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New FDA Clozapine Rules Improve Tracking and Could Increase Access

13 Oct 2015

October 14, 2015. The U.S. Food and Drug Administration (FDA) is making two major changes in the rules regulating clozapine prescriptions: The agency has created a new, centralized database that will track all clozapine prescriptions, and it has adjusted its recommendations for monitoring patients for signs of clozapine-induced severe neutropenia, a potentially fatal blood condition.

Clozapine, the prototypical atypical antipsychotic medication, is one of the most effective medications for treating symptoms, including auditory and visual hallucinations, in people with treatment-resistant schizophrenia. The medication has also been shown to reduce suicidal behavior in patients with schizophrenia and schizoaffective disorder (Meltzer et al., 2003), and findings from a recent research study suggest that a major clozapine metabolite may protect working memory in people with schizophrenia (see SRF related news report). A large, population-based study in Finland also concluded that clozapine was associated with the lowest mortality rate among major antipsychotic drugs (see SRF related news report).

Despite these benefits, the medication is not prescribed as often as it should be, many researchers believe. "It's under-utilized. We would expect that at least 25 percent of patients would be candidates for a trial of clozapine," said John Kane of Hofstra North Shore-LIJ School of Medicine and The Zucker Hillside Hospital. He estimates that just 6 percent are being treated with the drug.

Clozapine is not more widely used because a very small subset of patients who are prescribed it develop serious side effects, including severe neutropenia—the term for an abnormally low count of a certain kind of white blood cell called a neutrophil. The condition can put people at risk for infection, and before it was recognized, several dozen patients in Finland died from the side effect. "What you're concerned about is the loss of white blood cells and someone being unable to fight off infection, but we're able to manage that condition very successfully so that the fatality rate is extremely low," Kane told SRF.

But once people are found to have clozapine-induced neutropenia, the condition is likely to reoccur if they take the medication again in the future. Thus, it is important to track patients who have taken clozapine and their side effects. This is one reason that the FDA's new clozapine risk evaluation and mitigation strategy (or Clozapine REMS) includes an online database that will track all patients, prescribers, and pharmacies associated with clozapine prescriptions. This database is a centralized program that replaces the six existing registration systems run by the different clozapine manufacturers.

Herbert Meltzer of Northwestern University's Feinberg School of Medicine in Chicago described the previous processes of enrolling patients with the various manufacturer databases and applying for eligibility to prescribe clozapine as "cumbersome."

"The previous system was somewhat of a barrier to wider utilization of this drug," Meltzer says. But he expects the new rules will help: "This should facilitate more people getting access to clozapine."

Prescription and side effect information from all current patients who are prescribed clozapine will automatically be transferred from the old databases into the new database, which went live on October 12. In addition, prescribers and pharmacy personnel will be required to be certified in the Clozapine REMS Program, a process that involves reviewing information about clozapine and neutropenia risk as well as passing a "Knowledge Assessment for Healthcare Providers."

Better counts, greater access

Another change is that neutropenia monitoring via the database will no longer require total white blood cell count measurements and will instead only ask for a patient's absolute neutrophil count (ANC). "The absolute neutrophil count is a more biologically sound measure than the total white blood cell count, and it's always been a recommended measure of health or the status of one's ability to stave off an infection," said Meltzer. "I think it's a helpful change."

For outpatients, prescribers will need to report ANC numbers to the Clozapine REMS Program before the drug will be dispensed; inpatients must have their ANC numbers reported within seven days of their most recent blood sample. For most patients, clozapine-induced neutropenia will be suspected if their ANC falls below 1,000 cells per microliter.

Importantly, the FDA has also modified the ANC requirement for patients with benign ethnic neutropenia (BEN), a type of neutropenia that is commonly seen in people of African descent and that is not associated with an increased risk of infections (see Rajagopal). Under the new FDA guidelines, BEN patients with ANC counts as low as 500 cells per microliters will be able to be prescribed clozapine. "[The old cut-off] was based on Caucasians, and so it was unfair," Meltzer told SRF. "Now the guidelines are in sync with the medical reality."

Kane told SRF that this change could be a real boon to patients who have not been able to try clozapine. "When clozapine does work, when it does exert its therapeutic benefit, it can be quite dramatic," he said. "It's a shame if people don't have at least a chance to see whether or not they're going to derive that benefit."

A final change in the FDA's new clozapine monitoring rules is that healthcare providers will be able to re-prescribe clozapine to patients who had previous signs of clozapine-induced severe neutropenia "if they determine that the risk of psychiatric illness is greater than the risk of recurrent severe neutropenia" (see FDA announcement). This change should allow prescribers greater flexibility in helping some of their most at-risk patients.

There is one rule that the FDA did not change—and that is the requirement that patients on clozapine continue to get monthly blood tests to check their ANC levels. These tests can be a barrier for patients who might otherwise be interested in trying the drug. Meltzer would like the monthly blood test requirement to end after a patient has been on clozapine for 12 months, the point when risk of developing neutropenia would be the same as for many drugs that aren't monitored. "What [the FDA has] done will help a bit, but not as much as ending the monitoring—at some point. I'm not a fanatic about 12 months. But if you look at the data, that's a reasonable time. There are people that have been getting their blood drawn for 15 years, 20 years," he told SRF.

For his part, Kane fears that, despite the FDA's changes in its clozapine recommendations, the drug will remain under-utilized because some physicians feel uncomfortable prescribing it. "I think if people are uncomfortable using it, there are a couple of possibilities. One is that they should refer the patient to someone who isn't. Another possibility is that they should learn how to use it so they're comfortable," he said. "I think it's unfair if patients could potentially benefit from clozapine and they don't get a trial."

For more information about the FDA's changes to clozapine monitoring and prescribing, visit the FDA's fact sheet and the Clozapine REMS Program website.—Summer E. Allen.