Lilly Agrees to Zyprexa Labeling on Glucose-Metabolism Risk

After much negotiation with the Food and Drug Administration (FDA), Eli Lilly and Co. has recently updated the labeling information of its atypical antipsychotic drug olanzapine (Zyprexa) to highlight its effect on glucose metabolism.

The labeling for olanzapine had carried the class warnings for the risks of diabetes mellitus and weight gain as mandated by the FDA since 2003 (Psychiatric News, October 17, 2003).

Clinical reports have accumulated in recent years to suggest that olanzapine has a greater effect on weight gain and glucose metabolism than do other atypical antipsychotics. In the package insert for olanzapine, dated October 1, the warnings section has been expanded to include hyperglycemia, hyperlipidemia, and weight gain. Data in adults and adolescents are presented separately (olanzapine is not approved for use in patients under age 18). Notably, the warnings acknowledge that “the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum, and olanzapine appears to have a greater association than some other atypical antipsychotics.” The warnings also contain wordings about“ significant, sometimes very high (>500 mg/dL) elevations of triglyceride levels” and “modest mean increases in total cholesterol” associated with olanzapine use.

The drug-label changes reflect pooled adverse-event data in Lilly's clinical trials and reports in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and Comparison of Atypicals for First-Episode Psychosis (CAFE) studies, according to the company's press release on the labeling changes. Both studies involved long-term, head-to-head comparisons of atypical antipsychotic drugs. The CATIE study was funded by the National Institute of Mental Health, and the CAFE study was funded by AstraZeneca, the maker of quetiapine (Seroquel).

APA has commissioned a work group to review all available evidence concerning the metabolic risks of antipsychotic drugs. John Newcomer, M.D., who is a professor in the psychiatry, psychology, and medicine departments and medical director of the Center for Clinical Studies at Washington University School of Medicine in St. Louis and leads the APA effort, told Psychiatric News that the report resulting from the review will present a comprehensive overview of the background and available clinical evidence on this medical issue. The paper will also provide clinical recommendations for screening, monitoring, and reducing cardiovascular and metabolic risks in patients treated with antipsychotic medications. The draft is expected to be finalized soon.

The FDA's efforts that led to Lilly's olanzapine labeling change are an acknowledgement of the evidence, including high-quality data from the NIMH-funded CATIE study, that has consistently shown the differential risks of weight gain, altered triglyceride levels, and potential hyperglycemia across different antipsychotics, said Newcomer.

He strongly urged psychiatrists, primary care providers, and health care systems to screen and monitor schizophrenia patients more actively for weight, body mass index, lipid profiles, glucose levels, blood pressure, and key indicators of cardiometabolic risks.

“Unfortunately, psychiatrists cannot assume that an internist or primary care provider is taking care of [cardiovascular assessments and treatments], often because patients do not see any physician besides their psychiatrist. Psychiatrists should participate in the screening and monitoring of metabolic risk at the start of and during antipsychotic treatment and make appropriate referrals to primary or specialty care providers to address identified risk factors and, importantly, follow up on these referrals,” he said.

Earlier this year Lilly announced billions of dollars in legal settlements with patients who filed suits alleging that they were harmed by the drug. The plaintiffs also alleged that Lilly withheld or downplayed information regarding significant adverse effects associated with olanzapine, though Lilly denies any such wrongdoing, according to reports in the January 5 New York Times and February 2 Psychiatric News.

The updated labeling information for olanzapine is posted at<pi.lilly.com/us/zyprexa-pi.pdf>.▪