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FDA Issues a Complete Response Letter for Lilly's Olanzapine LAI for Treatment of Schizophrenia in Adults

Thursday, January 8, 2009 General News J E 4
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INDIANAPOLIS, Jan. 7 Eli Lilly and Company(NYSE: LLY) announced today that it received a complete response letter fromthe U.S. Food and Drug Administration (FDA) for olanzapine long-actinginjection (LAI) for acute and maintenance treatment of schizophrenia inadults. Lilly is continuing to work with the agency on the new drugapplication (NDA).

The FDA does not require any additional clinical trials for the continuedreview of the NDA. Per the agency's request, Lilly is preparing a proposedRisk Evaluation and Mitigation Strategy (REMS), which will be submitted in thenear future.

"We cannot speculate on the timing of a potential decision, but remainconfident that, if approved, the long-acting depot formulation of olanzapinewill offer an important option for treating this devastating and chronicillness," said Todd Durell, M.D., associate medical director for U.S.neuroscience for Lilly.

This treatment has been approved for use in the European Union and NewZealand under the trade name Zypadhera(TM). Independent regulatory reviews areongoing in other countries.

Notes for editors:

About Long-acting Injectable Antipsychotic Medications

The World Federation of Societies of Biological Psychiatry (WFSBP)guidelines state that poor or partial treatment compliance is a major problemin the long-term treatment of schizophrenia. Depot formulations should beconsidered as a treatment option if it is determined that a depot formulationis necessary to help with compliance.(1)

By administering long-acting medications, healthcare professionals knowwhen patients have received their medication and can immediately detect non-adherence when a patient fails to return for a scheduled injection.(2)Different from both oral and injected short-acting formulations, long-actingformulations of antipsychotics allow for stable concentrations of the activedrug to remain at a therapeutic range for an extended period of time.(3)

About Schizophrenia

Schizophrenia is a severe and debilitating illness with such symptoms asdelusions (false beliefs that cannot be corrected by reason), hallucinations(usually in the form of non-existent voices or visions), disorganized speechand severe disorganized or catatonic behavior. These signs and symptoms areassociated with marked social or occupational dysfunction. Features ofschizophrenia consist of characteristic signs and symptoms that have beenpresent for a significant portion of time during a one-month period, with somesigns of the disorder persisting for at least six months.(4) In addition tothese symptoms, patients with schizophrenia are at greater risk for medicalcomorbidities than the general population.

Safety information for Zyprexa

Zyprexa oral is indicated in the United States for the short- and long-term treatment of schizophrenia, acute mixed and manic episodes of bipolar Idisorder, and maintenance treatment of bipolar disorder.

In addition, compared to elderly patients with dementia-related psychosistaking a placebo, there was a significantly higher incidence ofcerebrovascular adverse events in elderly patients with dementia-relatedpsychosis treated with olanzapine.

Hyperglycemia, in some cases associated with ketoacidosis, coma, or death,has been reported in patients treated with atypical antipsychotics, includingolanzapine. While relative risk estimates are inconsistent, the associationbetween atypical antipsychotics and increases in glucose levels appears tofall on a continuum and olanzapine appears to have a greater association thansome other atypical antipsychotics. Physicians should consider the risks andbenefits when prescribing olanzapine to patients with an established diagnosisof diabetes mellitus, or having borderline increased blood glucose level.Patients taking olanzapine should be monitored regularly for worsening ofglucose control. Persons with diabetes who are started on atypicals should bemonitored regularly for worsening of glucose control; those with risk factorsfor diabetes should undergo baseline and periodic fasting blood glucosetesting. Patients who develop symptoms of hyperglycemia during treatmentshould undergo fasting blood glucose testing.

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

Potential consequences of weight gain should be considered prior tostarting olanzapine. Patients receiving olanzapine should receive regularmonitoring of weight.

Olanzapine may induce orthostatic hypotension associated with dizziness,tachycardia, bradycardia, and in some patients, syncope, especially during theinitial dose-titration period. Particular caution should be used in patientswith known cardiovascular disease, cerebrovascular diseases, or thosepredisposed to hypotension.

As with all antipsychotic medications, a rare and potentially fatalcondition known as Neuroleptic Malignant Syndrome (NMS) has been reported witholanzapine. If signs and symptoms appear, immediate discontinuation isrecommended. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity,altered mental status and evidence of autonomic instability (irregular pulseor 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 beconsistent with the need to minimize Tardive Dyskinesia (TD). The risk ofdeveloping TD and the likelihood that it will become irreversible are believedto increase as the duration of treatment and the total cumulative dose ofantipsychotic increase. The syndrome may remit, partially or completely, ifantipsychotic treatment is withdrawn.

Other potentially serious adverse events include seizures, elevatedprolactin levels, elevated liver enzymes, cognitive and motor impairment, bodytemperature elevation, and trouble swallowing.

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

Full prescribing information, including a boxed warning, is available atwww.zyprexa.com.

About Eli Lilly and Company

Lilly, a leading innovation-driven corporation, is developing a growingportfolio of first-in-class and best-in-class pharmaceutical products byapplying the latest research from its own worldwide laboratories and fromcollaborations with eminent scientific organizations. Headquartered inIndianapolis, Ind., Lilly provides answers - through medicines and information- for some of the world's most urgent medical needs. Additional informationabout Lilly is available at www.lilly.com.

P-LLY

This press release contains forward-looking statements about the safetyand efficacy of olanzapine long acting injection (LAI) and reflects Lilly'scurrent beliefs. However, as with any investigational pharmaceutical product,there are substantial risks and uncertainties in the process of research,development, regulatory milestones and commercialization. There is noguarantee that olanzapine LAI will be approved for the treatment ofschizophrenia or that if approved, it will be commercially successful. Forfurther discussion of these and other risks and uncertainties, see Lilly'sfilings with the United States Securities and Exchange Commission. Lillyundertakes no duty to update forward-looking statements.

1) Falkai P., Wobrock T., Lieberman J., Glenthoj B., Gattaz W.F., MollerH.J & Wfsbp Task Force On Treatment Guidelines For Schizophrenia. The WorldJournal of Biological Psychiatry, 2006; 7(1): 5/40

2) Kane J.M et al. Guidelines for depot antipsychotic treatment inschizophrenia. European Neuropsychopharmacology, Volume 8, Number 1, 1February 1998, pp. 55-66(12). p. 58.

3) Maxine X. Patel and Anthony S. David. Why aren't depot antipsychoticsprescribed more often and what can be done about it? Advances in PsychiatricTreatment (2005) 11: 203-211.

4) American Psychiatric Association. Diagnostic and Statistical Manual ofMental Disorders, fourth edition, 2000, pp. 298.

(Logo: http://www.newscom.com/cgi-bin/prnh/20031219/LLYLOGO )Olanzapine is not approved for the treatment of patients with dementia- ----------------------------------------------------------------------- related psychosis. Elderly patients with dementia-related psychosis ------------------------------------------------------------------- treated with antipsychotic drugs are at an increased risk of death. -------------------------------------------------------------------

SOURCE Eli Lilly and Company
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