider increasing the VERSACLOZ dose if necessary. Monitor for adverse reactions. Consider reducing the VERSACLOZ dose if necessary. 2.8 Renal or Hepatic Impairment, or CYP2D6 Poor Metabolizers It may be necessary to reduce the VERSACLOZ dose in patients with significant renal or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations (8.6 , 8.7) ] .
| Initiating VERSACLOZ while taking a co-medication | Adding a co-medication while taking VERSACLOZ | Discontinuing a co-medication while continuing VERSACLOZ | |
| Strong CYP1A2 Inhibitors | Use one third of the VERSACLOZ dose. | Increase VERSACLOZ dose based on clinical response. | |
| Moderate or Weak CYP1A2 Inhibitors | Monitor for adverse reactions. Consider reducing the VERSACLOZ dose if necessary. | Monitor for lack of effectiveness. Consider increasing VERSACLOZ dose if necessary. | |
| CYP2D6 or CYP3A4 Inhibitors | |||
| Strong CYP3A4 Inducers | Concomitant use is not recommended. However, if the inducer is necessary, it may be necessary to increase the VERSACLOZ dose. Monitor for decreased effectiveness. | Reduce VERSACLOZ dose based on clinical response. | |
| Moderate or weak CYP1A2 or CYP3A4 Inducers | Monitor for decreased effectiveness. Consider increasing the VERSACLOZ dose if necessary. | Monitor for adverse reactions. Consider reducing the VERSACLOZ dose if necessary. | |
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 VERSACLOZ is available as a free-flowing yellow oral suspension. Each mL contains 50 mg of clozapine. • Oral suspension: 50 mg per mL ( 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 VERSACLOZ is an atypical antipsychotic indicated for: • Treatment-resistant schizophrenia. Efficacy was established in an active-controlled study ( 1.1 , 14.1 ). • Reducing suicidal behavior in patients with schizophrenia or schizoaffective disorder. Efficacy was established in an active-controlled study ( 1.2 , 14.2 ). 1.1 Treatment-Resistant Schizophrenia VERSACLOZ is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, VERSACLOZ should be used only in patients who have failed to respond adequately to standard antipsychotic treatment [see Warnings and Precautions (5.1 , 5.5) ] . The effectiveness of clozapine in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing clozapine and chlorpromazine in patients who had failed other antipsychotics [see Clinical Studies (14.1) ] . 1.2 Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorders VERSACLOZ is indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death. The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT™ trial [see Clinical Studies (14.2) ] .
Spl product data elements
Usually a list of ingredients in a drug product.VERSACLOZ Clozapine CLOZAPINE CLOZAPINE GLYCERIN SORBITOL SODIUM PHOSPHATE, MONOBASIC, DIHYDRATE XANTHAN GUM METHYLPARABEN SODIUM PROPYLPARABEN SODIUM WATER SODIUM HYDROXIDE POVIDONE
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 PRINCIPAL DISPLAY PANEL-Container Label Rx Only Versacloz ® (clozapine) Oral Suspension 50 mg/mL label-carton-box
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.Boxed Warning 03/2023 Warnings and Precautions (5.8) 03/2023
VERSACLOZ: 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 (Patient Information and Instructions for Use). • Severe Neutropenia •Instruct patients (and caregivers) beginning treatment with VERSACLOZ about the risk of developing severe neutropenia and infection.•Instruct patients to immediately report to their physician any symptom or sign of infection (e.g., flu-like illness; fever; lethargy; general weakness or malaise; mucus membrane ulceration; skin, pharyngeal, vaginal, urinary, or pulmonary infection; or extreme weakness or lethargy) occurring at any time during VERSACLOZ therapy, to aid in evaluation for neutropenia and to institute prompt and appropriate management [see Warnings and Precautions (5.1) , (5.12) , and (5.14) ] .•Inform patients and caregivers VERSACLOZ is available only through a restricted program called the Clozapine REMS Program designed to ensure the required blood monitoring, in order to reduce the risk of developing severe neutropenia. Advise patients and caregivers of the importance of having blood tested as follows:•Weekly blood tests are required for the first 6 months.•An ANC is required every 2 weeks for the next 6 months if an acceptable ANC is maintained during the first 6 months of continuous therapy.•An ANC is required once every 4 weeks thereafter if an acceptable ANC is maintained during the second 6 months of continuous therapy . •VERSACLOZ is available only from certified pharmacies participating in the program. Provide patients (and caregivers) with website information and the telephone number on how to obtain the product [see Warnings and Precautions (5.2 )].• 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 (2.2, 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 (5.3) ] .• Falls: Inform patients of the risk of falls, which may lead to fractures or other injuries [see Warnings and Precautions (5.4) ]. • Seizures: Inform patients and caregivers about the significant risk of seizure during VERSACLOZ treatment. Caution them about driving and any other potentially hazardous activity while taking VERSACLOZ [see Warnings and Precautions (5.5) ]. • Gastrointestinal Hypomotility with Severe Complications: Educate patients and caregivers on the risks, prevention, and treatment of clozapine-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 VERSACLOZ with other drugs that cause QT interval prolongation. Instruct patients to inform their clinicians that they are taking VERSACLOZ before any new drug [see Warnings and Precautions (5.10) 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 (5.11) ] .• Interference with Cognitive and Motor Performance : Because VERSACLOZ 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 VERSACLOZ therapy does not affect them adversely [see Warnings and Precautions (5.17) ] .• Hepatotoxicity: Instruct patients to immediately report to their physician any symptoms or signs of potential liver injury (e.g. fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy) [see Warnings and Precautions (5.13) ] .• Missed Doses and Re-Initiating Treatment : Inform patients and caregivers that if the patient misses taking VERSACLOZ for more than 2 days, they should not restart his or her medication at the same dosage but should contact their physician for dosing instructions [see Dosage and Administration (2.6) and Warnings and Precautions (5.1 , 5.3 )]. • Pregnancy : Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with VERSACLOZ. Advise patients that VERSACLOZ may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to clozapine during pregnancy [see Use in Specific Populations (8.1) ]. • Lactation : Advise breastfeeding women using VERSACLOZ to monitor infants for excess sedation and to seek medical care if they notice this sign [see Use in Specific Populations (8.2) ]. • Concomitant Medication : Advise patients to inform their health care 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) ] .• Patient Instructions for Use : Educate the patient and caregiver about the Patient Instructions for Use if VERSACLOZ will be administered at home. Discuss the specific steps for administering the prescribed dose using the oral syringe [see Dosage and Administration (2.3) ]. Distributed by: TruPharma, LLC Tampa, FL 33609 U.S. Patent No. 8057811 VERSACLOZ ® is a trademark of Tasman Pharma. 309939
Spl patient package insert
Information necessary for patients to use the drug safely and effectively.Patient Information VERSACLOZ ® (VER sa kloz) (clozapine) Oral Suspension Read this Patient Information before you start taking VERSACLOZ and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about VERSACLOZ? VERSACLOZ can cause serious side effects, including: 1. Severe neutropenia, a blood disorder that can lead to serious infections and death. Severe neutropenia means that you do not have enough of certain white blood cells to fight infection. Tell your healthcare provider right away if you have any of the following symptoms or signs of neutropenia or infection: •Skin, throat, urinary tract, vaginal, pneumonia, or any other infection•Fever or chills•Sores or ulcers inside your mouth, gums or on your skin•Wounds that take a long time to heal•Feel like you have the flu•Pain or burning while urinating•Unusual vaginal discharge or itching•Abdominal pain•Sores or pain in or around your rectal area•Feel extremely tired or weak If you have symptoms of severe neutropenia or infection you will need to have a blood test right away to check if VERSACLOZ is causing your symptoms. You must have frequent blood tests while taking VERSACLOZ so your healthcare provider can make sure you are not getting severe neutropenia or infection. VERSACLOZ is available only through a restricted program called the Clozapine REMS Program. This program makes sure that you will receive each refill of VERSACLOZ only if you have a blood test and your blood test result is acceptable to your healthcare provider. During your first 6 months of clozapine treatment, you will have weekly blood tests. If you have not taken clozapine before, you will need weekly blood tests when you first start VERSACLOZ. If you have acceptable blood test results during your first 6 months of clozapine treatment, you can have a blood test every other week for the next 6 months. After a year of acceptable blood test results, you can have blood tests every 4 weeks while you are taking VERSACLOZ. 2. Decreased blood pressure (orthostatic hypotension), slow heart rate (bradycardia), or fainting (syncope) that can lead to death. Lightheadedness or fainting caused by a sudden change in your heart rate and blood pressure when you rise too quickly from a sitting or lying position can happen while you take VERSACLOZ and can be life threatening. These problems may happen more often when you are first starting treatment with VERSACLOZ or when your dose is increased. Tell your healthcare provider right away if you feel faint, lose consciousness, or have symptoms of slow heart rate or an irregular heart rhythm. 3. Seizures. Seizures can occur during VERSACLOZ treatment. Be especially careful while driving or during any other dangerous activity while taking VERSACLOZ. 4. Myocarditis (heart muscle inflammation) and cardiomyopathy (heart muscle weakness) that may lead to death. Symptoms of myocarditis and cardiomyopathy include: 5. Higher risk of death in elderly people with memory loss (dementia) or psychosis. VERSACLOZ can increase the risk of death in elderly people who have dementia. VERSACLOZ is not for treating psychosis in elderly people with dementia. What is VERSACLOZ? VERSACLOZ is a prescription antipsychotic medicine used to treat people with certain types of schizophrenia, including people who: •are not helped by other schizophrenia medicines•have been suicidal and may be at risk of suicidal behavior again It is not known if VERSACLOZ is safe and effective in children. Who should not take VERSACLOZ? Do not take VERSACLOZ if you: •have blood problems called neutropenia•are allergic to clozapine or any of the ingredients in VERSACLOZ. See the end of this Patient Information Leaflet for a complete list of ingredients in VERSACLOZ. What should I tell my healthcare provider before taking VERSACLOZ? Before you take VERSACLOZ, tell your healthcare provider about all of 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•have or have had liver or kidney problems•have or have had seizures or epilepsy•have or have had low levels of potassium or magnesium in your blood•have diabetes•have increased pressure in your eyes (glaucoma)•have had Neuroleptic Malignant Syndrome (NMS)•have or have had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia)•have or have had diarrhea or constipation•have or have had an enlarged prostate gland•smoke tobacco•plan to stop smoking tobacco while taking VERSACLOZ•use products containing caffeine•are pregnant or plan to become pregnant. It is not known if VERSACLOZ will harm your unborn baby. Talk to your healthcare provider if you become pregnant while taking VERSACLOZ. If you become pregnant while receiving clozapine, 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 breastfeeding or plan to breastfeed. VERSACLOZ can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take VERSACLOZ. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. VERSACLOZ and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take: •chemotherapy, radiation, or other medicines that cause agranulocytosis, neutropenia, low white blood cell count, or affect your bone marrow•other antipsychotics or other medicines that can affect the amount of clozapine in your blood•medicines used to treat anxiety, relax your muscles, or help you sleep•any medicines that make you feel sleepy•antibiotics•medicines used to treat heart problems•medicines used to lower the amount of water in your body (diuretics)•medicines used for birth control Ask your healthcare provider for a list of these medicines if you are not sure. 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 VERSACLOZ? •Read the “ Instructions for Use ” at the end of this Patient Information for specific information about the right way to use VERSACLOZ.•Your pharmacist should go over the instructions for how to use VERSACLOZ with you when you receive your first prescription.•Take VERSACLOZ exactly as your healthcare provider tells you to take it. Talk to your healthcare provider or pharmacist if you are not sure how to take VERSACLOZ.•Do not change your dose or stop taking VERSACLOZ without talking to your healthcare provider. The symptoms of VERSACLOZ overdose can include: If you miss a dose of VERSACLOZ for more than 2 days, check with your healthcare provider before starting to take it again to make sure you take the correct dose. What should I avoid while taking VERSACLOZ? •You should not drink alcohol while taking VERSACLOZ. It can increase your chances of getting serious side effects.•Do not drive, operate machinery, swim, climb, or do other dangerous activities until you know how VERSACLOZ affects you. What are the possible side effects of VERSACLOZ? VERSACLOZ may cause serious side effects, including: •See "What is the most important information I should know about VERSACLOZ?" • severe constipation and bowel problems. You may not feel or be aware of constipation symptoms. Contact your healthcare provider if you are having bowel movements at less than your normal frequency, especially if it is less than three times a week, you have hard or dry stools, or you have difficulty passing gas. Talk with your healthcare provider about ways to prevent constipation. Other symptoms associated with bowel problems include nausea, bloating or stomach swelling, stomach pain, and vomiting.• high count of a certain white blood cell (eosinophilia) • problems with your heartbeat. These heart problems can cause death. Call 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• high blood sugar (diabetes) and changes in the fat levels in your blood (dyslipidemia) • Neuroleptic Malignant Syndrome (NMS). NMS is a rare but very serious problem that can happen in people who take VERSACLOZ. NMS can cause death and must be treated in a hospital. Call your healthcare provider right away if you become severely ill and have any of these symptoms:•high fever•excessive sweating•stiff muscles•confusion•changes in your breathing, heartbeat and blood pressure• falls, which may lead to fractures or other injuries• liver problems. Call your healthcare provider right away if you have any of these symptoms:•nausea•vomiting•loss of appetite•feel tired•pain on the right side of your stomach (abdomen)•yellowing of your skin or the whites of your eyes• fever. Some people may have a fever that comes and goes while they take VERSACLOZ. This happens more often in the first 3 weeks you take VERSACLOZ. Talk to 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 and constipation (anticholinergic toxicity) • problems thinking clearly and moving your body • uncontrolled movements of your tongue, face, mouth, or jaw ( tardive dyskinesia) • stroke in elderly people (cerebrovascular problems) The most common side effects of VERSACLOZ include: Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of VERSACLOZ. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store VERSACLOZ? •Store VERSACLOZ at room temperature between 68°F to 77°F (20°C to 25°C).•Do not refrigerate or freeze VERSACLOZ.•Protect VERSACLOZ from light.•Shake your VERSACLOZ bottle well for 10 seconds before each use. Keep VERSACLOZ and all medicines out of the reach of children. General information about the safe and effective use of VERSACLOZ Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use VERSACLOZ for a condition for which it was not prescribed. Do not give VERSACLOZ to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information Leaflet summarizes the most important information about VERSACLOZ. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for more information about VERSACLOZ that is written for healthcare professionals. For more information, go to www.VERSACLOZ.com or call 1-800-520-5568. What are the ingredients in VERSACLOZ? Active ingredient: clozapine Inactive ingredients: glycerin, sorbitol (crystallizing), sodium dihydrogen phosphate dihydrate, xanthan gum, sodium methylparaben, sodium propylparaben, povidone, water, and sodium hydroxide Instructions for Use VERSACLOZ ® (VER sa kloz) (clozapine) Oral Suspension Supplies you will need to take your VERSACLOZ dose: •VERSACLOZ ® Oral Suspension bottle•a bottle neck adaptor•the correct oral syringe to measure your dose• If your dose is 1 mL (50 mg) or less , use the smaller 1 mL oral syringe.• If your dose is more than 1 mL (50 mg), use the larger 9 mL oral syringe. Disposal of your or al syringe, empty VER SACLOZ bottle and bottle neck adaptor: Place the cap back on the empty VERSACLOZ bottle before you throw it away. The oral syringe, empty bottle and bottle neck adaptor should be placed in your household trash when you finish your bottle of VERSACLOZ. The oral syringe should not be shared with other people or used for medicines other than VERSACLOZ. Distributed by: TruPharma, LLC Tampa, FL 33609 This Patient Information and the Instructions for Use have been approved by the U.S. Food and Drug Administration. 309939 Revised: March 2023 myocarditis.jpg overdose.jpg common-side -effects.jpg patient use instructions.jpg figure A-step 1.jpg figure B-step 2.jpg figure C-step 3.jpg step 4.jpg figure D.jpg figure E-step 5.jpg figure F-step 6.jpg figure G-step 7.jpg figure H-step 8.jpg figure I-step 9.jpg figure J-step 10.jpg figure K-step 11.jpg figure L-step 12.jpg figure M-step 13.jpg figure N-step 14.jpg
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 he 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 200–900 mg/day for clozapine and 5–20 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: 18–69). 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 figure-02 cumulative
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 VERSACLOZ to determine whether those over 65 years of age differ from younger subjects in their response to VERSACLOZ. Orthostatic hypotension and tachycardia can occur with clozapine treatment [see Boxed Warning and Warnings and Precautions (5.3 ) ]. Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects. Elderly patients may be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation [see Warnings and Precautions (5.16) ]. Carefully select VERSACLOZ doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy. Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women [see Warnings and Precautions (5.18) ].
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 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, during pregnancy. Health care providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmental health.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including VERSACLOZ, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ). Overall, available data from published epidemiologic studies of pregnant women exposed to clozapine 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 VERSACLOZ, 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 estimated 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 VERSACLOZ, 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 Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. 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 • Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure ( 8.1 ). 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including clozapine, during pregnancy. Health care providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmental health.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including VERSACLOZ, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ). Overall, available data from published epidemiologic studies of pregnant women exposed to clozapine 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 VERSACLOZ, 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 estimated 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 VERSACLOZ, 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 Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. 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 are reports 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 VERSACLOZ and any potential adverse effects on the breastfed-child from VERSACLOZ or from the underlying maternal condition. Clinical Considerations Infants exposed to VERSACLOZ should be monitored for excess sedation. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in clinical studies utilizing VERSACLOZ to determine whether those over 65 years of age differ from younger subjects in their response to VERSACLOZ. Orthostatic hypotension and tachycardia can occur with clozapine treatment [see Boxed Warning and Warnings and Precautions (5.3 ) ]. Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects. Elderly patients may be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation [see Warnings and Precautions (5.16) ]. Carefully select VERSACLOZ doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy. Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women [see Warnings and Precautions (5.18) ]. 8.6 Patients with Renal or Hepatic Impairment Dose reduction may be necessary in patients with significant impairment of renal or hepatic function. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration (2.8) , Clinical Pharmacology (12.3) ]. 8.7 CYP2D6 Poor Metabolizers Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration (2.8) , Clinical Pharmacology (12.3) ]. 8.8 Hospice Patients For hospice patients (i.e., terminally ill patients with an estimated life expectancy of 6 months or less), the prescriber may reduce the ANC monitoring frequency to once every 6 months, after a discussion with the patient and his/her caregiver. Individual treatment decisions should weigh the importance of monitoring ANC in the context of the need to control psychiatric symptoms and the patient's terminal illness.
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 Oral Suspension Free-flowing, yellow suspension (50 mg/mL) in amber bottle containing 100 mL. Each box contains 1 x 1 mL oral syringe, 1 x 9 mL oral syringe and 1 bottle adaptor. NDC No. 52817-601-38 16.2 Storage and Handling Store VERSACLOZ at or below 25°C (77°F). Do not refrigerate or freeze. Protect from light. Shake well for 10 seconds before use. The suspension is stable for 100 days after initial bottle opening. Keep out of reach of children.
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 AND CARDIOMYOPATHY, INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Severe Neutropenia Clozapine treatment has caused severe neutropenia, defined as an absolute neutrophil count (ANC) less than 500/µL. Severe neutropenia can lead to serious infection and death. Prior to initiating treatment with VERSACLOZ a baseline ANC must be at least 1500/µL for the general population, and must be at least 1000/µL for patients with documented Benign Ethnic Neutropenia (BEN). During treatment, patients must have regular ANC monitoring. Advise patients to immediately report symptoms consistent with severe neutropenia or infection (e.g., fever, weakness, lethargy, or sore throat) [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ]. Because of the risk of severe neutropenia, VERSACLOZ is available only through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program [see Warnings and Precautions (5.2) ]. Orthostatic Hypotension, Bradycardia, Syncope Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose escalation. These reactions can occur with the first dose, with doses as low as 12.5 mg per day. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages to minimize risk. Use VERSACLOZ cautiously in patients with cardiovascular/ or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications) [see Dosage and Administration [see Dosage and Administration ( 2.2 , 2.6 ), Warnings and Precautions (5.3) ]. Seizures Seizures have occurred with clozapine treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering VERSACLOZ to patients with a history of seizures or other predisposing risk factors for seizure (CNS pathology, medications that lower the seizure threshold, alcohol abuse). Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others [see Dosage and Administration (2.2 ) and Warnings and Precautions (5.5) ]. Myocarditis, Cardiomyopathy and Mitral Valve Incompetence Fatal myocarditis and cardiomyopathy have occurred with clozapine treatment. Discontinue VERSACLOZ and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with VERSACLOZ-related myocarditis or cardiomyopathy should not be rechallenged with VERSACLOZ. Consider the possibility of myocarditis or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur [see Warnings and Precautions (5.6) ]. Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VERSACLOZ is not approved for use in patients with dementia-related psychosis [see Warnings and Precautions (5.7) ]. WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. • Severe Neutropenia: Clozapine can cause severe neutropenia, which can lead to serious and fatal infections. Patients initiating and continuing treatment with VERSACLOZ must have a baseline blood absolute neutrophil count (ANC) measured before treatment initiation and regular ANC monitoring during treatment ( 2.1 , 5.1 ). • VERSACLOZ is available only through a restricted program called the Clozapine REMS ( 5.2 ). • Orthostatic Hypotension, Bradycardia, and Syncope: Risk is dose-related. Starting dose is 12.5 mg. Titrate gradually and use divided dosages ( 2.2 , 2.6 , 5.3 ). • Seizure: Risk is dose-related. Titrate gradually and use divided doses. Use with caution in patients with history of seizure or risk factors for seizure ( 2.2 , 5.5 ). • Myocarditis, Cardiomyopathy and Mitral Valve Incompetence : Can be fatal. Discontinue and obtain cardiac evaluation if findings suggest these cardiac reactions ( 5.6 ). • Increased Mortality in Elderly Patients with Dementia-Related Psychosis: VERSACLOZ is not approved for this condition ( 5.7 ).
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