Clozapine - Dosage TABLET
Dosage & 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).
required laboratory testing prior to initiation & during therapy
Prior to initiating treatment with clozapine tablets, 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)].
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 tablets can be taken with or without food [see Pharmacokinetics (12.3)].
maintenance treatment
Generally, patients responding to clozapine tablets 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:
- 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 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.
re-initiation of treatment
When restarting clozapine tablets in patients who have discontinued clozapine tablets (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.
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)].
| Co-medications | Scenarios | ||
| Initiating clozapine tablets while taking a co-medication | Adding a co-medication while taking clozapine tablets | Discontinuing a co-medication while continuing clozapine tablets | |
| Strong CYP1A2 Inhibitors | Use one-third of the clozapine tablets dose. | Increase clozapine tablets dose based on clinical response. | |
| Moderate or Weak CYP1A2 Inhibitors | Monitor for adverse reactions. Consider reducing the clozapine tablets dose if necessary. | Monitor for lack of effectiveness. Consider increasing clozapine tablets 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 tablets dose. Monitor for decreased effectiveness. | Reduce clozapine tablets dose based on clinical response. | |
| Moderate or weak CYP1A2 or CYP3A4 Inducers | Monitor for decreased effectiveness. Consider increasing the clozapine tablets dose if necessary. | Monitor for adverse reactions. Consider reducing the clozapine tablets dose if necessary. | |
renal or hepatic impairment or cyp2d6 poor metabolizers
It may be necessary to reduce the clozapine tablets dose in patients with significant renal or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations (8.6, 8.7)].
Dosage Form & Strengths
Clozapine tablets are available as 25 mg, 50 mg, 100 mg, and 200 mg pale-yellow tablets with a score on one side.
- 25 mg, 50 mg, 100 mg, and 200 mg tablets (3)
Overdosage
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.
management of overdosage
For the most up-to-date information on the management of clozapine overdosage, contact a certified Regional Poison Control Center (1-800-222-1222). Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference® . Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. There are no specific antidotes for clozapine.
In managing overdosage, consider the possibility of multiple-drug involvement.
Storage & Handling
how supplied
Clozapine Tablets USP are available as pale yellow, round, flat-faced, beveled-edge tablets, debossed “Ivax hourglass logo” and “7772” on one side and “100” and a bisect on the other side, containing 100 mg clozapine, USP.
- Available overbagged with 10 tablets per bag, NDC 55154-8285-0
storage & handling
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight container as defined in the USP, with a child-resistant closure (as required).
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
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