Re: Lamictal
From: art fougner, md (evsono@pipeline.com)
Wed May 10 13:15:33 2006
Lynn
are you not concerned that increased folate might interact adversely
with the drug? just asking ...
art
At Wed, 10 May 2006, Lynn Montgomery, MD wrote:
>
>Charlie,
>I have confronted this issue here for about four years, in that the primary
>neurologist here uses Lamictal exclusively. I am seeing more of it in the
>realm of neuropsychiatric therapy as well. There has been limited data on
>humans. The pharmaceutical company has a registry, but I called them and
>they told me their outcome data was confidential...
>
>It has effects on folate similar to any of the other anti-epileptic
>medications, therefore it would have the theoretical risk of increasing the
>risk of neural tube defects. As such, if one has the luxury of seeing the
>patient prior to conception, I recommend they take folate 4 mg while trying
>to conceive and at least during the first trimester. With the other
>anti-epileptic medications, European studies have shown a very low risk of
>spinal abnormalities with folate treatment.
>
>Below is the Reprotox summary on Lamictal:
>
>Agent Detail - LAMOTRIGINE Print this document
><http://www.reprotox.org/images/print_icon.gif> Print this summary
><http://www.reprotox.org/Members/PrintAgentDetail.aspx?a=3902>
>
>Agent #: 3902 CAS #: 84057-84-1
>Last Updated: 04/2006 Cross-references: LAMICTAL (84057-84-1)
>Agent Summary
>Quick take: Experimental animal studies have raised the concern that
>lamotrigine therapy might interfere with embryo development. An increase in
>oral clefts has been suspected based on results from pregnancy registries.
>
>* * *
>
>Lamotrigine (Lamictal) is a phenyltriazine anticonvulsant marketed as
>adjunctive therapy for partial epilepsy in adults. The manufacturer
>(GlaxoSmithKline, Research Triangle Park NC) reported teratology testing in
>mice, rats, and rabbits. There was no increase in congenital malformations
>in any of these species. Top doses were 1.3 (mice), 0.5 (rats), and 1.1
>(rabbits) times the maintenance dose recommended for humans on a mg/m2
>basis. Maternal toxicity and fetal toxicity (delayed ossification and
>decreased weight) were seen at these top doses in the rodent studies. Fetal
>death was increased in rats given intravenous lamotrigine at 0.6 times the
>human dose on a mg/m2 basis. We estimate that this dose would be about 3
>times the human maintenance dose on a mg/kg basis.
>
>A high dose study in rats has reported finding that lamotrigine exposure
>during organogenesis reduced fetal body weights and altered brain structure
>(7). Alterations in rat behavior (open field testing) were shown after
>antenatal exposures to as little as 5 mg/kg/d (maternal dose), about 60% of
>the recommended human maintenance dose on a mg/kg basis. Perinatal
>administration of lamotrigine in rats also showed an increase in stillbirth
>and pup death at maternally toxic doses, although the manufacturer states
>that some of these deaths appeared to be drug related rather than related to
>maternal illness. Lamotrigine did not interfere with fertility in male or
>female rats given 2.4 times the human maintenance dose on a mg/kg basis (0.4
>times the human dose on a mg/m2 basis).
>
>Lamotrigine is an inhibitor of dihydrofolate reductase and decreases
>embryonic folate levels in experimental animals (manufacturer data). Other
>antifolate medications have been associated with an increase in congenital
>abnormalities in experimental animals and in humans. This property plus the
>results of the animal experiments performed by the manufacturer raise the
>concern that human developmental toxicity will be increased by
>clinically-used doses of lamotrigine; however, we have not located published
>human data with which to evaluate this possibility.
>
>Case reports are available on a small number of successful pregnancies that
>have included exposure to lamotrigine (6). The manufacturer has set up a
>registry to collect information on pregnant women exposed to this agent
>(1,3). A report from this registry extending through September 2005 included
>outcomes for 707 pregnancies with first trimester exposure to the
>lamotrigine monotherapy. Of these pregnancies, 20 children had congenital
>malformations, for a rate of 2.8% (2). Among the defects reported were cleft
>palate, club foot, hydronephrosis with megaureter, anencephaly, anal
>atresis, cardiac defects, and an esophageal malformation. The background
>rate of congenital malformations is typically cited as 3 to 5%. For more
>information or to enroll a patient in the Registry, call 800-336-2176 or
>910-256-0549 (call collect). An Australian registry identified 68 women with
>first trimester exposure to lamotrigine, in combinations with other
>anti-epileptic drugs (9). Among the exposed offspring, there were three
>infants with defects including bone abnormalities of the face and skull and
>hypospadias (9). The AED Pregnancy Registry, based at the Massachusetts
>General Hospital, reported on 564 women who used lamotrigine monotherapy
>during the first trimester of pregnancy (10). There were 15 babies with
>malformations identified in the first 5 days of life, 5 of whom had oral
>clefts. Using a comparison group of unexposed children, the risk ratio for
>malformations was 1.7 (95% CI 1.0-2.7), the risk ratio for isolated cleft
>palate was 32.8 (95% CI 10.6-101.3), and the risk ratio for isolated cleft
>lip was 17.1 (95% CI 4.3-68.2).
>
>In studies involving 12 infants whose mothers were taking lamotrigine, the
>placental transfer of this agent close to term was demonstrated and its
>excretion in breast milk has been characterized (4,5,8). The median
>milk/maternal plasma concentration ratio was 0.61 (range, 0.47-0.77) 2-3
>weeks after delivery, and the nursed infants maintained plasma
>concentrations of approximately 30% (median, range 23-50%) of the mother's
>plasma levels (8). Lamotrigine was excreted in considerable amounts in
>breast milk (the dose to the infant was estimated to >/=0.2-1 mg/kg/day 2-3
>weeks postpartum), which in combination with a slow elimination in the
>infants, resulted in lamotrigine plasma concentrations comparable to those
>reported during active lamotrigine therapy (4,5,8). No adverse effects were
>seen in any of the infants.
>
>Lynn
>
> _____
>
>From: ob-gyn-l@obgyn.net [mailto:ob-gyn-l@obgyn.net] On Behalf Of Charlie
>Chambers
>Sent: Wednesday, May 10, 2006 10:48 AM
>To: Multiple recipients of list OB-GYN-L
>Subject: Lamictal
>
>Anyone have any experience with Lamictal and first trimester of pregnancy.
>Have a patient considering pregnancy. Most of the other mood stabilizers
>would be adverse. Thanks
>
>*************************************************************************
>Charlie Chambers
>
>--
>*************************************************************************
>Hood River, OR
>cchamber@alumni.rice.edu
>
>"No matter where you go...
>there you are."
>Dr. Buckaroo Banzai
>************************************************************************
>
>************************************************************************
>
--
art fougner, md
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