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| DO NOT DISCONTINUE ANY SEIZURE MEDICATION WITHOUT FIRST CONSULTING THE PRESCRIBER |
On September 29, the Food and Drug Administration (FDA) announced that the seizure and depression drug lamotrigine (LAMICTAL) may cause birth defects when taken during the first trimester of pregnancy.
Specifically, the drug may cause either or both cleft lip (a gap in the upper lip) and cleft palate (a gap the roof of the mouth) in babies.
The new FDA information is based on preliminary data...
| DO NOT DISCONTINUE ANY SEIZURE MEDICATION WITHOUT FIRST CONSULTING THE PRESCRIBER |
On September 29, the Food and Drug Administration (FDA) announced that the seizure and depression drug lamotrigine (LAMICTAL) may cause birth defects when taken during the first trimester of pregnancy.
Specifically, the drug may cause either or both cleft lip (a gap in the upper lip) and cleft palate (a gap the roof of the mouth) in babies.
The new FDA information is based on preliminary data from the North American Antiepileptic Drug Pregnancy Registry (NAAED Pregnancy Registry). The complete text of the posting is available on the FDA’s Web site at http://www.fda.gov/cder/drug/InfoSheets/HCP/lamotrigineHCP.htm.
Staff from the NAAED Pregnancy Registry presented their preliminary findings about lamotrigine and pregnancy at the Teratology Society’s annual meeting held from June 24 through June 29, 2006, in Tucson, Arizona. (Teratology is the study of birth defects.)
Of the 564 infants born to mothers who took lamotrigine in their first trimesters of pregnancy and delivered between 1997 and March 1, 2006, 15 infants — or 2.7 percent — had major malformations that were identified between birth and five days, NAAED Pregnancy Registry found. Three infants had cleft palate and two others had cleft lip.
Drug maker acknowledges defects
The National Electronic Library for Medicines (NeLM), the drug information portal for the single payer health insurance system in the UK, reported that lamotrigine-manufactured GlaxoSmithKline issued a letter to health care professionals on June 19 telling them about the birth defects related to the use of lamotrigine during pregnancy. (The NeLM report can be found online at http://www.druginfozone.nhs.uk/Record%20Viewing/viewRecord.aspx?id=566800.)
The GlaxoSmithKline letter made the following statements:
- An increased risk of oral clefts associated with the use of lamotrigine during early pregnancy has recently been detected in one pregnancy registry.
- The product information for lamotrigine will be updated with this new information.
- Lamotrigine should not be used in pregnancy unless, in the opinion of the physician, the potential benefits of treatment to the mother outweigh any possible risks to the developing fetus.
- Sudden discontinuation of antiepileptic therapy may lead to breakthrough seizures with serious consequences for both the mother and the fetus and should be avoided.
FDA refrains from judgment
The FDA has not yet reached a final conclusion about the significance of the reports of birth defects.
The agency approved lamotrigine for marketing in the United States in December 1994. In 2005, more than 4.4 million prescriptions were dispensed for the drug — 29 percent more than in 2004. Retail sales for lamotrigine topped $1 billion last year.
The FDA’s professional product labeling (also known as a package insert) for lamotrigine states that “[n]o evidence of teratogenicity [birth defects] was found in mice, rats or rabbits when lamotrigine was orally administered to pregnant animals during the period of organogenesis [organ development].” However, the professional label goes on to say, “[b]ecause animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.”
The professional label also encourages physicians and women to enroll in a pregnancy registry.
Other problems with lamotrigine
Patients taking lamotrigine may develop rashes which can result in hospitalization.
In patients younger than 16 years of age prescribed lamotrigine in addition to other drugs for seizure, the incidence of these rashes is approximately eight in 1,000. The incidence is lower in adult patients.
Because of the serious nature of the rashes associated with lamotrigine, the FDA has required that the drug’s professional product label display a black box warning. This type of warning is reserved for drugs that are known to cause serious injury or death. The full text of lamotrigine’s black box warning accompanies this article.
FDA BLACK BOX WARNING 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% (8 PER 1,000) IN PEDIATRIC PATIENTS (AGE <16 YEARS) RECEIVING LAMICTAL AS ADJUNCTIVE THERAPY FOR EPILEPSY AND 0.3% (3 PER 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% (0.8 PER 1,000) IN ADULT PATIENTS RECEIVING LAMICTAL AS INITIAL MONOTHERAPY AND 0.13% (1.3 PER 1,000) IN ADULT PATIENTS RECEIVING LAMICTAL AS ADJUNCTIVE THERAPY. IN A PROSPECTIVELY FOLLOWED COHORT OF 1,983 PEDIATRIC PATIENTS WITH EPILEPSY TAKING ADJUNCTIVE LAMICTAL, THERE WAS 1 RASH-RELATED DEATH. IN WORLDWIDE POSTMARKETING EXPERIENCE, RARE CASES OF TOXIC EPIDERMAL NECROLYSIS AND/OR RASH-RELATED DEATH HAVE BEEN REPORTED IN ADULT AND PEDIATRIC PATIENTS, BUT THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE ESTIMATE OF THE RATE. BECAUSE THE RATE OF SERIOUS RASH IS GREATER IN PEDIATRIC PATIENTS THAN IN ADULTS, IT BEARS EMPHASIS THAT LAMICTAL IS APPROVED ONLY FOR USE IN PEDIATRIC PATIENTS BELOW THE AGE OF 16 YEARS WHO HAVE SEIZURES ASSOCIATED WITH THE LENNOX-GASTAUT SYNDROME OR IN PATIENTS WITH PARTIAL SEIZURES. 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 VALPROATE (INCLUDES VALPROIC ACID AND DIVALPROEX SODIUM), (2) EXCEEDING THE RECOMMENDED INITIAL DOSE OF LAMICTAL, OR (3) EXCEEDING THE RECOMMENDED DOSE ESCALATION FOR LAMICTAL. HOWEVER, CASES HAVE BEEN REPORTED IN THE 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 SERIOUS OR LIFE THREATENING. ACCORDINGLY, LAMICTAL SHOULD ORDINARILY 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. |
What You Can Do
If you are taking lamotrigine and become pregnant, consult the prescribing physician immediately. DO NOT discontinue any seizure medication without first consulting the prescriber.
If you are taking lamotrigine and are considering becoming pregnant, discuss the information in this article from the NAAED Pregnancy Registry with your physician.
