VERSACLOZ Oral suspension Ref.[27741] Active ingredients: Clozapine

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 discontinued VERSACLOZ (i.e., 2 days or more since the last dose), re-initiate with 12.5 mg once daily or twice daily. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions (5.3)]. If that dose is well tolerated, the dose may be increased to the previously therapeutic dose more quickly than recommended for initial treatment.

2.7 Dosage Adjustments with Concomitant use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2, CYP3A4 Inducers

Dose adjustments may be necessary in patients with concomitant use of: strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin); moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine); CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline); CYP3A4 inducers (e.g., phenytoin, carbamazepine, St. John’s wort, and rifampin); or CYP1A2 inducers (e.g., tobacco smoking) (Table 1) [see Drug Interactions (7)].

Table 1. Dose Adjustment in Patients Taking Concomitant Medications:

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)].

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).

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.