Clozapinedosage

Recommended starting oral dosage is 12.5 mg once daily or twice daily. If well-tolerated, increase the total daily dosage in increments of 25 mg to 50 mg per day at target dosage of 150 mg to 225 mg twice per day by the end of two weeks Subsequently may increase the dosage in increments up to 100 mg, once or twice weekly. Maximum daily dosage is 450 mg twice daily. Administer with or without food. Clozapine ODT may be allowed to disintegrate or chewed, and may be taken with or without water. See additional administration instructions in full prescribing information. See dosage modification based on ANC results See recommendations for discontinuing Clozapine ODT treatment, restarting Clozapine ODT after interrupting dosing, dosage modifications for drug interactions, dosage recommendations in patients with renal or hepatic impairment and CYP2D6 poor metabolizers in the full prescribing information. Tablets rapidly disintegrate after placement in the mouth and may be chewed if desired. No water is needed.

2.1 Absolute

Neutrophil Count Testing Prior to Clozapine ODT Initiation Prior to initiating Clozapine ODT treatment, obtain a baseline absolute neutrophil count (ANC). Clozapine ODT initiation is not recommended in patients with an ANC less than 1500/µL. For patients with documented Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count)), obtain at least two baseline ANC levels. Clozapine ODT initiation is not recommended in patients with BEN with an ANC less than 1000/µL. For dosage modifications based on ANC results, see Dosage and Administration.

2.2 Recommended

Dosage and Administration Recommended Dosage To reduce the risk of orthostatic hypotension, bradycardia, and syncope, the recommended starting dosage is much lower than the target dosage. The recommended starting oral dosage of Clozapine ODT is 12.5 mg once or twice daily. If well-tolerated, increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly. The maximum recommended Clozapine ODT oral dosage is 450 mg twice daily. Administration Instructions Clozapine ODT can be taken with or without food, may be allowed to disintegrate or chewed, and may be taken with or without water. Just prior to use, peel the foil from the blister and gently remove the orally disintegrating tablet (ODT). Do not push the ODT through the foil, because this could damage the ODT. After removing Clozapine ODT from the blister pack or bottle, immediately place in the mouth.

2.3 Dosage Modifications

Based on ANC Results Table 1 provides recommended Clozapine ODT dosage modifications based on ANC results. For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2.

Table 1: Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing Recommended Dosage Modification Recommended Frequency of ANC Testing During Clozapine ODT Treatment ANC Within Normal Range (≥ 1500/µL) No dosage modification; continue treatment Day 1 to Month 6: Weekly Month 7 to Month 12: Every 2 weeks Month 13 and thereafter: Every month If Clozapine ODT treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now has a normal ANC level) for: < 30 days, continue the previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients who initiate treatment Mild Neutropenia (ANC between 1000 to 1499/µL) 1 No dosage modification; continue treatment Three times weekly Once ANC ≥ 1500/µL, recommend returning to the patient’s last Normal Range ANC testing frequency Moderate Neutropenia (ANC between 500 to 999/µL) 1 Interrupt treatment and recommend hematology consultation Resume treatment once ANC ≥1000/µL Daily Once ANC ≥ 1000/µL, three times weekly Once ANC ≥ 1500/µL, test weekly for 4 weeks. If ANC ≥ 1500/µL after monitoring weekly for 4 weeks, return to the patient’s last Normal Range ANC testing frequency Severe Neutropenia (ANC less than 500/µL) 1 Discontinue treatment and recommend hematology consultation Daily Once ANC ≥ 1000/µL, three times weekly Once ANC ≥ 1500/µL, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients who initiate treatment 1 Confirm all initial reports of ANC less than 1500/µL with a repeat ANC measurement within 24 hours

2.4 Dosage Modifications

Based on ANC Results for Patients with Benign Ethnic Neutropenia Table 2 provides recommended Clozapine ODT dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count).. For dosage modifications based on ANC results for patients without BEN, see Table 1.

Table 2: Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing in Patients with Benign Ethnic Neutropenia 1 Recommended Dosage Modification Recommended Frequency of ANC Testing During Clozapine ODT Treatment in Patients with BEN ANC Within the Normal Range for Patients with BEN (≥ 1000/µL ) No dosage modification; continue treatment Day 1 to Month 6: Weekly Month 7 to Month 12: Every 2 weeks Month 13 and thereafter: Monthly If Clozapine ODT treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now their ANC (≥ 1000/µL and ≥ the patient’s ANC baseline prior to treatment) for: < 30 days, continue previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients with BEN who initiate treatment Neutropenia in Patients with BEN (ANC level between 500 to 999/µL) 2 Recommend hematology consultation No dosage modification; continue treatment Three times weekly Once ANC ≥ 1000/µL and ≥ the patient’s ANC baseline, obtain ANC tests weekly for 4 weeks If ANC ≥ 1000/µL and ≥ the patient’s baseline after monitoring for 4 weeks, return to the patient’s last Normal ANC Range testing frequency for patients with BEN. Severe Neutropenia in Patients with BEN (ANC level less than 500/µL) 2 Discontinue treatment and recommend hematology consultation Daily Once ANC ≥ 500/µL, obtain ANC three times weekly Once ANC ≥ 1000/µL and ≥ the patient’s baseline, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients with BEN who initiate treatment 1 Benign Ethnic Neutropenia (BEN) is also known as Duffy-null associated neutrophil count. 2 Confirm all initial reports of ANC less than 1500/µL with a repeat ANC measurement within 24 hours

2.5 Discontinuation of

Clozapine ODT Treatment If discontinuing Clozapine ODT in patients with: Moderate or severe neutropenia, see Table 1. Normal or mild neutropenia, reduce the dosage gradually over a period of 1 to 2 weeks, and continue monitoring ANC levels until their ANC is ≥1500/µL. If discontinuing Clozapine ODT in patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) with: Neutropenia, see Table 2. ANC within their normal range of ANC reduce the dosage gradually over a period of 1 to 2 weeks. When discontinuing Clozapine ODT, monitor patients for the symptoms related to psychotic recurrence and cholinergic rebound (e.g., profuse sweating, headache, nausea, vomiting, diarrhea).

2.6 Restarting

Clozapine ODT Treatment After Interrupting Clozapine ODT When restarting Clozapine ODT in patients who have interrupted Clozapine ODT treatment, use a lower dosage to minimize the risk of hypotension, bradycardia, and syncope. If one day’s dosage is missed, resume Clozapine ODT treatment at 40% to 50% of the previous dosage. If two days of dosing is missed, resume Clozapine ODT treatment at approximately 25% of the previous dosage. For longer interruptions, restart Clozapine ODT treatment with a dosage of 12.5 mg once or twice daily. If this dosage is well-tolerated, may increase the dosage to the previous dosage more quickly than recommended than for initial Clozapine ODT treatment.

2.7 Dosage Modifications for

Drug Interactions See Table 3 for recommended dosage modifications to reduce the risk of Clozapine ODT-associated adverse reactions or reduce the risk of lower effectiveness.

Table 3: Clozapine ODT Dosage Modifications for Drug Interactions Strong CYP1A2 Inhibitors Administer one third of the Clozapine ODT dosage. Moderate or Weak CYP1A2 Inhibitors Consider reducing the Clozapine ODT dosage if necessary. CYP2D6 or CYP3A4 Inhibitors Strong CYP3A4 Inducers Concomitant use is not recommended. However, if concomitant use is necessary, it may be necessary to increase the Clozapine ODT dosage. Monitor for decreased effectiveness. Moderate or weak CYP1A2 or CYP3A4 Inducers Consider increasing the Clozapine ODT dosage if necessary.

2.8 Dosage Recommendations in

Patients with Renal or Hepatic Impairment, or CYP2D6 Poor Metabolizers It may be necessary to reduce the Clozapine ODT dosage in patients with significant renal impairment or hepatic impairment, or in CYP2D6 poor metabolizers.