The Clozapine REMS Program

Clozapine is associated with severe neutropenia (absolute neutrophil count (ANC) less than 500/µL). The requirements to prescribe, dispense, and receive clozapine are incorporated into a single, shared program called the Clozapine Risk Evaluation and Mitigation Strategy (REMS). A REMS is a strategy to manage known or potential risks associated with a drug or group of drugs, and is required by the FDA for clozapine to ensure that the benefits of the drug outweigh the risk of severe neutropenia. The Clozapine REMS Program replaces the individual clozapine patient registries and the National Non-Rechallenge Master File (NNRMF).

Prescriber

All prescribers of clozapine products must certify in the Clozapine REMS Program. Certification requires prescribers to:

• Enroll: Complete the Enrollment form (name, address, NPI, DEA)
• Educate: Review Clozapine and the Risk of Neutropenia: A Guide for Healthcare Providers
• Assess: Successfully complete the Knowledge Assessment

Pharmacy

All pharmacies dispensing clozapine products must certify in the Clozapine REMS Program. Certification requires pharmacies to:

• Enroll: Complete the Enrollment form (name, address, NPI, DEA)
• Educate: Review Clozapine and the Risk of Neutropenia: A Guide for Healthcare Providers
• Assess: Successfully complete the Knowledge Assessment
• Implement: Implement the necessary staff training and processes to comply with the Clozapine REMS Program requirements

Important Safety Information

Severe Neutropenia

Background

VERSACLOZ can cause neutropenia (a low absolute neutrophil count [ANC]), defined as a reduction below pre-treatment normal levels of blood neutrophils. The ANC is usually available as a component of the complete blood count (CBC), including differential, and is more relevant to drug-induced neutropenia than is the white blood cell (WBC) count. The ANC may also be calculated using the following formula: ANC equals the Total WBC count multiplied by the total percentage of neutrophils obtained from the differential (neutrophil “segs” plus neutrophil “bands”). Other granulocytes (basophils and eosinophils) contribute minimally to neutropenia and their measurement is not necessary [see Adverse Reactions (6.2) of the Prescribing Information]. Neutropenia may be mild, moderate, or severe (see Tables 2 and 3). To improve and standardize understanding, “severe neutropenia” replaces the previous terms severe leukopenia, severe granulocytopenia, or agranulocytosis.

Severe neutropenia, ANC less than (<) 500/µL, occurs in a small percentage of patients taking VERSACLOZ and is associated with an increase in the risk of serious and potentially fatal infections. Risk of neutropenia appears greatest during the first 18 weeks on treatment and then declines. The mechanism by which VERSACLOZ causes neutropenia is unknown and is not dose-dependent.

Two separate management algorithms are provided below, the first for patients in the general population, and the second for patients identified to have baseline neutropenia.

VERSACLOZ Treatment and Monitoring in the General Patient Population (see Table 2)

Obtain a CBC, including the ANC value, prior to initiating treatment with VERSACLOZ to ensure the presence of a normal baseline neutrophil count (equal to or greater than 1500/µL) and to permit later comparisons. Patients in the general population with an ANC equal to or greater than (≥)1500/µL are considered within normal range (Table 2) and are eligible to initiate treatment. Weekly ANC monitoring is required for all patients during the first 6 months of treatment. If a patient’s ANC remains equal to or greater than 1500/µL for the first 6 months of treatment, monitoring frequency may be reduced to every 2 weeks for the next 6 months. If the ANC remains equal to or greater than 1500/µL for the second 6 months of continuous therapy, ANC monitoring frequency may be reduced to once every 4 weeks thereafter.

Table 2: VERSACLOZ Treatment Recommendations Based on Absolute Neutrophil Count (ANC) Monitoring for the General Patient Population

ANC Level	VERSACLOZ Treatment Recommendations	ANC Monitoring
Normal range (≥1500/µL)	Initiate treatment If treatment interrupted: <30 days, continue monitoring as before ≥30 days, monitor as if new patient	Weekly from initiation to 6 months Every 2 weeks from 6 to 12 months Monthly after 12 months
	Discontinuation for reasons other than neutropenia	See Section 2.5 of the Prescribing Information
Mild Neutropenia (1000 to 1499/µL)*	Continue treatment	Three times weekly until ANC ≥1500/µL Once ANC ≥1500/µL, return to patient’s last “Normal Range” ANC monitoring interval**
Moderate Neutropenia (500 to 999/µL)*	Recommend hematology consultation Interrupt treatment for suspected clozapine-induced neutropenia Resume treatment once ANC ≥1000/µL	Daily until ANC ≥1000/µL, then Three times weekly until ANC ≥1500/µL Once ANC ≥1500/µL, check ANC weekly for 4 weeks, then return to patient’s last “Normal Range” ANC monitoring interval**
Severe Neutropenia (less than 500/µL)*	Recommend hematology consultation Interrupt treatment for suspected clozapine-induced neutropenia Do not rechallenge unless prescriber determines benefits outweigh risks	Daily until ANC ≥1000/µL, then Three times weekly until ANC ≥1500/µL If patient rechallenged, resume treatment as a new patient under “Normal Range” monitoring once ANC ≥1500/µL

* Confirm all initial reports of ANC less than 1500/µL with a repeat ANC measurement within 24 hours
** If clinically appropriate

VERSACLOZ Treatment and Monitoring in Patients with Benign Ethnic Neutropenia
(see Table 3)

Benign ethnic neutropenia (BEN) is a condition observed in certain ethnic groups whose average ANC values are lower than “standard” laboratory ranges for neutrophils. It is most commonly observed in individuals of African descent (approximate prevalence of 25-50%), some Middle Eastern ethnic groups, and in other non-Caucasian ethnic groups with darker skin. BEN is more common in men. Patients with BEN have normal hematopoietic stem-cell number and myeloid maturation, are healthy, and do not suffer from repeated or severe infections. They are not at increased risk for developing VERSACLOZ-induced neutropenia. Additional evaluation may be needed to determine if baseline neutropenia is due to BEN. Consider hematology consultation before initiating or during VERSACLOZ treatment as necessary.

Patients with BEN require a different ANC algorithm for VERSACLOZ management due to their lower baseline ANC levels. Table 3 provides guidelines for managing VERSACLOZ treatment and ANC monitoring in patients with BEN.

Table 3: Patients with Benign Ethnic Neutropenia (BEN); VERSACLOZ Treatment Recommendations Based on Absolute Neutrophil Count (ANC) Monitoring

ANC Level	Treatment Recommendations	ANC Monitoring
Normal BEN Range (Established ANC baseline ≥1000/µL )	Obtain at least two baseline ANC levels before initiating treatment If treatment interrupted <30 days, continue monitoring as before ≥30 days, monitor as if new patient	Weekly from initiation to 6 months Every 2 weeks from 6 to 12 months Monthly after 12 months
	Discontinuation of treatment for reasons other than neutropenia	See Section 2.5 of the Prescribing Information
BEN Neutropenia (500 to 999/µL)*	Recommend hematology consultation Continue treatment	Three times weekly until ANC ≥1000/µL or ≥patient’s known baseline Once ANC ≥1000/µL or at patient’s known baseline, check ANC weekly for 4 weeks, then return to patient’s last “Normal BEN Range” ANC monitoring interval.**
BEN Severe Neutropenia (less than 500/µL)*	Recommend hematology consultation Interrupt treatment for suspected clozapine-induced neutropenia Do not rechallenge unless prescriber determines benefits outweigh risks	Daily until ANC ≥500/µL, then Three times weekly until ANC ≥ patient's baseline If patient rechallenged, resume treatment as a new patient under “Normal Range” monitoring once ANC ≥1000/µL or at patient’s baseline

* Confirm all initial reports of ANC less than 1500/µL with a repeat ANC measurement within 24 hours
** If clinically appropriate

General Guidelines for Management of All Patients with Fever or with Neutropenia

• Fever: Interrupt VERSACLOZ as a precautionary measure in any patient who develops fever, defined as a temperature of 38.5°C [101.3°F] or greater, and obtain an ANC level. Fever is often the first sign of neutropenic infection.
• ANC less than 1000/µL: If fever occurs in any patient with an ANC less than 1000/µL, initiate appropriate workup and treatment for infection and refer to Tables 2 or 3 for management.
• Consider hematology consultation.
• See Neuroleptic Malignant Syndrome (NMS) and Fever under WARNINGS AND PRECAUTIONS (5) and Instructions for Patients, under PATIENT COUNSELING INFORMATION (17) of the Prescribing Information.

Rechallenge after an ANC less than 500/µL (severe neutropenia)

For some patients who experience severe VERSACLOZ-related neutropenia, the risk of serious psychiatric illness from discontinuing VERSACLOZ treatment may be greater than the risk of rechallenge (e.g., patients with severe schizophrenic illness who have no treatment options other than VERSACLOZ). A hematology consultation may be useful in deciding to rechallenge a patient. In general, however, do not rechallenge patients who develop severe neutropenia with VERSACLOZ or a clozapine product.

If a patient will be rechallenged, the clinician should consider thresholds provided in Tables 2 and 3, the patient’s medical and psychiatric history, a discussion with the patient and his/her caregiver about the benefits and risks of VERSACLOZ rechallenge, and the severity and characteristics of the neutropenic episode.

Using VERSACLOZ with Other Drugs Associated with Neutropenia

It is unclear if concurrent use of other drugs known to cause neutropenia increases the risk or severity of VERSACLOZ-induced neutropenia. There is no strong scientific rationale to avoid VERSACLOZ treatment in patients concurrently treated with these drugs. If VERSACLOZ is used concurrently with an agent known to cause neutropenia (e.g., some chemotherapeutic agents), consider monitoring patients more closely than the treatment guidelines provided in Tables 2 and 3. Consult with the treating oncologist in patients receiving concomitant chemotherapy.

Please see the full Prescribing Information for Important Safety Information, including
BOXED Warning.

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