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A reduction in the required frequency of blood monitoring for Clozaril (clozapine) users has the potential to lower the cost of taking the drug and may lead to more use and better compliance, according to clinicians who prescribe the medication.
The U.S. Food and Drug Administration (FDA) has reduced the required frequency of white blood cell (WBC) monitoring for clozapine users from a permanent weekly regimen to biweekly after the first six months for those patients with acceptable WBC counts, according to clozapine maker Novartis Pharmaceuticals. An acceptable count is defined by the FDA as at least 3,000 white cells per cubic millimeter and an absolute neutrophil count (ANC) of at least 1,500 per cubic millimeter.
John Kane, M.D., chairs the department of psychiatry at Hillside Hospital, a division of Long Island Jewish Medical Center in New York. He has been a clozapine proponent since 1976.
"I think from the clinician's perspective [the FDA action is] very helpful because it makes it easier to convince patients to initiate and comply with the medication regimen," said Kane. "The FDA action also reduces the costs associated with medication management. The hope is that in the future, the required frequency of monitoring will be reduced even further for patients who have been on the drug for six months [without complications]."
So far none of the newer atypical antipsychotic drugs has matched clozapine's effectiveness in treatment-resistant patients, Kane said. "I think this is another incremental step in making clozapine easier to use. But I still think clozapine is underutilized, and anything we can do to make it easier to use and more accessible will in the long run help more patients."
Clozapine is a drug of last resort, indicated for schizophrenia patients who have failed to respond to treatment with appropriate courses of two standard antipsychotic drugs. In that population, which is between 5 percent and 25 percent of people with schizophrenia, according to a December 1996 article in the British Journal of Psychiatry, it has proven highly effective.
The small but significant risk of potentially lethal agranulocytosis, however, has been an issue since 1975, when an outbreak of agranulocytosis among 16 clozapine-using patients in Finland resulted in eight deaths, according to spokesperson Tim Lum. When Sandoz, now part of Novartis, applied to the FDA in 1983 for U.S. approval, the application was rejected on grounds that the risk was too great for the U.S. market. But the FDA indicated that it would reconsider if an adequate blood monitoring system was developed. Sandoz reapplied to the FDA in 1987, and clozapine was finally approved for U.S. marketing in September 1989, although it did not reach the market until February 1990.
Although early clinical trials found an incidence of between 1 percent and 2 percent of patients getting clozapine developed agranulocytosis, current data from the Clozaril National Registry (CNR) indicate that with frequent monitoring, the incidence has declined to less than 1 percent.
Although agranulocytosis is the most serious risk associated with clozapine, there have been rare instances of seizure and cardiorespiratory arrest associated with use.
For many treatment-resistant patients, however, clozapine continues to be the final lifeline to a more normal existence. Because frequent blood testing may be physically uncomfortable for some recipients and inconvenient for families, the FDA action "may lead to greater acceptance of Clozaril as a viable treatment option for this patient population," said Thomas Koestler, global vice president of drug regulatory affairs for Novartis.
"Most people with treatment-resistant schizophrenia have limited treatment options available to them," commented Laurie Flynn, executive director of the National Alliance on Mental Illness. The need for frequent testing "presented a barrier to practical care for treatment-resistant individuals who either ceased taking or did not initiate Clozaril therapy" due to the requirements, she added.