The risk of oral clefts

June 15^th, 2006

Dear Health Care Professional:

GlaxoSmithKline (GSK) would like to inform you about important new safety information regarding lamotrigine [Lamictal®].

-An increased risk or oral clefts associated with the use of lamotrigine [Lamictal®] during early pregnancy has recently been detected in one pregnancy registry.

.The product information for lamotrigine [Lamictal®] will be updated with this new information-

- The possible risk of oral clefts should be balanced against the needs for treatment. Sudden discontinuation of antiepileptic therapy may lead to breakthrough seizures with serious consequences for both mother and the foetus and should be avoided.

Background:

Emerging data from the North American Antiepileptic Drug (NAAED) pregnancy Registry suggests an association between Lamotrigine [Lamictal®] and an increased risk on non-syndromic oral clefts. Specifically, the NAAED Pregnancy Registry detected an elevated incidence of isolated, non syndromic cleft palate deformity occurring in infants exposed to lamotrigine monotherapy during the first trimester of pregnancy compared to the reference population used in this Registry. Recently published data from the Registry report three cases of isolated, non syndromic cleft palate and two cases of isolated , non syndromic cleft lip without cleft palate in infants form 564 first trimester lamotrigine monotherapy exposures giving a rate of 8.9 per 1000. This compares with a prevalence rate of 0.37 per 1000 seen in the general population of the Brigham and Women's Hospital (BWH) Surveillance Program ( relative risk in lamotrigine-treated patients vs. BWH general population of 24;95% Cl 10.0-57.4). For reference, the overall rate of major malformations reported by the NAAED registry was 15/564 (2.7% , 27 per 1000)   and not different from the reference population

The prevalence of oral clefts noted in the NAAED registry is also higher than the background prevalence of  non-syndromic oral clefts reported in the literature , including studies from the United States, Australia and Europe. While different studies have differing results due to geographic and case ascertainment variation, the reported range is 0.50 to  to 2.16/1000.

Whereas this finding has not been confirmed by other studies, GlaxoSmithKline (GSK) is in discussion with regulatory authorities around the world about these newly reported data and other relevant information, including outcomes in over 2000 pregnancies from other pregnancy registries , to further understand the significance of this finding. (GSK) is working wit the local regulatory agency of the Ministry of Health to update the prescribing information to reflect these new data.

Lamictal ® [Lamotrigine] prescribing information:

The above information has been communicated to the Regulatory Department of the Saudi Ministry of Health. Changes to the prescribing information will follow soon.

Kindly find below the change in the wording in the Pregnancy Section of the Insert Leaflet.

Previous wording:

Postmarketing data from several prospective pregnancy registries have documented outcomes in over 1000 women exposed to lamotrigine montherapy during the first trimester of pregnancy. The data do not suggest an increased risk o f major birth defects compared to the general population. The data on use of lamotrigine in polytherapy combination are insufficient to assess whether the risk of malformation associated with other agents is affected by concomitant lamotrigine use.

New wording:

Postmarketing data from several prospective pregnancy registries have documented outcomes in over 2000 women exposed to lamotrigine monotherapy during the first trimester of pregnancy. Whilst the data provide no evidence for a substantial increase in the overall risk of major birth malformations associated with lamotrigine use, one registry has reported an increase in the risk of isolated oral cleft malformations. This increased risk has not been confirmed in a pooled analysis of the data from six other registries. The data on use of lamotrigine in polytherapy combinations are insufficient to assess whether the risk of malformation associated with other agents is affected by concomitant lamotrigine use.