###  Background

Clozapine orally disintegrating tablets 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)] . 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 clozapine orally disintegrating tablets 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 clozapine orally disintegrating tablets cause 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.

###  Clozapine Orally Disintegrating Tablets Treatment and Monitoring in the General Patient Population (see Table 2)

Obtain a CBC, including the ANC value, prior to initiating treatment with clozapine orally disintegrating tablets 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.

###  Clozapine Orally Disintegrating Tablets 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 clozapine orally disintegrating tablets-induced neutropenia. Additional evaluation may be needed to determine if baseline neutropenia is due to BEN. Consider hematology consultation before initiating or during clozapine orally disintegrating tablets treatment as necessary.

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

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

  * Fever: Interrupt clozapine orally disintegrating tablets 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). 



###  Rechallenge After an ANC Less Than 500/µL (Severe Neutropenia)

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

###  Using Clozapine Orally Disintegrating Tablets 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 clozapine orally disintegrating tablets-induced neutropenia. There is no strong scientific rationale to avoid clozapine orally disintegrating tablets treatment in patients concurrently treated with these drugs. If clozapine orally disintegrating tablets are 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.