Lamotrigine (marketed as Lamictal) is one of the new-generation antiepileptic drugs (AEDs) brought in as an alternative to the traditionally prescribed AEDs such as carba-mazepine, phenobarbitol, pheny-toin, primidone and valproate sodium. 

These newer agents, which also include felbamate, gabapentin, levetiracetam, topiramate and zonisamide, have been hailed as an effective treatment for epilepsy with fewer adverse effects and drug interactions than the older AEDs. In addition, they are supposed to be safer for women of childbearing age. 

But these claims may have to be changed in light of new preliminary information from the North American Antiepileptic Drug Pregnancy Registry (NAAED). The NAAED data, reported in a Food and Drug Administration (FDA) alert last month (http://www.fda.gov/cder/drug/ infopage/lamotrigine/default.htm), suggests that babies exposed to lamotrigine during the first trimester of pregnancy may have an increased chance of being born with a cleft lip or palate—where there is incomplete closure of the upper lip or roof of the mouth.

Oral clefts reported in the NAAED registry were few—five cases among 564 women: two with isolated cleft lip and three with isolated cleft palate. But this translates to a frequency of 8.9 per 1000 births—compared with 0.37 per 1000 in the registry’s reference population. The oral clefts reported were not part of a syndrome that included other birth defects.

The NAAED frequency of oral clefts is also higher than the prevalence of oral clefts among infants of non-epileptic mothers not taking lamotrigine in other studies carried out in the US, Australia and Europe. While these latter studies have differing results, the reported range was 0.50 to 2.16 per 1000 population. 

The NAAED findings show “a very significant risk of oral clefts among infants exposed in pregnancy to lamotrigine as monotherapy” (Birth Defects Res Part A: Clin Molec Teratol, 2006; 76: 318). However, according to the FDA, other pregnancy registries of a similar size have not come up with figures that support the NAAEDdata. 

Nevertheless, the NAAED preliminary results are hardly sur-prising. Although there are little data on the new-generation AEDs, virtually all antiepileptic drugs tested so far have been found to be teratogenic—that is, capable of causing malformations in an embryo or fetus (Birth Defects Res B Dev Reprod Toxicol, 2003; 68: 428–38).

Even GlaxoSmithKlein, the manufacturer of the drug, admits on the product label information that “lamotrigine decreases fetal folate [a B vitamin] concentrations in rats, an effect known to be associated with teratogenesis in animals and humans.”

And pregnant women are not the only ones who should be worried. Also included in the labelling is a black-box warning emphasizing that life-threatening rashes, includ-ing Stevens–Johnson syndrome—also known as ‘toxic epidermal necrolysis’, this is a severe immune-complex-mediated hypersensitivity syndrome affecting the skin and mucous membranes—have been reported with the use of lamot-rigine. Those under 16 years of age are most at risk, with serious rashes that require hospitalization and discontinuation of treatment occurring in eight out of every 1000 patients receiving this drug for epilepsy. In adults, the rate is only three per 1000 users affected by such an adverse effect. 

Other warnings noted on the drug’s label include multiple-organ failure (severe enough to cause death in some cases), blood abnormalities and potentially fatal hypersensitivity reactions. 

In addition, lamotrigine may actually make seizures worse. In a study of 21 infants with myoclonic epilepsy, the vast majority showed worsening of at least one type of seizure after receiving add-on therapy with lamotrigine. Even-tually, all but two of these infants discontinued the drug—and all but one of them improved on stopping the drug (Epilepsia, 1998; 39: 508–12).

Despite all the risks associated with lamotrigine, the drug continues to be prescribed for a broad spectrum of seizure types, including partial and generalized seizures. It is also approved as maintenance therapy for adults with bipolar I disorder.

Most recently, the drug received approval for treatment of primary generalized tonic-clonic seizures, one of the most serious types of seizure, which marks the fifth FDA approval for lamotrigine use in epilepsy.

As for the new NAAED data, the FDA says that it is “considering, but has not reached a final conclusion about, this information.”

Dangerous drug interactions

As well having side-effects on its own—including headache, dizziness, nausea, cold-like symptoms with runny noses or sore throats, infections, confusion, impaired memory, sleep disorders, non-specific body pain, disruption of menstrual cycles and life-threatening rashes—lamotrigine can interfere with other medications.

Patients taking lamotrigine should inform their healthcare professional

if they already take any of the following:

• oral contraceptives
• hormone replacement therapy (HRT)
• valproic acid (Depakene)
• divalproex (Depakote)
• carbamazepine (Tegretol)
• phenytonin (Dilantin)
• primidone (Mysoline)
• rifampin (Rifadin).

Joanna Evans