Although clozapine is the medication with the clearest benefits in treatment-resistant schizophrenia, many eligible patients never receive it. In the United States, 20% to 30% of patients with schizophrenia can be classified as treatment resistant, but clozapine accounts for <5% of antipsychotics prescribed.1,2 Clinicians worldwide tend to under-prescribe clozapine3—a reluctance one author coined as “clozaphobia.”4
Admittedly, clozapine has had a turbulent history—both lauded as a near-miracle drug and condemned as a deadly agent. The FDA has overhauled its prescribing and monitoring guidelines, however, offering psychiatrists a perfect opportunity to reacquaint themselves with this potentially life-changing intervention.
We begin this article with clozapine’s story, then spotlight new terrain the FDA created in 2015 when the agency introduced the Clozapine Risk Evaluation and Mitigation Strategy (REMS). Our goal in the 3 articles of this series is to deepen your appreciation for this tricyclic antipsychotic and provide practical clinical guidance for using it safely and effectively.
Setbacks, but the drug has an enduring presenceThe 1950s was an exciting era of exploration for new psychotropic medications. While searching for tricyclic antidepressants, Wander Laboratories discovered neuroleptic tricyclics, with clozapine identified in 1959 (Figure 1). Haloperidol’s development and release in the 1960s reinforced the prevailing dogma of the time that effective neuroleptics correlated with extrapyramidal symptoms, thus limiting interest in the newly discovered, but pharmacologically unique, clozapine. Throughout the 1960s, most research on clozapine was published in German, with less of an international presence.5
Agranulocytosis deaths. Clozapine earned its scarlet letter in 1975, when 8 patients in Finland died of agranulocytosis.6 Sandoz, its manufacturer, withdrew clozapine from the market and halted all clinical trials. The Finnish epidemic triggered detailed investigations into blood dyscrasias and early identification of agranulocytosis associated with clozapine and other antipsychotics.7
Clozapine endured only because of its unique efficacy. When psychiatrists witnessed relapses in patients who had to discontinue clozapine, some countries allowed its use with strict monitoring.5 The FDA kept clozapine minimally available in the United States by allowing so-called “compassionate need programs” to continue.7
New data, FDA approval. Two studies in 1987 and 1988 that compared clozapine with chlorpromazine for treatment-refractory schizophrenia demonstrated clozapine’s superior effect on both negative and positive symptoms.8,9 The FDA approved clozapine for refractory schizophrenia in 1989, and clozapine became clinically available in 1990.
Initially, the high annual cost of clozapine’s required “bundle” ($8,900 per patient for medication and monitoring) led to political outcry. As patients and their family struggled to afford the newly released medication, multiple states filed antitrust lawsuits. A federal court found both the manufacturer and individual states at fault and required expanded access to clozapine and its necessary monitoring. National clozapine registries were formed, and bundling was eliminated.7
The clozapine REMS programSix clozapine registries operated independently, each managed by a different manufacturer,10 until the FDA introduced REMS in September 2015. The REMS program created a centralized registry to monitor all U.S. patients treated with clozapine and made important changes to prescribing and monitoring guidelines.11,12 It also incorporated the National Non-Rechallenge Master File (NNRMF).
Initially, the REMS program was scheduled for rollout October 12, 2015, the closing date of the 6 registries. Since November 2015, pharmacies have been required to register with the program to dispense clozapine. A similar registration deadline for clozapine prescribers was extended indefinitely, however, because of technical problems. Once the deadline is finalized, all clozapine prescribers must complete 3 steps to be certified in the REMS program (Table 1).11
New requirements. Certified clozapine prescribers will have new responsibilities: enrolling patients and submitting lab results. They can designate someone else to perform these tasks on their behalf, but designees must enroll in the REMS program and the prescriber must confirm the designee. Pharmacists can no longer enroll patients for clozapine therapy unless they are confirmed as a prescriber designee. For outpatients, the absolute neutrophil count (ANC) must be reported before the pharmacy can dispense clozapine. For inpatients, the ANC must be reported within 7 days of the patient’s most recent blood draw.
Once the system is fully operational, Social Security numbers will no longer be used as patient identification for dispensing clozapine. Instead, outpatient pharmacies will obtain a predispense authorization, or PDA, from the REMS program. A person initiated on clozapine as an inpatient must be re-enrolled after discharge by their outpatient prescriber.
The REMS program includes information about clozapine patients who were maintained through the 6 registries, and these patients have been allowed to continue clozapine treatment. Data pertaining to patients last prescribed clozapine before October 1, 2012, did not transfer into the new system unless their name was on the NNRMF.