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FDA Approves Symbyax

Symbyax Eli Lilly - Treatment for Bipolar Depression

Lilly Announces FDA Approval of First Medication for Bipolar Depression

INDIANAPOLIS, December 29, 2003 – Eli Lilly and Company (NYSE:LLY) announced today that the U.S. Food and Drug Administration (FDA) has approved Symbyax (olanzapine and fluoxetine HCl) for the treatment of depressive episodes associated with bipolar disorder. Symbyax (pronounced SIMM-bee-ax), which is a combination of olanzapine, the active ingredient in Zyprexa, and fluoxetine, the active ingredient in Prozac, is the first FDA approved medication for bipolar depression, a notoriously difficult-to-treat condition that afflicts millions of Americans.

"There is a desperate need for an effective treatment for bipolar depression, a devastating condition which often leads patients to take their own lives," said Terence A. Ketter, M.D., associate professor of psychiatry & behavioral sciences, and chief, Bipolar Disorders Clinic, Stanford University School of Medicine.

"We are pleased to be able to provide clinicians with Symbyax, the first FDA-approved option to help physicians help their patients with bipolar depression," said Mauricio Tohen, M.D., Dr.P.H., Lilly clinical research fellow, Lilly Research Laboratories and Zyprexa Product Team Leader. "Patients suffering from this debilitating condition can now benefit from the combination of the active ingredients in Zyprexa and Prozac, two of the most successful and proven medications in neuroscience history."

Bipolar disorder is a complex mental illness characterized by debilitating mood swings ranging from episodes of deep depression marked by feelings of extreme guilt, sadness, anxiety and, at times, suicidal thoughts to episodes of mania (abnormal euphoria, elation and irritability), interspersed with periods of normal mood.

Patients with bipolar disorder spend more than three times longer in the depressive phase than in the manic phase of the disorder and take longer to recover from it. Additionally, the depressive phase of bipolar disorder is associated with higher rates of morbidity and mortality. It is estimated that one in four people with bipolar disorder will attempt suicide at least once, and the relative risk of suicide among patients with bipolar depression has been shown to be nearly 35 times greater than for patients in the manic phase of bipolar disorder.

Symbyax Patients Experienced Robust Symptom Relief In Clinical Trials

According to a study (Tohen, et al.) published in the November 2003 issue of Archives of General Psychiatry, Symbyax helped to treat the symptoms of bipolar depression more effectively and at a significantly faster rate than placebo. In the pooled eight-week studies, patients in the Symbyax group experienced significantly greater improvement in depressive symptoms at weeks one, three, four, six and eight, compared with patients taking placebo. That robust symptom improvement was sustained throughout the entire eight weeks of the study. In addition, Symbyax patients had no statistically greater risk of treatment-emergent mania than patients taking placebo. In patients with bipolar depression, a manic episode is a potential consequence of treatment with a conventional antidepressant alone.

"Medications that clinicians have traditionally used to treat bipolar patients in a depressive phase can often take several weeks to work and have the additional risk of sending the patient into a manic episode," said Dr. Ketter. "Having a medication that can provide symptom relief quickly, while avoiding mania, will be so important to physicians in effectively treating patients with bipolar depression, particularly because these individuals are at a high risk of suicide."

Important Information on Symbyax

Symbyax is indicated in the United States for the treatment of depressive episodes associated with bipolar disorder

The most common adverse events reported in patients taking Symbyax in clinical trials was drowsiness. Other common events noticed in clinical trials were weight gain, increased appetite, feeling weak, swelling, tremor, sore throat, and difficulty concentrating. Hyperglycemia, in some cases associated with ketoacidosis, coma or death, has been reported in patients treated with atypical antipsychotics, including olanzapine, and concomitant olanzapine and fluoxetine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. The available data are insufficient to provide reliable estimates of differences in hyperglycemia-related adverse-event risk among the marketed atypical antipsychotics. All patients taking atypicals should be monitored for symptoms of hyperglycemia. Persons with diabetes who are started on atypicals should be monitored regularly for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting bloodglucose testing. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood-glucose testing.

Although Symbyax is not approved for elderly patients with dementia it is important to note the label for Symbyax includes a warning for patients in this population. The warning states that strokes or mini-strokes (also called transient ischemic attacks or TIAs), including fatalities were reported in elderly patients with dementia-related psychosis participating in clinical trials for olanzapine, an active ingredient in Symbyax. In fact, Symbyax has not been studied in elderly patients with dementia, nor do we expect Symbyax to be used to treat these patients. Symbyax may induce orthostatic hypotension (a drop in blood pressure when standing up), associated with dizziness, speeding or slowing of heart rate, and in some patients, fainting, especially during initial therapy.

Symbyax prescribing should be consistent with the need to minimize the risk of neuroleptic malignant syndrome, tardive dyskinesia, and orthostatic hypotension. Symbyax should not be administered until at least two weeks have passed since discontinuing an MAO inhibitor, and an MAO inhibitor is contraindicated for at least five weeks after discontinuation with Prozac. Thioridazine should not be administered with Symbyax or within a minimum of 5 weeks after discontinuing Symbyax. Symbyax should be discontinued immediately if rash or other possibly allergic phenomena appear for which an alternative explanation cannot be identified.

Due to the cyclical nature of bipolar disorder, patients should be monitored for the signs of mania and hypomania during treatment with Symbyax.

Patients should inform their physicians if they are taking Zyprexa, Prozac, Sarafem or fluoxetine.

Prescribing Information and Availability

Full prescribing information is accessible at www.symbyax.com. Symbyax will be available in pharmacies by mid-January of 2004.

Bipolar Disorder Background

Bipolar disorder, also known as manic-depressive illness, affects an individual's mood, behavior and thinking. Unlike many illnesses, symptoms may be quite different in different phases of the illness. Treatment is more challenging because some therapies that are effective in one phase of the illness may be counterproductive in another, such as the observation that treatment with an antidepressant alone can precipitate manic episodes. More than 2.5 million Americans live with a diagnosis of bipolar disorder, but recent research indicates the real number may be as high as 10 million. The results of untreated bipolar disorder can be catastrophic. An estimated 25 percent of patients with bipolar disorder attempt suicide at least once and approximately 20 percent actually succeed. This is one of the highest rates for any psychiatric disorder and three times higher than that of the general population. The World Health Organization estimates that bipolar disorder is the sixth leading cause of disability in the world.

Zyprexa Background

Zyprexa is indicated in the United States for the treatment of schizophrenia and the short-term treatment of acute manic episodes associated with bipolar disorder and for the long-term therapy and maintenance of treatment response of schizophrenia. Additionally, Zyprexa is under review by the FDA for long-term maintenance of bipolar disorder. (Zyprexa is not indicated for the treatment of bipolar depression.) Since Zyprexa was introduced in 1996, it has been prescribed to more than 12.5 million people worldwide.

The most common treatment-emergent adverse event associated with Zyprexa in placebocontrolled, short-term schizophrenia and bipolar mania trials was drowsiness. 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.

A small number of patients in premarketing trials experienced asymptomatic elevations of hepatic transaminase; none of these patients developed jaundice. Periodic assessment of transaminases is recommended in patients with significant hepatic disease. Prescribing should be consistent with the need to minimize the risk of neuroleptic malignant syndrome, tardive dyskinesia, seizures, and orthostatic hypotension.

Hyperglycemia, in some cases associated with ketoacidosis, coma or death, has been reported in patients treated with atypical antipsychotics, including Zyprexa. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. The available data are insufficient to provide reliable estimates of differences in hyperglycemia-related adverse-event risk among the marketed atypical antipsychotics. All patients taking atypicals should be monitored for symptoms of hyperglycemia. Persons with diabetes who are started on atypicals should be monitored regularly for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood-glucose testing. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood-glucose testing.

Full prescribing information is available at www.zyprexa.com.

Prozac Background

Prozac was the first of a new class of drugs, called selective serotonin reuptake inhibitors (SSRIs), to be approved for use in the United States. This type of medication helps patients with depression by increasing the availability of serotonin in the brain. Scientists believe serotonin affects many types of activity in the brain, including the regulation of mood. Prozac was initially approved for treatment of depression in Belgium in 1986 and in the United States in 1987. (Prozac is not indicated for the treatment of bipolar depression.) Since then, it has been approved and marketed in more than 90 countries and used by more than 40 million people worldwide. The safety and effectiveness of Prozac have been thoroughly studied in clinical trials with more than 11,000 patients. There have been more than 3,500 publications on Prozac in medical and scientific journals.

The most commonly observed adverse events associated with the use of Prozac vs. placebo in U.S.-controlled clinical trials for depression, obsessive compulsive disorder (OCD) and bulimia combined were nausea (23 vs. 10 percent), headache (21 vs. 20 percent), insomnia (20 vs. 11 percent), anxiety (13 vs. 8 percent), nervousness (13 vs. 9 percent) and somnolence (13 vs. 6 percent).

Prozac is contraindicated until at least two weeks have passed since discontinuing an MAO inhibitor, and an MAO inhibitor is contraindicated for at least five weeks after discontinuation with Prozac. Thioridazine should not be administered with Prozac or within a minimum of 5 weeks after discontinuing Prozac. Prozac should be discontinued immediately if rash or other possibly allergic phenomena appear for which an alternative explanation cannot be identified. Full prescribing information is available at www.prozac.com.

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

This press release contains forward-looking statements about the potential of Symbyax for the treatment of the depressive phase of bipolar disorder and reflects Lilly's current beliefs. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization. There is no guarantee that the product will prove to be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's filings with the United States Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.

Posted: December 2003

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