2.1 Required Laboratory Testing Prior to Initiation and During Therapy
Prior to initiating treatment with Clozapine ODT, 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 Important Administration Instructions
Clozapine orally disintegrating tablets should be immediately placed in the mouth after removing the tablet from the blister pack or bottle. The tablet disintegrates rapidly after placement in the mouth. The tablets can be allowed to disintegrate, or they may be chewed. They may be swallowed with saliva. No water is necessary for administration.
The orally disintegrating tablets in a blister pack should be left in the unopened blister until the time of use. Just prior to use, peel the foil from the blister and gently remove the orally disintegrating tablet. Do not push the tablets through the foil, because this could damage the tablet.
2.3 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)].
Clozapine ODT can be taken with or without food [see Pharmacokinetics (12.3)].
2.4 Maintenance Treatment
Generally, patients responding to Clozapine ODT 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 Clozapine ODT 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 38.5ºC or 101.3ºF, 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 Clozapine ODT in patients who have discontinued Clozapine ODT (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: Dosage Adjustment in Patients Taking Concomitant Medications
Co-medications
Scenarios
Initiating Clozapine ODT while taking a co-medication
Adding a co-medication while taking Clozapine ODT
Discontinuing a co-medication while continuing Clozapine ODT
Strong CYP1A2 Inhibitors
Use one third of the Clozapine ODT dose.
Increase Clozapine ODT dose based on clinical response.
Moderate or Weak CYP1A2 Inhibitors
Monitor for adverse reactions. Consider reducing the Clozapine ODT dose if necessary.
Monitor for lack of effectiveness. Consider increasing Clozapine ODT 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 Clozapine ODT dose. Monitor for decreased effectiveness.
Reduce Clozapine ODT dose based on clinical response.
Moderate or Weak CYP1A2 or
CYP3A4 Inducers
Monitor for decreased effectiveness. Consider increasing the Clozapine ODT dose if necessary.
Monitor for adverse reactions. Consider reducing the Clozapine ODT dose if necessary.
2.8 Renal or Hepatic Impairment or CYP2D6 Poor Metabolizers
It may be necessary to reduce the Clozapine ODT dose in patients with significant renal or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations (8.6, 8.7)].
