BUNDESGESETZBLATT FÜR DIE REPUBLIK ÖSTERREICH Jahrgang 2006 Ausgegeben am 19. Juli 2006 266. Verordnung: Veterinär-Arzneispezialitäten-Anwendungsverordnung 2006 266. Verordnung der Bundesministerin für Gesundheit und Frauen über die Anwendung von Veterinär-Arzneispezialitäten unter Einbindung des Tierhalters (Veterinär- Arzneispezialitäten-Anwendungsverord
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Epilepsyandpregnancy.co.ukTopiramate in pregnancyPreliminary experience from the UK Epilepsy and Pregnancy Register ABSTRACT
Objectives: Topiramate (Topamax®) is licensed to be used, either in monotherapy or as adjunctive
treatment, for generalized tonic clonic seizures or partial seizures with or without secondary generalization and for prevention of migraine. The safety of topiramate in human pregnancy is largely unknown. Here we report on our experience of pregnancies exposed to topiramate.
Methods: This study is part of a prospective, observational, registration and follow-up study.
Suitable cases are women with epilepsy who become pregnant while taking topiramate either singly or along with other antiepileptic drugs (AEDs), and who are referred before outcome of the pregnancy is known. The main outcome measure is the major congenital malformation (MCM) rate.
Secondary outcomes include risk of specific MCM, minor malformation rate, birthweight, andgestational age at delivery.
Results: Full outcome data are available on 203 pregnancies. Of these, 178 resulted in live birth;
reprint requests to Dr. JohnCraig, Department of Neurology, 16 had an MCM (9.0%; 95% CI 5.6% to 14.1%). Three MCMs were observed in 70 mono- therapy exposures (4.8%; 95% CI 1.7% to 13.3%) and 13 in cases exposed to topiramate as part of a polytherapy regimen (11.2%; 95% CI 6.7% to 18.2%). Four of the MCMs were oral clefts (2.2%; 95% CI 0.9% to 5.6%). Four cases of hypospadias were reported (5.1%; 95% CI0.2% to 10.1%) among 78 known live male births of which two were classified as major malfor-mations.
Conclusions: The number of outcomes of human pregnancies exposed to topiramate is low, but
the major congenital malformation rate for topiramate polytherapy raises some concerns. Overall,
the rate of oral clefts observed was 11 times the background rate. Although the present data
provide new information, they should be interpreted with caution due to the sample size and wide
confidence intervals. Neurology® 2008;71:272–276
AED ϭ antiepileptic drug; MCM ϭ major congenital malformation; SGA ϭ small for gestational age.
It is widely accepted that prenatal exposure to antiepileptic drugs (AEDs) increases the risk ofmajor congenital malformations (MCM) from the background risk of 1% to 2%1-3 to between4% and 9%.3-5 However, except for lamotrigine,5,6 levetiracetam,7 and oxcarbazepine,8 infor-mation is limited on the other newly available AEDs (vigabatrin, gabapentin, topiramate,tiagabine, pregabalin, and zonisamide).
Topiramate is licensed for use both in monotherapy and as adjunctive treatment for gener- alized tonic clonic seizures or partial seizures with or without secondary generalization. During2004 it was also licensed by the Food and Drug Administration for prophylaxis of migraine.
From the Department of Neurology (S.H., J.M., J.C.) and Bostock House (R.W., B.I.), Royal Group of Hospitals, Belfast; Department of ClinicalNeurophysiology (A.R.), Southern General Hospital, Glasgow; The Surgery (W.H.S.), Escrick, York; Department of Neurology (L.P.), St Albans CityHospital, Herts; Obstetrics and Gynaecology Department (I.R.), Lancashire Teaching Hospitals NHS Trust, Preston; and Department of MedicalGenetics (P.J.M.), Belfast City Hospital Trust, and School of Biological Sciences, University of Ulster, Coleraine, UK.
Disclosure: The study was made possible by a research grant from the Epilepsy Research Foundation and a number of unrestricted educational grantsfrom pharmaceutical companies (Glaxo-Smith-Kline, Sanofi-Aventis, UCB-Pharma, Janssen-Cilag, Pfizer, Eisai). An Internet-based Web site detailingthe aims of the UK Epilepsy and Pregnancy Register was made possible by a grant from Glaxo-Smith-Kline. Over the lifetime of the register, thesegrants have exceeded $10,000 from each company/grant awarding body. S.H., J.C., A.R., W.H.S., L.P., P.M., R.W., B.I., and J.M. have attendedmeetings with the support of various pharmaceutical companies, including Janssen-Cilag. J.C., L.P., P.M., and J.M. have given lectures at the bequestof pharmaceutical companies, including Janssen-Cilag, for which they have received honoraria. No individual has received personal compensation inexcess of $10,000. I.R. reports no conflicts of interest.
Copyright 2008 by AAN Enterprises, Inc.
Outcomes of pregnancies exposed to topiramate
Topiramate as part
Safety data for topiramate in human preg- monotherapy
of a polytherapy
nancy are limited. A company sponsored ab- No. of exposures
stract reported outcomes for 75 pregnancies exposed to topiramate.10 Of 29 monotherapy Live births
exposures two malformations (micrognathia, Spontaneous abortions
phimosis) were noted. Of the remaining 46 Induced abortions
pregnancies that had also been exposed to at Stillbirths
least one other AED seven infants had a mal- Mean dose TPM (range), mg
formation (cleft palate, cleft lip, tetralogy of Mean gestational age
Fallot, hand malformation, ureteral stenosis, at enrollment (range), wk
pyloric stenosis, and one infant with cleft lip Mean gestational age at delivery, wk
and palate, fixed extension of upper limb, bi- Mean birthweight, g
lateral radial deviation of hands, brachydac- METHODS The UK Epilepsy and Pregnancy Register is a
prospective pregnancy register set up to determine the relative Mode of delivery
safety of all AEDs taken in pregnancy. Here we report our resultsfor first-trimester exposures to topiramate, through August 31, Spontaneous vaginal deliveries
Suitable cases are women with epilepsy who became preg- nant while taking topiramate, either singly or along with other Ventouse
AEDs, and who were referred before the outcome of the preg-nancy was known. The main outcome measure was the MCM Abortions
rate. Cases where any prenatal test (fetal ultrasound, blood test) Not recorded
had shown an abnormality and cases resulting in a pregnancy Seizures in pregnancy
loss (induced abortion, spontaneous abortion, stillbirth) in Tonic-clonic ؎ other
which an abnormality had been identified before referral to theregister had been made were excluded.
A major seizure is defined as a tonic-clonic seizure. A minor or other seizure denotes seizures without convulsive activity.
Outcome data were collected at 3 months after the expected Major malformations [rate (95% CI)]
date of delivery by sending the patient’s general practitioner astandardized questionnaire for completion.
Any malformation [rate (95% CI)]
An MCM was defined as an abnormality of an essential em- bryonic structure requiring significant treatment and present atbirth or discovered during the first 6 weeks of life. Disorders notconforming to this definition were assigned as minor malforma- tions based on the definitions and lists of disorders in the EU- genic in mice, rats, and rabbits.9 In mice doses The MCM rate was calculated as [total number of live births with an MCM] ϩ [total number of pregnancy losses with an MCM] Ϭ [total number of live births] ϩ [total number of preg- Major congenital malformations with topiramate monotherapy
TPM ϭ topiramate; GTC ϭ generalized tonic– clonic seizure; NR ϭ not recorded.
Minor congenital malformations with topiramate monotherapy
TPM ϭ topiramate; GTC ϭ generalized tonic– clonic seizure; NR ϭ not recorded.
nancy losses with an MCM]. Spontaneous pregnancy losses and mate, 178 (87.7%) resulted in a live birth. Of these, 31 induced abortions where no abnormalities were reported were pregnancies had an abnormality of some kind (17.4%; not included for analysis as we do not know if they were exam- 95% CI 12.5% to 23.7%) with 16 of these being an ined in detail and therefore cannot know the outcome. The total MCM (9.0%; 95% CI 5.6% to 14.1%). Four MCMs numbers presented for each group are therefore either the totalnumber of outcomes or the total number of informative out- were oral clefts (2.2%; 95% CI 0.9% to 5.6%) with comes—that is, excluding pregnancy losses with no abnormali- three infants having both cleft lip and cleft palate. Four ties reported. Full details on study methodology have been cases of hypospadias were reported (5.1%; 95% CI 0.2% to 10.1%) among 78 known live male births of RESULTS Through August 31, 2007, complete
which two were classified as major malformations. Full outcome data were available on 203 prospectively re- details on major and minor malformations are shown in ported pregnancies that had had first trimester expo- sure to topiramate, of which 70 had been exposed to For the three infants who had an MCM and who were exposed to topiramate in monotherapy the av- Pregnancy outcome details for all exposures are erage total daily dose was 400 mg of topiramate com- shown in table 1. Of all pregnancies exposed to topira- pared to 238 mg in those without an MCM (p ϭ Major congenital malformations with topiramate polytherapy
GTC seizure in
TPM ϭ topiramate; AED ϭ antiepileptic drug; GTC ϭ generalized tonic– clonic seizure; NR ϭ not recorded; JME ϭ juvenile myoclonic epilepsy.
Minor congenital malformations with topiramate polytherapy
retard 1,400;clobazam 10;levetiracetam 2,500 TPM ϭ topiramate; AED ϭ antiepileptic drug; GTC ϭ generalized tonic– clonic seizure; NR ϭ not recorded.
0.123). Of the 61 cases exposed to topiramate in (260 mg, p ϭ 0.019). We have no data on maternal monotherapy for which there was information about gestational age, six infants (9.8%) were born at 37 Co-administration of valproate with topiramate weeks gestation or less. The average total daily dose either as part of a duotherapy regimen (n ϭ 12, for those born prematurely (250 mg) was not signifi- MCM rate 36.4%; 95% CI 15.2 to 64.6%) or as part cantly different from those born after 37 weeks (246 of a regimen of three or more AEDs (n ϭ 23, MCM mg (p ϭ 0.934). Of the 56 monotherapy outcomes rate 23.8%; 95% CI 10.6 to 45.1%) was associated for which there were full data on gestational age and with the highest rates of MCM. This compared with birthweight, 8 (14.3%) were small for gestational age a lower rate of MCM for exposures not including (SGA). The mean total daily dose for those who were valproate (n ϭ 110, MCM rate 8.4%; 95% CI 4.3% SGA (346 mg) was not significantly different from those who were not SGA (239 mg, p ϭ 0.084).
For polytherapy outcomes 32 combinations of at DISCUSSION The MCM rate for monotherapy ex-
least one AED in addition to topiramate were re- posures to topiramate was well within the range corded. Thirteen infants born with a major malfor- quoted for other AEDs.5 For polytherapy exposures mation were exposed on average to 342 mg per day the MCM rate was higher, consistent with previous of topiramate compared with 294 mg per day for live reports comparing monotherapy and polytherapy ex- births without an MCM (p ϭ 0.539). Of the 111 posures to all AEDs.3-5 The MCM rates for combina- cases exposed to topiramate as part of a polytherapyregimen, for which there was information on gesta- tions containing valproate in addition to topiramate tional age, 17 infants (15.3%) were born at 37 weeks were higher than for combinations not containing or less gestation. The mean total daily dose for those valproate. While it is not clear if this is a consequence born prematurely (347 mg) was not significantly dif- of an interaction between these drugs, is a reflection ferent from those born after 37 weeks (288 mg, p ϭ of unidentified patient characteristics, or is due to 0.891). Of 103 live births exposed to topiramate as valproate, which has increasingly been shown to be part of a polytherapy regimen and for which there associated with a high risk of MCMs, either in were data regarding birthweight and gestational age, monotherapy or as part of a polytherapy regimen,5,12 20 infants (19.4%) were SGA. The mean total daily is unclear. Clearly these results need to be replicated dose for those infants who were SGA (405 mg) was in larger numbers and from different registers before significantly different from those who were not SGA we might counsel women of child-bearing age against using combinations including topiramate Received November 19, 2007. Accepted in final form April 2, All of the MCMs observed have already been de- REFERENCES
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Quality Interchange Program January 2007 Prior Authorization or Step Therapy may be necessary for coverage of certain medications for BCN’s Commercial members. Clinical criteria, based on current medical information as approved by the BCBSM/BCN Pharmacy and Therapeutics Committee must be met, or other information must be provided, before coverage is approved for these drugs. Drugs subjec