LAMOTRIGINE

Drugs in Pregnancy and Lactation

Name: LAMOTRIGINE
Class: Anticonvulsant Risk Factor: CM

Fetal Risk Summary

Breast Feeding Summary
References

Fetal Risk Summary

Lamotrigine is an anticonvulsant, chemically unrelated to existing antiepileptic drugs, that is used as adjunctive therapy for the treatment of partial seizures in patients
with epilepsy (1).

Lamotrigine was not teratogenic in animal reproductive studies involving mice, rats, and rabbits using oral doses that were 1.2, 0.5, and 1.1 times, respectively, the
highest usual human maintenance dose (500 mg/day) on a mg/m2 basis (HUHMD) (1). Secondary fetal toxicity consisting of reduced fetal weight or delayed
ossification, however, was observed at these doses in mice and rats, but not in rabbits. Behavioral teratogenicity was observed in the offspring of rats dosed with 0.1
and 0.5 times the HUHMD during organogenesis. No teratogenic effects were observed after IV bolus doses in the above animals, but an increased incidence of
intrauterine fetal death occurred in rats dosed at 0.6 times the HUHMD (1). Similarly, an increase in fetal deaths occurred in rats dosed orally at 0.1, 0.14, or 0.3 times
the HUHMD during the latter part of gestation (15–20 days). Postnatal deaths were also observed with the two highest doses.

Lamotrigine reduces fetal folate levels in rats, an effect known to be associated with malformations in animals and humans (1). Human fetal folate levels have
apparently not been investigated, but in studies with nonpregnant humans, the drug's weak inhibitory action of dihydrofolate reductase did not produce a significant
reduction in folate levels (2). Serum folate and red blood cell folate concentrations were within the 95% confidence interval (CI) of the baseline values.

Lamotrigine crosses the human placenta (3,4). A 24-year-old woman had been treated before and throughout gestation with the anticonvulsant (300 mg/day) in
combination with valproic acid (3). The latter drug was discontinued during the 3rd week of pregnancy. Her lamotrigine serum levels decreased from 17.8 µg/mL (2
weeks after her last dose of valproic acid) to 2.52 µg/mL at week 34, but she remained seizure-free throughout pregnancy. She delivered a healthy, 3620-g male infant
at 39 weeks' gestation. The umbilical cord blood lamotrigine concentration was 3.26 µg/mL, indicating a probable cord:maternal serum ratio of 1 (maternal serum level
at delivery not reported). On the second day after delivery and a few hours after commencing suckling, the serum concentrations in the infant and mother were 2.79
and 3.88 µg/mL, respectively, a ratio of 0.7.

In a 2000 report, maternal and cord plasma concentrations of lamotrigine were determined at term delivery in nine women (10 pregnancies; one woman with two
pregnancies also reported in reference 3) (4). Maternal and cord plasma levels were similar. At 72 hours postpartum, median lamotrigine levels in the infants were 75%
of the cord plasma levels (range 50%–100%). The placental transfer is consistent with the low molecular weight (about 256). Moreover, during the first 2 weeks after
delivery, the median increase in maternal plasma concentration/dose ratio was 170%, a significant increase (4).

An interim report of the Lamotrigine Pregnancy Registry, an ongoing project conducted by the manufacturer, was issued in 2000 (5). The data contained in the report
covered pregnancy exposures to the anticonvulsant from 1 September 1992 through 31 March 2000. A total of 362 prospective pregnancies (reported before the
pregnancy outcome was known) have been enrolled in the Registry. Of these, 66 outcomes are pending and 52 have been lost to follow-up. Outcomes are known for
244 pregnancies (248 outcomes; 1 set of triplets and 2 sets of twins). The earliest exposure to lamotrigine occurred in the 1st trimester in 235 pregnancies (237
outcomes, 2 sets of twins), 3 in the 2nd trimester, 2 in the 3rd trimester, and 4 with an unspecified time of earliest exposure (6 outcomes, 1 set of triplets). Lamotrigine
monotherapy was used in 98 outcomes with earliest exposure in the 1st trimester, 2 outcomes with earliest exposure in the 2nd trimester, and 5 outcomes (1 set of
triplets) with unspecified exposure timing. For 1st trimester exposures, the outcomes were 9 spontaneous pregnancy losses (<20 weeks' gestation), 27 elective
abortions (2 with birth defects), 1 fetal death (³20 weeks'), 14 live infants with birth defects, and 186 live infants without birth defects (includes 2 sets of twins). When the
earliest exposure was in the 2nd or 3rd trimesters, or the exposure timing was unspecified, the outcomes were three, two, and six live born infants, respectively, without
birth defects (5).

Lamotrigine Monotherapy—1st trimester exposure

Esophageal malformation—surgically repaired;
Cleft soft palate;
Right club foot

Lamotrigine + Other Anticonvulsants—1st trimester exposure

(other anticonvulsants shown in parentheses)
One extra digit on one hand (carbamazepine);
Bilateral talipes (valproic acid);
Cardiac murmur and patent foramen ovale, died following corrective surgery at 3 months (phenytoin and primidone);
Skin tags on left ear, no opening to ear canal on right ear, (gabapentin);
Lumbar neural tube defect, early evidence of ventriculomegaly, derangement of the posterior fossa, induced abortion (clobazam);
Hydrocephalus, sacral spina bifida (myelomeningocele), patent foramen ovale and ductus arteriosus, ultrasound suggested Arnold-Chiari malformation, induced
abortion (valproate);
Facial asymmetry, especially of the mandible, resulting in feeding difficulty (valproate);
Cleft palate, hypertelorism, broad nasal bridge, low set and posteriorly rotated ears, down-turned mouth, bilateral transverse palmar creases, short proximal
thumbs, and supra-umbilical hernia (valproate);
Wide set eyes, no epicanthic folds, infra creases, broad nose, large mouth, bilateral undescended testes, right facial palsy, persistent patent ductus arteriosus,
mother had gestational diabetes (valproate);
Persistent patent ductus arteriosus, atrium septum defect (oxcarbamazepine);
Atrial septal defect (valproate);
Light facial dysmorphy: no philtrum, syndactyly 2nd and 3rd toes bilateral (valproate);
Pulmonary stenosis, attempted surgical repair, baby died (valproate)

Retrospective cases (reported after the pregnancy outcome was known) are often biased (only adverse outcomes are reported), but they are useful in identifying
specific patterns of anomalies and can identify early signals of new drug risks (5). A total of 44 infants with congenital malformations or other adverse effects were
reported retrospectively, 14 involved lamotrigine monotherapy and 30 were exposed to lamotrigine and other anticonvulsants. The earliest exposure to lamotrigine was
in the 1st trimester in 41 cases and was not specified in 3 cases (see reference for descriptions of the specific defects) (5). (See required statement below.)

The FDA has received three disparate reports of birth defects in which lamotrigine, in combination with other anticonvulsants, was used during the affected pregnancy
(F. Rosa, personal communication, FDA, 1996).

A 1998 non-interventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed
drugs by general practitioners in England (6). Data were obtained by questionnaires sent to the prescribing physicians one month after the expected or possible date of
delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester with birth defects noted in 14 (2.5%)
singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were
examined. Lamotrigine was taken during the 1st trimester in 59 pregnancies. The outcomes of these pregnancies included 10 spontaneous abortions, 1 missed
abortion, 9 elective abortions, 35 normal newborns (4 premature), and 4 newborns with congenital malformations (6). The malformations observed were: ventricular
septal defect; congenital respiratory stridor; palatal cleft (soft palate only), hypospadiasis, undescended testes (mother had convulsions early in gestation); abdominal
distension with possible congenital intestinal obstruction. In three of these cases, lamotrigine was given in various combinations with other anticonvulsants (e.g.,
carbamazepine, phenytoin, phenobarbital, and/or sodium valproate). In addition, the study lacked the sensitivity to identify minor anomalies because of the absence of
standardized examinations. Late appearing major defects may also have been missed due to the timing of the questionnaires (6).

In summary, the animal and human data do not appear to indicate a major risk for congenital malformations or fetal loss following 1st trimester exposure to lamotrigine.
At least two reviews have concluded that this anticonvulsant may be associated with a lower risk of teratogenicity (7,8). In general, women with epilepsy have a higher
risk of delivering an infant with a malformation than those who do not have this condition. In some cases, the cause of a defect is most likely the anticonvulsant, but
based on the small number of diverse anomalies described above, there does not appear to be a pattern suggesting that lamotrigine is a significant human teratogen
(5). More data are needed, however, to confirm or refute this initial assessment.

Required statement: The number of exposed pregnancy outcomes accumulated to date represent a sample of insufficient size for reaching definitive conclusions
regarding the possible teratogenic risk of lamotrigine. To date, the sample size (N=202—first trimester exposures excluding spontaneous loss, induced abortions, and
fetal loss not involving defects) remains too small for formal comparisons of the frequency of all birth defects or specific birth defects or to make conclusions about
specific subgroups. If the baseline risk of total defects in women with epilepsy is 3–5%, then sample sizes needed to detect a twofold risk with 80% power range
between 200 and 342. If the baseline risk of a specific birth defect is 1/1000, the sample size needed to detect a 10-fold risk with 80% power is 418. The Committee
has recognized an apparent disproportionate frequency of birth defects identified for pregnancies exposed to the combination of lamotrigine and valproate. The
Committee cannot make any recommendations about the use of lamotrigine and valproate in combination at this time. However, the Committee will continue to monitor
this occurrence as well as investigate other sources of data on birth defects and valproate therapy alone or in combination with lamotrigine to determine if the apparent
pattern is replicated. Comparison of risk of birth defects in the Lamotrigine Pregnancy Registry to risk observed in the general population could overestimate risk
related to lamotrigine use because of 1) known elevated risk due to other antiepileptic drugs also used by women in this registry and 2) elevated risk related to maternal
epilepsy.

Breast Feeding Summary

Lamotrigine is excreted into breast milk (1,3,4). A 24-year-old mother had been treated throughout gestation with lamotrigine (see details above) and on the second day
following delivery, she began nursing her infant (3). At this time she was taking 300 mg/day, decreased to 200 mg/day approximately 6 weeks postpartum to lessen the
drug exposure of the infant. From day 2 to day 145 after delivery, 11 maternal serum and 9 milk samples (about 2–3 hours after the morning dose) were drawn, with
lamotrigine serum concentrations ranging from 3.59 to 9.61 µg/mL and milk levels ranging from 1.26 to 6.51 µg/mL. The mean milk:serum ratio was 0.56 with a high
correlation (r=0.959, p<0.01) between the serum and milk (3). The infant's serum levels (about 1–2 hours after breast feeding), determined at the same times as the
mother's, ranged from <0.2 µg/mL (during weaning) to 2.79 µg/mL. No adverse effects were observed in the nursing infant either during breast feeding or during
weaning.

In a 2000 report, nine women (10 pregnancies, one woman with two pregnancies also reported in reference #3) received lamotrigine throughout gestation (see Fetal
Risk Summary above) and continued the drug during breast feeding (4). The median milk:maternal plasma ratio 2–3 weeks after delivery was 0.61 (range 0.47–0.77).
The lamotrigine plasma concentrations in the infants were approximately 30% (range 23%–50%) of the corresponding maternal plasma levels. The estimated infant
lamotrigine dose was ³0.2–1 mg/kg/day, assuming a milk intake of 150 mL/kg/day, about 9% of the weight-adjusted maternal daily dose. Because of the slow
elimination in the infant (most likely due to reduced hepatic glucuronidation capacity), the marked increase in maternal plasma lamotrigine concentrations that occurred
after birth (see Fetal Risk Summary above), and the fact that infant drug levels may not have reached steady-state concentrations, the infant exposure could eventually
result in therapeutic plasma lamotrigine levels (4). No adverse effects in the nursing infants were observed.

As with any drug, a mother who must take lamotrigine to control her disease and who chooses to nurse her infant should carefully monitor the infant for adverse
effects. Some anticonvulsants have produced adverse effects in nursing infants (e.g., see Phenobarbital and Primidone), whereas others are considered compatible
with breast feeding (e.g., see Carbamazepine, Phenytoin, and Valproic Acid). Although no adverse effects have been seen in nursing infants of mothers taking
lamotrigine, the number of known cases are too small adequately assess the safety of this drug during lactation. Monitoring infant serum levels of lamotrigine may be
required.

References

1. Product information. Lamictal. Glaxo Wellcome, 1997.

2. Betts T, Goodwin G, Withers RM, Yuen AWC. Human safety of lamotrigine. Epilepsia 1991;32(Suppl 2):S17–S21.
3. Rambeck B, Kurlemann G, Stodieck SRG, May TW, Jurgens U. Concentrations of lamotrigine in a mother on lamotrigine treatment and her newborn child. Eur J Clin Pharmacol 1997;51:481–4.
4. Ohman I, Vitols S, Tomson T. Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia 2000;41:709–13.
5. Lamotrigine Pregnancy Registry. Interim Report. 1 September 1992 through 31 March 2000. Glaxo Wellcome, July 2000.
6. Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol
1998;105:882–9.
7. Dichter MA, Brodie MJ. New antiepileptic drugs. N Engl J Med 1996;334:1583–90.
8. Morrell MJ. The new antiepileptic drugs and women: efficacy, reproductive health, pregnancy, and fetal outcome. Epilepsia 1996;37(Suppl 6):S34–S44.

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