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FDA Approves Lamictal (Lamotrigine) For Long-Term Maintenance Treatment Of Bipolar I Disorder

RESEARCH TRIANGLE PARK, NC -- June 23, 2003 -- GlaxoSmithKline (NYSE: GSK) announced today the U.S. Food and Drug Administration's (FDA) approval of Lamictal® (lamotrigine) tablets for the long-term maintenance treatment of Bipolar I Disorder.

Specifically, the FDA approved Lamictal for the maintenance treatment of adults with Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. Additionally, the FDA has noted that findings for Lamictal maintenance treatment were more robust in bipolar depression.

Maintenance treatment of bipolar depression is one of the most significant medical needs in the treatment of this devastating illness. The effectiveness of Lamictal in the acute treatment of mood episodes has not been established. Lamictal is the first FDA-approved therapy since Lithium for maintenance treatment of bipolar I disorder.

Bipolar disorder, a serious, chronic illness marked by disabling mood swings from high (manic) to low (depressed) states,(1) is one of the most common mental illnesses in the United States. Recent research suggests bipolar symptoms may affect three times as many people -- nearly eight million American adults (or one in 30 people) -- as previously believed.(2) A recent study in patients with bipolar disorder showed that the total time spent depressed exceeded time spent manic by a factor of three, indicating that the depressive phases of bipolar illness were more problematic and treatment-resistant.(3) Most attempted and completed suicides occur during the depressive or mixed phases.

"The finding that Lamictal possesses long-term efficacy in the treatment of bipolar disorder is extremely important," said Joseph R. Calabrese, M.D., Director of the Mood Disorders Center, University Hospitals of Cleveland and professor of psychiatry, Case Western University School of Medicine. "The last time the FDA approved a long-term treatment for bipolar disorder was lithium in the 1970s. In addition, the results are more robust for depression, the phase of illness in which patients spend the majority of their time."

The FDA's approval of Lamictal was based on the results of two landmark, randomized, placebo-controlled 18-month studies, which evaluated adult patients who were either currently or recently manic or depressed. Combined, these studies represent the largest, prospectively defined, placebo-controlled maintenance data set in bipolar disorder (1,305 patients). Following the open- label phase, patients who reached stabilization criteria entered the randomized phase. Findings from these studies show Lamictal significantly delays the time to intervention for mood episodes (depression, mania, hypomania, and mixed episodes) in patients with bipolar I disorder. Intervention was defined as additional pharmacotherapy or electroconvulsive therapy (ECT) for a mood episode or one that was emerging. Specifically, in recently depressed patients, the median days to intervention were 200 for Lamictal and 93 for placebo, which represents 115% more intervention-free days. Similarly, in recently manic or hypomanic patients, the median days to intervention was 141 for Lamictal and 85 for placebo, which represents 66 percent more intervention-free days. The combined analysis for the two studies revealed a statistically significant benefit for Lamictal over placebo in delaying the time to occurrence of both depression and mania, although the finding was more robust for depression. Lamictal was associated with a favorable tolerability profile in these studies.

The most common (=5% and numerically >placebo) side effects associated with Lamictal in the randomized phase of these studies were: nausea (14%) insomnia (10%) somnolence (9%) back pain (8%) fatigue (8%) rhinitis (7%) non-serious rash, (7%), abdominal pain (6%) dry mouth (6%), constipation (5%), vomiting (5%), exacerbation of cough (5%) pharyngitis (5%).

Adverse events that occurred in =5% and were numerically more common in patients during the dose escalation phase of these trials, when patients may have been receiving concomitant psychotropic medications, compared to the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%) and pruritus (6%).

Serious rashes requiring hospitalization and discontinuation of treatment have been reported in association with the use of Lamictal. For further important safety information on serious rash, see "About Lamictal" section below and accompanying prescribing information.

"Combined, these studies are unique in that they not only included bipolar patients who were recently manic but also others who were recently depressed, which is reflective of how bipolar patients present in the clinic," said Robert Leadbetter, M.D., Senior Director of Psychiatry, clinical Development and Medical Affairs at GlaxoSmithKline. "Going into these studies, our goal was to extend stability by delaying the time to occurrence of mood episodes and we are excited by the results achieved by patients on Lamictal, compared to those on placebo."

About Bipolar Disorder
Bipolar I disorder is characterized by the occurrence of one or more manic or mixed episodes and often individuals also have had one or more major depressive episodes; in bipolar II disorder, a person experiences one or more major depressive episodes and hypomania (a milder form of mania with less severe symptoms). If manic and depressive symptoms overlap for a period of time, it is called a "mixed" episode.

Although there is no cure for bipolar disorder, the revised APA treatment guidelines stressed that treatment can significantly improve symptoms associated with the illness.(4) One of the most serious risks of bipolar disorder is suicide, which is associated most often with the depressive phase.(5)

Suicide completion rates may be as high as 10-15 percent of patients with bipolar I disorder(6) making it one of the most serious and deadly psychiatric illnesses. Additionally, researchers estimate that more than 40 percent of individuals with bipolar disorder have problems with alcohol or drugs during their illness.(7) When left untreated, bipolar disorder can worsen and patients can experience a greater frequency of events. For more information on bipolar I disorder, visit http://www.bipolar.com.

About Lamictal
Lamictal is available in over 90 countries and has been used by an estimated 5 million patients worldwide.

Lamictal has been available in the U.S. since 1994 and also is indicated as adjunctive therapy for partial seizures in adults and pediatric patients ((2 years of age). Lamictal is also indicated as adjunctive therapy for the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients ((2 years of age). Lamictal is indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with a single enzyme-inducing antiepileptic drug.

The safety and effectiveness of Lamictal have not been established 1) as initial monotherapy, 2) for conversion to monotherapy from non-enzyme-inducing anti epileptic drugs (e.g. valproate), or 3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs). Safety and effectiveness in patients below the age of 16 other than those with partial seizures and the generalized seizures of Lennox-Gastaut syndrome have not been established.

Serious rashes requiring hospitalization and discontinuation of treatment have been reported in association with the use of Lamictal. The incidence of these rashes, which have included Stevens-Johnson Syndrome, is approximately 0.8 percent (8/1,000) in pediatric patients under the age of 16 years receiving Lamictal as adjunctive therapy for epilepsy, and 0.3 percent (3/1,000) in adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood disorders, the rate of serious rash was 0.08 percent (0.8/1,000) in adult patients receiving Lamictal as initial monotherapy and 0.13 percent (1.3/1,000) in adult patients receiving Lamictal as adjunctive therapy.

In a prospectively followed cohort of 1,983 pediatric patients taking adjunctive Lamictal, there was one rash-related death. In worldwide post- marketing experience, rare cases of toxic epidermal necrolysis (TEN) and/or rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate. Lamictal ordinarily should be discontinued at the first signs of rash, unless the rash is clearly not drug-related.

The risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose escalation of Lamictal is exceeded. There are suggestions, yet to be proven, that the risk of severe, potentially life- threatening rash may be increased by 1) coadministration of Lamictal with valproic acid; 2) exceeding the recommended initial dose of Lamictal; or 3) exceeding the recommended dose escalation of Lamictal. However, cases have been reported in the absence of these factors. Therefore, it is important that the dosing recommendations be followed closely. For more information on Lamictal, log on to http://www.lamictal.com.

References:

(1) American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000.

(2) Hirschfeld RMA, Calabrese JR, Weissman MM, et al., Screening for Bipolar Disorder in the Community. J Clin Psychiatry, January 2003; 64(1): 53-59.

(3) Post, et al. "Presentations of Depression in Bipolar Illness." Clinical Neuroscience Research; 2 (2002); 142-157.

(4) Hirschfeld RMA, et al. "Practice Guideline for the Treatment of Patients with Bipolar Disorder (Revision)." American Journal of Psychiatry. 2002; 159:4.

(5) Tondo L, Baldessarini RJ. "Reduced Suicide Risk during Lithium Maintenance Treatment." Journal of Clinical Psychiatry 2000; 61 (suppl 9) 97-104.

(6) Baldessarini RJ, et al. "Effects of Lithium Treatment and its Discontinuation on Suicidal Behavior in Bipolar Manic-Depressive Disorders." Journal of Clinical Psychiatry 1999; 60 (suppl 2) 77-84.

(7) Regier DA, et al. "Comorbidity of Mental Disorders with Alcohol and other Drug Abuse: Results from the Epidemiologic Catchment Area (ECA) Study." JAMA 1990; 264:2511-2518.


SOURCE: GlaxoSmithKline

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