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Side-Effect Concerns Derail Schizophrenia-Drug Approval

The FDA issues a not-approvable letter for long-acting olanzapine injection for schizophrenia treatment out of concerns about an unpredictable, and potentially serious, side effect.

The Food and Drug Administration (FDA) does not believe the long-acting olanzapine pamoate injection is ready for marketing as a treatment for schizophrenia because of concerns about its adverse effects, even though the FDA's Psychopharmacologic Drugs Advisory Committee voted in favor of the formulation's efficacy and safety.

In its determination letter, the FDA asked Eli Lilly, which makes the drug, to provide additional information on a potentially serious adverse effect with symptoms of excessive drowsiness, altered consciousness, and possibly seizure and coma that was seen in about 1 percent of patients who received the long-acting olanzapine pamoate injections in clinical trials.

The FDA convened the public advisory meeting in February to seek advice from a panel of 11 experts regarding the new drug application for the depot formulation, a reconstituted suspension for intramuscular administration that can be given once every two or four weeks.

The advisory committee unanimously agreed that data from two controlled clinical trials supported the drug's efficacy as an acute and maintenance treatment for schizophrenia. The main concern of both the committee and the agency reviewers was the unpredictable and sometimes severe occurrence of excessive sedation.

In addition to the expected side-effect profile associated with oral olanzapine tablets, olanzapine pamoate depot injections have been linked to cases of severe drowsiness, sometimes with confusion, loss of consciousness, seizures, and, in some instances, coma. The severe drowsiness was characterized by "unanticipated degrees of sedation," and "confusion, dysarthria, ataxia," Eli Lilly's representatives said at the meeting. The FDA termed it "excessive sedation," but some committee members noted that some of the clinical symptoms went beyond sedation.

Of the 2,054 patients who had received the injections as of September 2007, 24 had experienced 25 cases of this adverse event, including one patient who had this event twice, according to the data submitted to the FDA. Jing Zhang, M.D., Ph.D., a medical officer with the FDA's Division of Psychiatry Products, characterized the incidence as "relatively common" and stated that the "sedation symptoms tended to be severe."

Of the 24 patients who had cases of excessive sedation, 20 were hospitalized or visited an emergency department. Five reported temporary loss of consciousness, including three who could not be aroused for a period of time. One of these patients was clinically diagnosed with coma, and another with "symptoms consistent with coma." Two patients were intubated. All patients recovered, and 12 continued to receive additional olanzapine pamoate injections, company representatives said.

All the excessive sedation events occurred within three hours of the injection, with the majority (21 of 25 events) within one hour. There seemed to be no predictable patterns, as some of these events occurred after the first injection while some occurred months into a clinical trial. Nor did the occurrences appear to correlate with the dosage administered or the frequency of injections.

The clinical presentation of the excessive sedation is consistent with oral olanzapine overdose, Sara Corya, M.D., a medical director at Eli Lilly told the panel. The company believes that the excessive sedation is caused by rapid dissolution of solid olanzapine pamoate particles when they come into contact with blood. The pamoate particles are supposed to dissolve slowly in muscle tissues and achieve therapeutic serum concentrations of olanzapine. If there is bleeding at or near the injection site, however, olanzapine pamoate can dissolve quickly and a large amount can enter the blood stream in a short time, which in turn leads to olanzapine overdose. The company representatives conceded, however, that this mechanism has not been proven.

Other currently available depot injections of antipsychotics, such as fluphenazine decanoate, haloperidol decanoate, and risperidone extended-release, use formulations different from olanzapine pamoate and have not been associated with this type of excessive sedation, FDA representatives told the advisory committee.

Some of the committee members expressed concerns about the unpredictable nature and severity of the symptoms in these cases. Enhanced training for technicians on the preparation and injection techniques did not appear to prevent additional events, which might occur even if the technician saw no aspirated blood at the time of intramuscular injection, the company admitted. The panel urged the FDA and the company to devise appropriate restrictions and warnings in product labeling to inform clinicians and patients about the risks.

In the end, the panel voted 10-0, plus one abstention, in favor of the drug's safety for approval, citing the need for more injectable depot antipsychotics to address patient-compliance problems.

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