Dear Health Care Professional:

Glaxo Wellcome would like to advise you of new warnings in the labeling for LAMICTAL (lamotrigine) Tablets, an antiepileptic drug indicated for adjunctive therapy of partial seizures in adults with epilepsy. These new warnings pertain to reports of severe, potentially life-threatening rash, including Stevens-Johnson syndrome, and rarely, toxic epidermal necrolysis, reported in association with the use of LAMICTAL.

The revised labeling now includes a boxed warning which emphasizes that LAMICTAL is not indicated for use in patients below the age of 16 years. Specifically, reports from clinical trials suggest that as many as 1 in 50 to 1 in 100 pediatric patients treated with LAMICTAL develop a potentially life-threatening rash, as compared with a rate of approximately one in every thousand adults.

These revisions to the labeling, agreed in consultation with the US Food and Drug Administration, reflect additional information obtained through worldwide clinical experience in an estimated 600,000 patients and the ongoing Glaxo Wellcome clinical development program for LAMICTAL.

Other related changes have been made in the INDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE EVENTS, and DOSAGE and ADMINISTRATION sections of the labeling. A full copy of the revised package insert is enclosed; the major changes are summarized below:

• A boxed warning has been added, as follows:

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  SEVERE, POTENTIALLY LIFE-THREATENING RASHES HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF LAMICTAL. THESE REPORTS, OCCURRING IN APPROXIMATELY ONE IN EVERY THOUSAND ADULTS, HAVE INCLUDED STEVENS-JOHNSON SYNDROME (SJS), AND RARELY, TOXIC EPIDERMAL NECROLYSIS (TEN). RARE DEATHS HAVE BEEN REPORTED, BUT THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE ESTIMATE OF THE RATE.

  THE INCIDENCE OF SEVERE, POTENTIALLY LIFE-THREATENING RASH IN PEDIATRIC PATIENTS, HOWEVER, IS VERY MUCH HIGHER THAN THAT REPORTED IN ADULTS USING LAMICTAL; SPECIFICALLY, REPORTS FROM CLINICAL TRIALS SUGGEST AS MANY AS 1 IN 50 TO 1 IN 100 PEDIATRIC PATIENTS DEVELOP A POTENTIALLY LIFE-THREATENING RASH. IT BEARS EMPHASIS, ACCORDINGLY, THAT LAMICTAL IS NOT APPROVED FOR USE IN PATIENTS BELOW THE AGE OF 16 (SEE INDICATIONS).

  OTHER THAN AGE, THERE ARE AS YET NO FACTORS IDENTIFIED THAT ARE KNOWN TO PREDICT THE RISK OF OCCURRENCE OR THE SEVERITY OF RASH ASSOCIATED WITH LAMICTAL. THERE ARE SUGGESTIONS, YET TO BE PROVEN, THAT THE RISK OF RASH MAY ALSO BE INCREASED BY 1) COADMINISTRATION OF LAMICTAL WITH VALPROIC ACID (VPA); 2) EXCEEDING THE RECOMMENDED INITIAL DOSE OF LAMICTAL; OR 3) EXCEEDING THE RECOMMENDED DOSE ESCALATION FOR LAMICTAL. HOWEVER, CASES HAVE BEEN REPORTED IN ABSENCE OF THESE FACTORS.

  NEARLY ALL CASES OF LIFE-THREATENING RASHES ASSOCIATED WITH LAMICTAL HAVE OCCURRED WITHIN 2 TO 8 WEEKS OF TREATMENT INITIATION. HOWEVER, ISOLATED CASES HAVE BEEN REPORTED AFTER PROLONGED TREATMENT (E.G., 6 MONTHS). ACCORDINGLY, DURATION OF THERAPY CANNOT BE RELIED UPON AS A MEANS TO PREDICT THE POTENTIAL RISK HERALDED BY THE FIRST APPEARANCE OF A RASH.

  ALTHOUGH BENIGN RASHES ALSO OCCUR WITH LAMICTAL, IT IS NOT POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE LIFE-THREATENING. ACCORDINGLY, LAMICTAL SHOULD BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG-RELATED. DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM BECOMING LIFE-THREATENING OR PERMANENTLY DISABLING OR DISFIGURING.

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  The WARNINGS section has been revised to include the following information regarding hypersensitivity reactions:

  "Hypersensivity reactions: Hypersensitivity reactions, some fatal or life-threatening, have also occurred. Some of these reactions have included clinical features of multiorgan dysfunction such as hepatic abnormalities and evidence of disseminated intravascular coagulation. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. LAMICTAL should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

  Prior to initation of treatment with LAMICTAL, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately."

Glaxo Wellcome is committed to helping you treat your epilepsy patients, and encourages you to familiarize yourself with these changes to the package insert so that the proper use of LAMICTAL may be facilitated through your clinical care and treatment of patients. If you have any questions about the new information in the package insert for LAMICTAL Tablets, please contact the Drug Information Department at Glaxo Wellcome (1-800-334-0089)

Sincerely,

Richard S. Kent, MD
Vice President and Chief Medical Officer
Glaxo Wellcome Inc.

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