Seizure Medication Lamotrigine (LAMICTAL) Approved For Use In Bipolar Disorder

GlaxoSmithKline of Research Triangle Park, NC announced in June 2003 that their seizure medication lamotrigine (LAMICTAL) had been approved by the Food and Drug Administration (FDA) for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes such as depression, mania (periods of severe highs), hypomania, or mixed episodes in patients also being treated with standard therapy.

Lamotrigine was originally approved in the U.S. in December 1994 for certain types of seizure disorders. Over 1.8 million prescriptions for the drug were dispensed in U.S. pharmacies in 2002 with retail sales of over $ 400 million.

Bipolar I disorder is a disease in which a person has long bouts of depression and long bouts of mania or mixed episodes of both. When these mixed episodes occur in rapid succession the condition is referred to as rapid-cycling bipolar disorder.

The FDA based its approval of lamotrigine for this new purpose on two studies, both of which have been published. Our usual practice before commenting on the effectiveness of a drug is to wait until the FDA has made its evaluation of data submitted by manufacturers for a new use publicly available. We do this because often the image of the therapeutic value of a drug in the published literature is inflated compared with the reviews done by FDA scientists. Because many more patients are likely to be taking lamotrigine for its new approved use, and the fact that there are major safety issues with this drug, these studies are discussed below.

The first study was published in the Journal of Clinical Psychiatry in November 2000. This study examined the use of lamotrigine alone for the prevention of mood episodes in patients with rapid-cycling bipolar disorder. In the preliminary phase of the study lasting six weeks, 324 patients were given increasing doses of lamotrigine with adjustment of their doses of standard bipolar drugs. Patients were eligible to enter the randomized phase of the study (lamotrigine or placebo) if they remained well, had no change in lamotrigine dosage during the final week of the preliminary phase, and had no mood episodes requiring additional drug treatment or electroconvulsive treatment. Of the original 324 patients, 182 patients (56%) qualified for the randomized phase of the study.

The primary measure used to define the effectiveness of lamotrigine was the time to the need for additional drug treatment for emerging mood symptoms. Overall, both for patients with bipolar I and bipolar II disorder, there was no statistical difference between lamotrigine and the placebo. When the analysis was limited to just those patients classified as having bipolar I disorder, again, statistically there was no difference between lamotrigine and the placebo.

The authors of the study concluded:

This was the largest and only prospective placebo-controlled study of rapid-cycling bipolar disorder patients to date; results indicate lamotrigine monotherapy is a useful treatment for some patients with rapid-cycling bipolar disorder.

Despite the fact that this study was mainly negative for lamotrigine, GlaxoSmithKline described it as a “landmark” study on their web site.

The second study was published in the April 2003 issue of Archives of General Psychiatry. It used a similar design to the Journal of Clinical Psychiatry study; 349 patients began the first phase of the study with 175 (50%) entering the randomized phase of the study. These 175 patients were randomly assigned to receive lamotrigine, lithium (LITHOBID, LITHONATE), or placebo. Lithium is FDA approved for the treatment and maintenance therapy for mania in patients with bipolar illness. The main measure of effectiveness, similar to the study published in the Journal of Clinical Psychiatry, was the time to the need for additional drug or electroconvulsive treatment for emerging mood symptoms.

In this study, for the main measure of effectiveness, both lamotrigine and lithium were statistically superior to placebo. Overall, there was no difference between lamotrigine and lithium in prolonging the appearance of any type of mood episode. Lamotrigine was found to be statistically superior to placebo in prolonging the time to an episode of depression. Lithium was not. Lithium was determined to be statistically superior to placebo in prolonging the time to an episode of mania, hypomania, or a mixed episode. Lamotrigine was not.

In these two studies that were the basis of the FDA’s approval of lamotrigine for bipolar I illness, one study was negative and one was positive for lamotrigine. In the past, the FDA has used the default of two positive studies as the basis for approval. The law and regulations do not require two positive studies but two positive studies are generally considered more scientifically sound than just one in reaching an approval decision.

The Clinical Trials section of lamotrigine’s FDA approved professional product labeling or package insert gives a hint as to how the agency may have arrived at the conclusion that lamotrigine is effective:

Although these studies [the two studies discussed above] were not designed to separately evaluate time to the occurrence of depression or mania, a combined analysis for the 2 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.

It appears that the FDA has allowed GlaxoSmithKline to re-analyze each of the studies for time to a mania episode and time to an episode of depression and then combine the time to mania and depression groups from both studies to reach their conclusion for approval of the drug. This type of analysis is generally frowned upon because the results seen in these subgroups retrospectively may be due to chance rather than the effect of the drug. However, this type of analysis is a good way to identify theories about the effect of drugs that need to be verified by further studies that look specifically at the subgroups.

We must wait until the FDA releases its data analysis into the public domain to evaluate the adequacy of the agency’s rationale for approving lamotrigine. At this time, we wish the data for lamotrigine in bipolar I illness were stronger.

There are two major safety issues with lamotrigine. The first is the risk of life-threatening rash. The FDA has required a black box warning on lamotrigine’s professional product labeling concerning rash. A black box warning is the strongest type of warning that the FDA can require on a drug’s professional labeling. This rash is more prevalent in children less than 16 years than in adults, and lamotrigine should be stopped if it occurs. Unfortunately, stopping lamotrigine may not prevent a rash from becoming life threatening or permanently disabling or disfiguring.

In the first study discussed above, rash occurred in 14 percent of the patients in the preliminary phase and in 3 percent of lamotrigine users in the randomized phase. In the second study, 11 percent of patients experienced rash in the preliminary phase and 3 percent of those taking lamotrigine in the randomized phase.

The text of lamotrigine’s black box warning appears below:

The second safety issue is dispensing errors. Dispensing errors have occurred between Lamictal and other drugs, most commonly Lamisil, lamivudine, Ludiomil, labetalol, and Lomotil. Patients who do not receive Lamictal for their seizure disorder would be inadequately treated and could experience serious consequences. On the other hand, patients mistakenly receiving Lamictal (instead of one of the drugs listed above), especially high initial doses, would be unneces-sarily subjected to a risk of serious adverse effects such as skin rash.

What You Can Do

If you make the decision to use lamotrigine for bipolar I disorder and if a rash appears, report it to your physician immediately and the drug should be discontinued.

You can help prevent dispensing errors by knowing the name of the drug you are being prescribed before you have your prescription filled. At the pharmacy, check or ask the pharmacist if the drug you have been dispensed is the drug that was prescribed.