Lilly's Zyprexa IM has cleared FDA three years after a pre-approval inspection for the intramuscular antipsychotic triggered a period of Good Manufacturing Practices compliance issues for the company.

FDA approved the intramuscular formulation of Zyprexa (olanzapine) for the treatment of agitation associated with schizophrenia and bipolar mania March 29. Lilly filed the application in June 2000.

The company received an FDA warning letter following a pre-approval inspection for Zyprexa IM in 2001 (¹ Also see "Zyprexa IM Manufacturing Issues To Be Discussed By FDA, Lilly March 15" - Pink Sheet, 12 March, 2001., p. 26).

That letter was the first indication of widespread GMP issues that delayed several Lilly applications.

The inspection was followed by an "approvable" letter on March 29, 2001, exactly three years before the drug was actually approved (² Also see "Lilly Zyprexa IM "Approvable"; GMP Consultants Hired In Wake Of Inspections" - Pink Sheet, 16 April, 2001., p. 35).

Lilly said in January that it expected the IM formulation to be approved "shortly" after a successful inspection of its sterile injectables plant (Building 105 in Indianapolis) in December (³ [A#00660020016], p. 33).

Approval of Zyprexa IM is the strongest indication yet that Lilly has turned the corner in addressing FDA's GMP concerns.

The three-year delay was costly for Lilly in terms of competitive positioning. Zyprexa IM was expected to be the first injectable atypical antipsychotic. It is now the second short-acting, injectable atypical antipsychotic to enter the market.

Pfizer's intramuscular formulation of Geodon (ziprasidone) cleared FDA June 21, 2002 (⁴ Also see "Pfizer Adds Muscle To Geodon; IM Could Agitate Schizophrenia Market" - Pink Sheet, 1 July, 2002., p. 26). The product is indicated for rapid control of agitation in schizophrenic patients.

The schizophrenia market also now includes Janssen's long-acting injectable Risperdal Consta , which approved for schizophrenia but not specifically agitation (⁵ Also see "J&J Risperdal Consta Priced Comparable To Zyprexa; Clears FDA Oct. 29" - Pink Sheet, 3 November, 2003., p. 8).

The wholesale acquisition price of Zyprexa IM will be $17.75 for an initial 10 mg dose. The cost for Risperdal Consta (risperidone) calculated on a daily basis works out to be $19.83 average wholesale price when using the recommended starting dose of 25 mg administered every two weeks.

Oral formulations of Risperdal and Zyprexa carry lower price tags. Zyprexa, the market-leading antipsychotic, costs $9.64 for a 10 mg dose (⁶ Also see "Risperdal Consta Priced Aggressively; J&J Sets High Premium To Zyprexa" - Pink Sheet, 10 November, 2003., p. 13).

Zyprexa IM will be shipped to wholesalers by April 12, Lilly said.

The product is the first in its class to be indicated for the treatment of agitation associated with both bipolar mania and schizophrenia.

⁷ Labeling cites the DSM-IV definition of "psychomotor agitation," which is "excessive motor activity associated with a feeling of inner tension."

"Patients experiencing agitation often manifest behaviors that interfere with their diagnosis and care...leading clinicians to the use of intramuscular antipsychotic medications to achieve immediate control of the agitation," labeling states.

The efficacy of Zyprexa IM was demonstrated in three short-term (24 hours of treatment) placebo-controlled trials in agitated patients. On the Positive and Negative Symptom Scale Excited Component, "10 mg injections of Zyprexa IntraMuscular were significantly superior to placebo at the first time point measured (15 or 30 minutes) after injection."

Labeling states that "if agitation warranting additional intramuscular doses persists following the initial dose" of 10 mg, "subsequent doses up to 10 mg may be given." However, "the efficacy of repeated doses of intramuscular olanzapine for injection in agitated patients has not been systematically evaluated in controlled clinical trials."

"Also, the safety of total daily doses greater than 30 mg, or 10 mg injections given more frequently than two hours after the initial dose, and four hours after the second dose, have not been evaluated in clinical trials."

Adverse events associated with Zyprexa IM include somnolence (6%), dizziness (4%) and muscle weakness (2%).

FDA Approves Zyprexa IM; Milestone In Lilly GMP Turnaround

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