Eli Lilly and Company has received a not approvable letter from the US Food and Drug Administration for Zyprexa long-acting injection (olanzapine LAI) for the treatment and maintenance treatment of schizophrenia in adults. Zyprexa LAI is an investigational formulation that combines the atypical antipsychotic medication Zyprexa (olanzapine) with a pamoate salt, resulting in an extended delivery of up to four weeks.

In its letter, the FDA said it needs more information to better understand the risk and underlying cause of excessive sedation events that have been observed in about 1 per cent of patients in clinical trials. These events were discussed during the FDA's Feb. 6 Psychopharmacologic Drugs Advisory Committee hearing. At the conclusion of that meeting, the committee voted that there were circumstances under which Zyprexa LAI would be acceptably safe and effective for the treatment of acutely exacerbated schizophrenia and maintenance treatment of schizophrenia in adults.

In its letter, however, the FDA cited a new excessive sedation event that occurred shortly before the Feb. 6 hearing. Lilly alerted the agency and the advisory committee about the existence of a possible new case on Feb. 6, noting that Lilly was investigating the details of the event including conflicting information about the time of onset. After collecting additional information, Lilly was able to confirm after the advisory committee hearing that this was a case of excessive sedation and that it began between 3 to 5 hours after injection. All previous excessive sedation events had begun within three hours of injection. As with all previous patients with excessive sedation, this patient fully recovered.

"We are disappointed by the FDA's decision and we are committed to ongoing discussions to better understand the agency's perspective regarding this recent case of excessive sedation and to define the path forward and the associated timeline," said Dr. Jennifer Stotka, vice president, US Regulatory Affairs, Eli Lilly and Company. "Given the chronic and severe nature of schizophrenia, persistent challenges with adherence, and the limited number of approved depot formulations, we continue to believe that, if approved, Zyprexa LAI would provide a valuable treatment option for patients suffering from schizophrenia."

Independent regulatory reviews of Zyprexa LAI applications are ongoing in the European Union and other countries including Canada and Australia.

Zyprexa is indicated in the United States for the short- and long-term treatment of schizophrenia, acute mixed and manic episodes of bipolar disorder, and maintenance treatment of bipolar disorder. Since Zyprexa was introduced in 1996, it has been prescribed to approximately 24 million people worldwide. Zyprexa is not approved for patients under 18 years of age.

Zyprexa is not approved for the treatment of patients with dementia-related psychosis. Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared with those patients taking a placebo.

In addition, compared to elderly patients with dementia-related psychosis taking a placebo, there was a significantly higher incidence of cerebrovascular adverse events in elderly patients with dementia-related psychosis treated with Zyprexa.

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including Zyprexa.

While relative risk estimates are inconsistent, 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. Physicians should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or who have borderline increased blood glucose level. Patients taking olanzapine should be monitored regularly for worsening of glucose control. Persons with risk factors for diabetes who are starting on atypical antipsychotics should undergo baseline and periodic fasting blood glucose testing. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose testing.

Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and follow-up lipid evaluations in patients using olanzapine, is advised. Significant, and sometimes very high, elevations in triglyceride levels have been observed with olanzapine use. Modest mean increases in total cholesterol have also been seen with olanzapine use.

Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring of weight.

As with all antipsychotic medications, a rare and potentially fatal condition known as NMS has been reported with Zyprexa. If signs and symptoms appear, immediate discontinuation is recommended. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

Also, as with all antipsychotic treatment, prescribing should be consistent with the need to minimize Tardive Dyskinesia (TD). The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic increase. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

The most common treatment-emergent adverse event associated with Zyprexa in placebo-controlled, short-term schizophrenia and bipolar mania trials was somnolence. Other common events were dizziness, weight gain, personality disorder (COSTART term for nonaggressive objectionable behaviour), constipation, akathisia, postural hypotension, dry mouth, asthenia, dyspepsia, increased appetite and tremor.