VERSACLOZ® (clozapine) oral suspension

VERSACLOZ® (clozapine) oral suspension

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VERSACLOZ® (clozapine) oral suspension

VERSACLOZ, an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8- chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine.

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.

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 (D2) and the serotonin type 2A (5-HT2A) receptors. VERSACLOZ also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.

Pharmacodynamics

Clozapine demonstrated binding affinity to the following receptors: histamine H1 (Ki 1.1 nM), adrenergic α1A (Ki 1.6 nM), serotonin 5-HT6 (Ki 4 nM), serotonin 5-HT2A (Ki 5.4 nM), muscarinic M1 (Ki 6.2 nM), serotonin 5-HT7 (Ki 6.3 nM), serotonin 5-HT2C (Ki 9.4 nM), dopamine D4 (Ki 24 nM), adrenergic α2A (Ki 90 nM), serotonin 5-HT3 (Ki 95 nM), serotonin 5-HT1A (Ki 120 nM), dopamine D2 (Ki 160 nM), dopamine D1 (Ki 270 nM), dopamine D5 (Ki 454 nM), and dopamine D3 (Ki 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

Absorption

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 to 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 AUCss or Cmin,ss, however Cmax was reduced about 20%, and there was a slight delay in Tmax of 0.5 hour from a median Tmax of 2.0 hours under fasted conditions to 2.5 hours under fed conditions. The decrease in Cmax 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.

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.

Indications

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.

Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder: 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.

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.

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.

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VERSACLOZ can be taken with or without food

Maintenance Treatment

Generally, patients responding to VERSACLOZ should continue maintenance treatment on their effective dose beyond the acute episode.

Discontinuation of Treatment

Method of treatment discontinuation will vary depending on the patient’s last ANC:

  • 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
  • Monitor all patients carefully for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea.

Re-Initiation of Treatment

When restarting VERSACLOZ in patients who have discontinued VERSACLOZ (i.e., 2 days or more since the last dose), re-initiate with 12.5 mg once daily or twice daily. This is necessary to minimize the risk of hypotension, bradycardia, and syncope. If that dose is well tolerated, the dose may be increased to the previously therapeutic dose more quickly than recommended for initial treatment.

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

Warnings and precautions

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)

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.

Orthostatic Hypotension, Bradycardia, Syncope: Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose escalation. These reactions can occur with the first dose, with doses as low as 12.5 mg per day. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages. Use VERSACLOZ cautiously in patients with cardiovascular/cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications).

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

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.

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 dementiarelated psychosis.

Adverse reactions
  • Severe Neutropenia
  • Orthostatic Hypotension, Bradycardia, and Syncope Falls.
  • Seizures
  • Myocarditis, Cardiomyopathy and Mitral Valve Incompetence
  • Increased Mortality in Elderly Patients with Dementia-Related Psychosis
  • Gastrointestinal Hypomotility and Severe Complications
  • Eosinophilia
  • QT Interval Prolongation
  • Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)
  • Neuroleptic Malignant Syndrome
  • Hepatotoxicity
  • Fever
  • Pulmonary Embolism
  • Anticholinergic Toxicity
  • Interference with Cognitive and Motor Performance
  • Tardive Dyskinesia
  • Cerebrovascular Adverse Reactions
  • Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation
Use in specific populations

Pregnancy: Neonates exposed to antipsychotic drugs, including VERSACLOZ, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery. 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. There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including VERSACLOZ, during pregnancy

Lactation: 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. 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.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

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.

Overdosage

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.

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).

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