CASE
Is Mr. A a candidate for clozapine?Age 28, with schizophrenia, Mr. A is highly disorganized and psychotic when brought to the emergency room by police for inappropriate behavior. His family arrives and reports that similar events have occurred several times over the past few years. Mr. A’s outpatient psychiatrist has prescribed 3 different antipsychotic medications at adequate dosages, including 1 long-acting injectable, but Mr. A has remained consistently symptomatic.
Although disorganized and psychotic, Mr. A does not meet criteria for long-term involuntary hospitalization. His family wants to take him home, and the treatment team discusses clozapine as an antipsychotic option. Mr. A and his family agree to a trial of clozapine during voluntary hospitalization, but they would like him home within a week to attend his sister’s birthday party.
The treatment team decides to initiate clozapine and monitor his response in a controlled setting for a few days before transitioning him to outpatient care.
Initiating clozapine therapyThe case of Mr. A exemplifies a situation in which initiating clozapine is a reasonable clinical consideration. As the first step, we recommend checking baseline lab values and vital signs (Table 2), keeping in mind that the REMS program requires a baseline ANC within 7 days of initiating clozapine. When working with a highly disorganized or agitated patient, balance benefits of testing against the risk of harm to staff and patient.
REMS guidelines recommend a baseline ANC ≥1,500/µL for a new patient starting clozapine, except when benign ethnic neutropenia (BEN) has been confirmed. (Initiation guidelines for BEN are discussed later in this article.)
Dosing alternatives. We recommend following the manufacturer’s dosing guidelines when initiating clozapine (Figure 2).13,14 Three oral forms are available: tablet, disintegrating tablet, and suspension. All can be titrated using the schedule suggested with tablets. The disintegrating tablets or suspension might be beneficial for a patient with either:
- a history of “cheeking” or otherwise disposing of tablets
- a medical condition that affects swallowing or absorption.
The disintegrating tablet is available in 12.5-mg, 25-mg, 100-mg, 150-mg, and 200-mg doses. It dissolves without requiring additional liquids. Each mL of the suspension contains 50 mg of clozapine.
Rapid titration? One group, working in Romania, examined the safety and efficacy of rapid titration of clozapine in 111 inpatients with schizophrenia.15 In the absence of additional studies, we do not recommend routine rapid titration of clozapine.
Monitoring: Greater flexibilityUnder the REMS program, laboratory monitoring of clozapine treatment must continue indefinitely. If not, pharmacies cannot dispense clozapine. Fortunately, the ANC is the only lab value tracked by the registry, and the frequency of required blood draws decreases over time (Figure 3).
Other guideline changes provide clinicians with greater flexibility to make patient-specific treatment decisions; for example, the allowable ANC to continue clozapine therapy has decreased. Usually, clozapine therapy should be interrupted for an ANC <1,000/µL if the prescriber suspects clozapine-induced neutropenia. Even when the ANC drops below 1,000/µL, however, prescribers can now continue clozapine treatment if they consider the benefits to outweigh risks for a given patient.
Separate guidelines now exist for patients with BEN, most commonly observed in persons of certain ethnic groups. BEN typically is diagnosed based on repeated ANC values <1,500/µL over several months. Patients with BEN do not have an increased risk of oral or systemic infections, as occur with other congenital neutropenias.16 In patients with BEN, clozapine therapy:
- can be initiated only after at least 2 baseline ANC measurements ≥1,000/µL
- should be interrupted for an ANC <500/µL if the prescriber suspects clozapine-induced neutropenia.
Substantial drops in ANC no longer require action (repeat lab draws) unless the drop causes neutropenia. Prescribers will receive an automated notification any time a patient experiences neutropenia that is considered mild (ANC 1,000 to 1,499/µL), moderate (ANC 500 to 999/µL), or severe (ANC <500/µL).
The NNRMF list is no longer definitive. All patients are now eligible for rechallenge, assuming they meet the new clozapine initiation criteria.
Next, when rediscovering clozapine: Adverse effectsDespite an intimidating list of side effects and interactions, clozapine is associated with a significant reduction in patients’ risk of overall mortality. In Part 2 of this series in the August 2016 issue, we discuss early identification of clozapine’s adverse effects and provide guidance for management.