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FDA Approves Risperidone for Treatment of Bipolar Mania

Titusville, N.J. - December 5, 2003 - The U.S. Food and Drug Administration (FDA) has approved RISPERDAL® (risperidone) as monotherapy (alone) or in combination with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder, also known as bipolar mania. In research studies, patients with bipolar mania who took Risperdal showed significant improvement in manic symptoms compared to placebo.

Bipolar disorder affects more than 2 million people in the United States and is characterized by dramatic mood swings, alternating between the highs of mania and the lows of depression. In mixed episodes, people with bipolar disorder experience symptoms of both mania and depression. Mania, a state of excessive excitement and hyperactivity, can lead to delusional thinking and dangerous risk-taking behavior. Nearly 40 percent of people with untreated bipolar illness abuse alcohol or drugs. Job loss, divorce and even suicide are not uncommon consequences of the illness.

"Bipolar mania is a serious, life-long illness with many hazardous consequences. We are desperately in need of new treatment options," said Robert Hirschfeld, MD, chair of the department of psychiatry at the University of Texas Medical Branch in Galveston, TX. "Because Risperdal is effective and generally well tolerated, it offers an attractive choice for patients and physicians."

Clinical Trial Findings
The effectiveness of Risperdal in treating acute manic or mixed episodes of bipolar disorder was established in three studies - two that analyzed the medication as monotherapy and one in which Risperdal was used in combination with lithium or valproate. In all studies, patients who received Risperdal, given in doses of 1 mg to 6 mg per day, experienced significantly greater symptom improvements than those in the control groups.

In all studies, efficacy was measured using the Young Mania Rating Scale (YMRS), which clinicians use to assess the degree of a patients manic symptoms (such as irritability, disruptive/aggressive behavior, elevated mood, increased activity, language/thought disorder and other measures) from 0 (no manic features) to 60 (maximum score). The primary outcome in these studies was change from baseline in the YMRS total score. Clinical response also was defined as a 50 percent or greater reduction in the total YMRS score from baseline to endpoint.

Summary of Study Results
In one, three-week, placebo-controlled study of 246 adult patients diagnosed with bipolar I disorder, who were in an acute manic episode, with or without psychotic symptoms, Risperdal was superior to placebo in reducing the YMRS total score. Participants taking Risperdal, on average, experienced an 11 point reduction on the YMRS compared to a five point reduction among placebo patients. Forty-three percent of the patients treated with Risperdal versus 24 percent of the patients given placebo had at least a 50 percent reduction in total manic symptom scores.

The second, similarly designed, monotherapy trial studied 286 bipolar I patients with manic or mixed episodes. Again, Risperdal monotherapy was superior to placebo. On average, Risperdal patients had a total reduction of 22.7 points on the YMRS, versus a 10.5 point reduction in the placebo patients. At endpoint, 73 percent of patients receiving Risperdal compared to 36 percent of patients given placebo achieved clinical response.

The combination therapy study was a three-week, placebo-controlled trial in 148 adults diagnosed with bipolar I disorder experiencing a manic or mixed episode, with or without psychotic features, and with or without rapid cycling between moods. At the conclusion of the study, participants taking Risperdal had experienced, on average, a 14.3 total YMRS point reduction versus an 8.2 point reduction among placebo patients. Fifty-seven percent of patients treated with Risperdal versus 38 percent of patients who received placebo had at least a 50 percent improvement in manic symptoms.

In these studies, all doses of Risperdal were generally well tolerated, with the percentage of patients who discontinued the study due to side effects comparable to the dropout rate among those who received placebo. In one of the monotherapy studies, 3.9 percent of patients experienced a 7 percent or greater increase in body weight. In the other monotherapy trial, 2.8 percent of patients had a weight increase of 7 percent or greater. In the combination therapy study, 10.5 percent of patients had a weight increase of 7 percent or greater.

The most common side effects experienced in the Risperdal monotherapy studies included extrapyramidal symptoms (reversible movement disorders or muscle disturbances such as restlessness, tremors and muscle stiffness), sleepiness, dyspepsia, nausea, abnormal vision and increased saliva. In the combination therapy study, the most common side effects included sleepiness, dizziness, Parkinsonism (abnormal muscle movements), increased saliva, akathisia (restlessness), abdominal pain and urinary incontinence.

Drug interactions with some anticonvulsants and Risperdal have been noted. Co-administration of carbamazepine and Risperdal led to a 50 percent reduction in plasma concentrations of Risperdal. Risperdal had no effect on the average plasma concentration of valproate, however a 20 percent increase in peak plasma concentrations was seen. In addition, Risperdal had no affect on the plasma concentrations of lithium.

Bipolar Mania
When in a manic state, a person's behavior becomes unpredictable and his or her judgment is impaired. People often make reckless decisions during periods of mania, and they become oblivious to the negative consequences of their extreme actions. Spending sprees, alcohol and drug abuse, and hypersexuality are common. In patients with mixed mania, both symptoms of mania and depression occur within the same episode. For example, a person experiencing a mixed episode may have a very sad, hopeless mood while at the same time feel extremely energized. Nearly 80 percent of those suffering from bipolar disorder are either misdiagnosed or undiagnosed altogether. One reason for misdiagnosis is that the symptoms of the disease are common to other conditions, such as depression and substance abuse. In some cases, patients don't seek treatment because the feelings associated with acute mania can be exhilarating. Often they deny that they have any sort of problem or illness. Once patients are diagnosed, there are a variety of treatments available that can help manage the symptoms of bipolar disorder.

Risperdal was discovered and developed at the Janssen Research Foundation, now part of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD). Researchers at J&JPRD led the development of Risperdal as a treatment for acute manic or mixed episodes associated with bipolar I disorder.

Risperdal has been marketed in tablet form in the United States by Janssen Pharmaceutica Products, L.P., since 1994, and also is available in oral solution and quick dissolving tablet forms. Approved for marketing in more than 100 countries, Risperdal is the most widely prescribed atypical antipsychotic in the world. In a study published in the January 2002 issue of The New England Journal of Medicine, Risperdal was found to be significantly more effective in reducing the risk of relapse in patients with schizophrenia than haloperidol, a conventional antipsychotic.

Risperdal is available in 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg doses. Risperdal currently is available as a standard, oral tablet; a quick-dissolving tablet (Risperdal® M-Tab) in 0.5 mg, 1 mg, and 2 mg doses; and an oral solution in a 1.0 mg/mL dose. Risperdal M-Tab contains phenylalanine. Risperdal is indicated for the treatment of acute manic or mixed episodes associated with bipolar I disorder and schizophrenia. In clinical trials, Risperdal was generally well tolerated. However, as with all other psychotropic medications, Risperdal was associated with adverse events. For more information, refer to the full prescribing information for Risperdal or visit www.risperdal.com or www.janssen.com.

Source: Janssen

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