Clozapine Schizophrenia Study May Have No Practical Effect In U.S.

Shaking off stigma of life-threatening blood cell disorder will be almost impossible, says analyst.

Media hoopla aside, there's reason to believe a new Lancet study showing mortality rates are much lower for people taking the generic schizophrenia drug clozapine compared to AstraZeneca's Seroquel and other drugs won't change U.S. prescribing patterns.

"Right now the headlines are compelling, but the new information is not market-changing," said Leerink Swann analyst Seamus Fernandez in an interview.

The main reason lies in clozapine's potential to cause agranulocytosis, a side-effect that results in the global destruction of white blood cells in a subset of patients taking the medication. The label for clozapine, originally introduced in the early 1970s by Sandoz, indicates a mortality rate of 1 percent to 2 percent for this condition. Nowadays, generic versions of clozapine are manufactured by Novartis, Ivax and Caraco, among others.

Because of the potential for fatalities, the product's use is restricted in many countries. In the U.S., clozapine patients' white blood cell counts and absolute neutrophil counts need to be measured once a month following one year of successful therapy so that the disorder may be detected early and treated ('The Pink Sheet' DAILY, June 3, 2005).

Monitoring patients creates practical challenges and adds to the cost of care, so physicians may instead prescribe branded, second-generation atypical anti-psychotic drugs, including Eli Lilly's Zyprexa (olanzapine) and Seroquel (quetiapine).

But a new nationwide study of Finnish patient registries published online in the Lancet July 13 questions policies restricting clozapine in favor of some of the newer, costlier atypical anti-psychotics.

The epidemiological study assessed mortality rates in 67,000 schizophrenia patients versus the total population of 5.2 million between 1996 and 2006. Patients taking the atypical anti-psychotic medications Seroquel, generic haloperidol, Johnson & Johnson's Risperdal (risperidone) and Zyprexa had increased mortality rates (41 percent, 37 percent, 34 percent and 13 percent respectively) compared to those taking perphenazine. In contrast, the death rates of patients taking clozapine were 26 percent lower than those taking the typical anti-psychotic.

Researchers said the difference in mortality between clozapine and the other antipsychotic drugs may be due to more intensive monitoring during treatment, greater effectiveness, lower safety of other drugs, or all of these factors.

Everyone has known for years now how good the efficacy of clozapine is, Fernandez observed. For example, research has shown a 24 percent attempted suicide rate for clozapine over a two-year period, compared to 32 percent on Zyprexa, so the "data is already out there."

The Lancet study does not cite rates of agranulocytosis or even mention the condition by name. Fernandez interprets the study results as suggesting that in terms of overall mortality, the benefits of preventing suicides may outweigh the risk of agranulocytosis.

Still, the analyst doubts the research will have an impact on the industry in the near term, because the stigma of agranulocytosis is likely to stick.

"Getting physicians to shake off the safety perception of the blood cell [disorder] side effect quickly is almost impossible. Certainly it's impossible in the U.S.," he said.

Also, a number of the atypical anti-psychotics will lose their patent status within the next three years, so cost will be less of an issue in the near future, he said.

- Emily Hayes ( [email protected] )