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CONFIDENTIAL HM2007/00486/00

UPDATE OF FINDINGS ON IN UTERO EXPOSURE TO LAMOTRIGINE MONOTHERAPY AND MAJOR BIRTH DEFECTS IN ANTI-EPILEPTIC DRUG PREGNANCY REGISTRIES AND THE

EUROPEAN NETWORK OF CONGENITAL ANOMOLIES AND TWINS (EUROCAT) REGISTRY NETWORK

Authors: Manager, NeuroSciences

WW Epidemiology

September 2007


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TABLE OF CONTENTS

PageEXECUTIVE SUMMARY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

1. BACKGROUND. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2. EUROCAT CASE CONTROL STUDY OF LAMOTRIGINE AND ORALCLEFTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52.1. Aims . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52.2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

2.2.1. Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52.2.2. Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52.2.3. Outcome Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52.2.4. Exposure Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62.2.5. Covariate Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62.2.6. Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72.2.7. Validation Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

2.3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72.3.1. Oral Cleft Case Control Study . . . . . . . . . . . . . . . . . . . . . . . . . 72.3.2. Validation Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

2.4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102.5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

3. UPDATE ON FINDINGS ON IN UTERO EXPOSURE TO LAMOTRIGINEMONOTHERAPY IN ANTI-EPILEPTIC DRUG PREGNANCYREGISTRIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113.1. International Lamotrigine Pregnancy Registry . . . . . . . . . . . . . . . . . . 143.2. UK Epilepsy and Pregnancy Registry . . . . . . . . . . . . . . . . . . . . . . . . 143.3. EURAP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153.4. NAAED . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153.5. Swedish Medical Birth Register and Danish Multi-Centre Registry . . 15

4. CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

5. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

APPENDIX 1: Protocol WEUKSTV2169/EPI40486 EUROCAT case controlstudy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

APPENDIX 2: Summary Data received from the registries . . . . . . . . . . . . . . . 31


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EXECUTIVE SUMMARY

This report is provided to update regulatory agencies on the latest data available to GlaxoSmithKline on exposure to lamotrigine in pregnancy.

Risk of Non Syndromic Oral Clefts

• A modified case control study, using malformed controls, conducted on data from the European Network for Congenital Anomalies and Twins (EUROCAT) registries recently reported and found no signal of an increased risk of non-syndromic oral clefts associated with in utero exposure to lamotrigine monotherapy.

• The EUROCAT study was conducted to test the hypothesis related to an increased risk of non-syndromic oral clefts which was generated through the North American Anti-Epileptic Drug (NAAED) and the Swedish pregnancy registries. This signal was previously reported to regulatory agencies.

• GSK will continue to monitor for trends around isolated oral clefts in ongoing pregnancy registries.

Risk of Anencephaly

• A signal for increased risk of anencephaly following first trimester lamotrigine monotherapy exposure in the International Lamotrigine Pregnancy Registry was previously reported to regulatory agencies.

• No other cases of anencephaly have been reported to other registries.

Risk of All Major Birth Defects

• There is growing consistency across pregnancy registries concerning the overall risk of all major birth defects associated with first trimester lamotrigine monotherapy exposure (2.6% in the International Lamotrigine Registry, 2.6% in the North American Anti-Epileptic Drug (NAAED), 2.7% in the UK Epilepsy and Pregnancy Registry).

• Higher risks reported from the International Registry for Anti-epileptic drugs in Pregnancy (EURAP) (4.0%) and the Swedish Medical Birth Register (4.0%) will reflect the inclusion of chromosomal and minor birth defects as well as longer infant follow up in the case of EURAP.

• The International Lamotrigine Pregnancy Registry and UK Epilepsy and Pregnancy Register have both passed the milestone of 1000 first trimester monotherapy exposures and have therefore met their primary objective to rule out a signal for a substantial increase in the risk of all birth defects associated with lamotrigine.


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1. BACKGROUND

In January and March, 2006, GlaxoSmithKline (GSK) provided information on the use of lamotrigine and congenital malformations to regulatory agencies. This information was related to data emerging from the North American Anti-Epileptic Drug (NAAED) Registry concerning a signal for an increased risk of non syndromic oral clefts in women who had taken lamotrigine monotherapy during the first trimester of pregnancy. NAAED reported three cases of isolated, non syndromic cleft palate and two cases of isolated, non syndromic cleft lip among 564 first trimester cases. This gave a risk of 8.9 per 1000 which compared to 0.65 per 1000 for all non syndromic clefts seen in the general population of the Brigham and Women’s Hospital (BWH) Surveillance Program utilised as a comparison group by NAAED [Holmes, 2006]. The prevalence of non syndromic oral clefts reported in the literature ranges from 0.5 to 2.2 per 1000 [Tolarova, 1998; Das, 1995; Croen, 1998; Hashmi, 2005; DeRoo, 2003; Menegotto, 1991; Vallino-Napoli, 2004; Christensen, 1999; Bille, 2005; Kallen, 2003; Becker, 1998; Robert, 1996; Stoll, 2000; Teconi, 1998; Harville, 2005].

In response to this finding GSK revised the lamotrigine Global Data Sheet and issued a Dear Health Care Professional letter. In an effort to better understand these emerging data, GSK committed to actively monitor and to regularly report data from other Anti-Epileptic Drug (AED) pregnancy registries to regulatory agencies. The registries being monitored include the GSK International Lamotrigine pregnancy registry, the UK Epilepsy and Pregnancy Register, NAAED, the International (previously European) Registry of Antiepileptic drugs in Pregnancy (EURAP) and the Swedish Medical Birth Registry.

The first such report was provided in December, 2006. At this time the Swedish Medical Birth Registry reported three cases of non syndromic oral clefts (one cleft palate and two cleft lip with palate) among the 347 first trimester lamotrigine monotherapy exposures. This gave an absolute risk of 8.6/1000 which compared with a risk of 1.5/1000 in the general Swedish population giving a relative risk of 4.4 (two sided 95% CI 0.9 – 12.9)

PC; GlaxoSmithKline International Pregnancy Registry, 2007]. No signal was observed in the GSK International Lamotrigine pregnancy registry, the UK Epilepsy and Pregnancy Registry and EURAP with denominators ranging from 445 to 908 first trimester lamotrigine monotherapy exposures [GlaxoSmithKline International Pregnancy Registry, 2007; 2007; 2007].

GSK also committed to assess the feasibility of conducting a case control study specifically designed to test the hypothesis generated through the NAAED and Swedish registries. Given the rare nature of the oral cleft outcome and lamotrigine exposure, a dataset with a large population base was needed. The European Network of Congenital Anomoly and Twin (EUROCAT) registries, which surveys 1.5 million births a year, was identified as the optimal dataset to test this hypothesis. This report provides a summary of the latest data from ongoing AED pregnancy registries and the results of the EUROCAT case control study of lamotrigine and oral clefts.


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2. EUROCAT CASE CONTROL STUDY OF LAMOTRIGINE AND ORAL CLEFTS

This study was sponsored by GlaxoSmithKline and completed by the EUROCAT organisation. The principal investigators were Professor (principal investigator of EUROCAT), based at the UK, and Professor

based at the The Netherlands. The study protocol is provided in APPENDIX 1. A draft manuscript will be provided as soon as this becomes available.

2.1. Aims

The aim of the EUROCAT study was to investigate whether in utero exposure to lamotrigine monotherapy in the first trimester of pregnancy was associated with an increased risk of isolated orofacial clefts using a case control design.

2.2. Methods

2.2.1. Study Population

EUROCAT is a network of 40 congenital anomaly registries covering 20 countries and 1.5 million births per year (29% of births in the European Union and 19% of births in non European Union states). The standard database captures information on congenital birth defects reported from live births, stillbirths and terminations of pregnancies following prenatal diagnosis. In addition, details of maternal illness before and during pregnancy and medications taken during the first trimester of pregnancy are captured

2.2.2. Study Design

This was an observational case control study using malformed controls.

2.2.3. Outcome Definitions

Reports of orofacial clefts were identified from the birth defect registries using International Disease Classification (ICD)-9 and-10 codes. Reports were reviewed independently by three medical geneticists to identify three case groups: 1. Isolated, non-syndromic clefts

2. Non-syndromic clefts i.e. clefts occurring with other major defects but not assessed to be part of a syndrome. This category will contain isolated oral clefts. It was considered that excluding non isolated, but non syndromic clefts would lose potentially valuable information.

3. Isolated and all non-syndromic cleft palate as the original signal from NAAED indicated a higher risk of cleft palate than cleft lip.

Where there was disagreement between the independent medical geneticists in the classification of the cleft cases, open adjudication was employed to reach a decision.


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Since EUROCAT is a network of congenital birth defect registries, all data captured are from malformed infants/foetuses. Hence a modified case control approach was applied with two malformed control groups:

a. Non chromosomal, non oral cleft defects. Any oral cleft, whether or not syndromic, was excluded from this group.

b. All chromosomal defects, a group considered very unlikely to be related to drug.

Although control group a. could contain some birth defects associated with lamotrigine, the assumption was made that such defect risks would be diluted by the entire control group. Anti-epileptic drug pregnancy registry data have also failed to observe a strong signal for other specific defect types, hence it was considered that an excess of lamotrigine exposure in the case groups (see above as isolated or non-syndromic oral clefts and cleft palate) versus control group a. would represent an excess risk of oral clefts associated with lamotrigine [Holmes, 2006; GlaxoSmithKline International Pregnancy Registry, 1992; 2007; Morrow, 2006]. Cases and controls included live births, fetal deaths greater than 20 weeks gestation and terminations of pregnancy following prenatal diagnosis. Ten controls were matched per case to increase the analytical power of the study.

2.2.4. Exposure Definitions

The methods for reporting medication exposure data vary between the birth defect registries forming EUROCAT, though most data come from obstetric records of maternal interviews during pregnancy. As such, additional exposure data quality control criteria were applied. For study inclusion, the defect registries needed to fulfil the following criteria for AED data:

• An AED prevalence exposure of at least 3 per 1000 malformed infants was required.

• The specific AED name or complete seven digit ATC code was required for at least 80% of reported AED exposures.

These criteria were based on previous validation work by Meijer et al. for the AED class [Meijer, 2006].

Further exclusions were made for birth defect registrations with maternal epilepsy without a record of AED use to eliminate potential misclassification of AED exposure.

The primary exposure of interest was first trimester exposure to lamotrigine monotherapy. Further analyses compared exposure to all AEDs and all AED monotherapy across case and control groups.

2.2.5. Covariate Definitions

Data on maternal age and birth outcome, including gestational age, type of delivery, were extracted from the participating EUROCAT registries. Data on smoking and other medication related to oral clefts (steroids and barbiturates) were not systematically


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available, but were not expected to be differentially distributed between users and non users of lamotrigine and other AEDs.

2.2.6. Data Analysis

Standard logistic regression, controlling for registry and age of the mother were completed. The primary exposure comparisons were:

• Lamotrigine monotherapy v. no AED

• Any AED v. no AED

• Any AED monotherapy v. no AED. Secondary analyses assessed lamotrigine polytherapy and any AED polytherapy versus no AED.

The output was a measure of the excess lamotrigine (or any AED or any AED monotherapy in secondary analyses) exposure in oral cleft cases versus non oral cleft defect controls. As such this does not represent a true odds ratio.

The EUROCAT registries approached covered approximately 3.5 million births across the observation period, 1995-2005 (observation period varied slightly by registry depending on date of launch of lamotrigine in individual countries). Assuming an isolated oral cleft rate of 1.0 per 1000 (EUROCAT working group 2000) and an exposure rate of lamotrigine monotherapy of 0.8 per 1000 (EUROCAT private communication), with 10 controls per case the study was powered to detect an odds ratio of 5.

2.2.7. Validation Study

As this was the first large scale case control study within the EUROCAT network to look at the risk of a specific birth defect in relation to anti-epileptic drug exposure, an additional validation study was completed. This study aimed to replicate the known association between valproate monotherapy and spina bifida. This analysis considered the case group of spina bifida and a control group of non chromosomal, non spina bifida defects. Analytic comparisons were completed between valproate monotherapy and non AED exposure.

2.3. Results

2.3.1. Oral Cleft Case Control Study

Nineteen EUROCAT registries agreed to participate in the study and met exposure data inclusion criteria. These birth defect registries covered a base of 3.9 million births between 1995 and the end of 2005. These 3.9 million births gave 98,075 congenital birth defect registrations, 11,784 were chromosomal and 86,291 were non chromosomal. After excluding birth defect registrations with maternal epilepsy without AED use and registrations of syndromic oral clefts there were 5,511 oral cleft cases and 80,052 non cleft controls available for analysis. A description of birth defect registrations by case/control group and birth outcome is given in Table 1


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Table 1 Number of registrations by case/control status and birth outcome

All defect Registrations

N (%)

Isolated Cleft Cases N (%)

All Non-Syndromic Cleft

Cases N (%)

Non Cleft Controls

N (%)

Live births Fetal deaths Terminations

78,528 (91.8) 1,157 (1.4%) 5,877 (6.9%)

4,526 (99.0) 24 (0.5) 21 (0.5)

5,274 (95.7) 78 (1.4)

159 (2.9)

73,255 (91.5) 1,079 (1.4) 5,718 (7.1)

Total 85,562 4,571 5,511 80,052

There was a slightly higher proportion of live births in the isolated and all non-syndromic cleft case group compared with the non cleft controls which may reflect the nature of the defect under consideration (i.e. not life threatening and ability to correct surgically after birth).

There were insufficient numbers of chromosomal controls to allow ten controls to one case matching ratio. As this analysis was severely underpowered it was not pursued further.

There were 495 AED exposed cases and controls, an AED exposure rate of 5.8 per 1000. Over 80% (409/495) were exposed to AED monotherapy. There were 72 lamotrigine exposed cases and controls in the dataset of which 40 were exposed to lamotrigine monotherapy, a rate of 0.5 per 1000. The prevalence of exposure to different AEDs is described in Table 2 below.


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Table 2 Prevalence of AED exposure among cases and controls

Number(Cases and Controls) Per 1, 000 Defect Registrations (n = 85,563)

Any AED 495 5.79

Any AED monotherapy Valproate monotherapy

Carbamazepine monotherapy Lamotrigine monotherapy

Other monotherapy

409 181 125 40 63

4.78 2.12 1.46 0.47 0.74

Any AED polytherapy Including valproate

Including carbamazepine Including lamotrigine

Other polytherapy

86 57 39 32 4

1.01 0.67 0.46 0.37 0.05

A description of AED exposure between case and control groups is given in Table 3.

Table 3 AED exposures across non-syndromic oral cleft case and non cleft control groups

Non-syndromic oral cleft cases (N=5,511)

Non cleft controls (N=80,052)

No AED Any AED

Any AED monotherapy Lamotrigine monotherapy Lamotrigine polytherapy

Any AED polytherapy

5,467 44 37 2 3 7

79,601 451 372 38 29 79

There were 37 AED monotherapy exposures among the 5,511 non-syndromic oral clefts and 372 AED monotherapy exposures among the 80,051 non oral cleft controls. There were two lamotrigine monotherapy exposures among the non-syndromic oral clefts and 38 lamotrigine monotherapy exposures among the non oral cleft controls. The odds ratios for AED and lamotrigine exposure versus no AED exposure among cases and controls are presented in Table 4.


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Table 4 Adjusted odds ratios*Delta (and 95% CI) for AED exposure across oral cleft cases and non oral cleft malformed controls

Isolated clefts Non-syndromic clefts

Isolated cleft palate

Non-syndromic cleft palate

No AED 1.0 1.0 1.0 1.0 Any AED 1.21 (0.82-1.72) 1.43 (1.03-1.93) 1.86 (1.07-2.94) 2.37 (1.54-3.43) Any AED

monotherapy 1.23 (0.81-1.79) 1.46 (1.02-2.02) 2.11 (1.20-3.42) 2.55 (1.61-3.77)

Lamotrigine monotherapy

0.80 (0.11-2.85) 0.67 (0.10-2.34) 1.01 (0.03-5.57) 0.79 (0.03-4.35)

Lamotrigine polytherapy

1.00 (0.14-3.60) 1.34 (0.29-3.95) 0 1.02 (0.03-5.61)

Any AED polytherapy

1.04 (0.37-2.40) 1.24 (0.51-2.57) 0.48 (0.02-2.58) 1.41 (0.32-3.94)

*The odds ratios can be interpreted as follows: an odds ratio above one indicates an excess of AED/lamotrigine exposure in the oral cleft cases versus non cleft controls and hence a signal for an increased risk of clefts associated with exposure. δOdds ratios adjusted for maternal age only. The number of exposed cases and controls limited the numbers of covariates that could be robustly controlled for in the analysis. As maternal age was associated with both outcome and exposure it was determined to be the most important covariate to control for.

There was not a signal of an increased risk of oral clefts (isolated, non-syndromic or cleft palate) with lamotrigine monotherapy versus no AED exposure. There was however, a signal for an increased risk of both non-syndromic clefts and cleft palate (isolated alone or non-syndromic) in those exposed to any AED or any AED monotherapy versus no AED exposure.

2.3.2. Validation Study

The same dataset contained 1933 non chromosomal spina bifida cases and 83,643 non spina bifida, non chromosomal controls. Twenty-three of the spina bifida cases were exposed to valproate monotherapy, as were 158 of the non spina bifida malformed controls. The odds of valproate monotherapy exposure versus no AED exposure were compared across cases and controls. The resulting adjusted odds ratio was 6.3 (95% CI 3.9 – 9.8), thus validating the ability of the data to detect the known increased risk for spina bifida following exposure to valproate.

2.4. Discussion

This study did not find evidence of an increased risk of isolated, non-syndromic oral clefts relative to non oral cleft malformations following in utero exposure to lamotrigine monotherapy (OR 0.80, 95% CI 0.11 – 2.85). This is a modified case control design using malformed non oral cleft controls and as such the odds ratio cannot be interpreted as a relative risk. The odds ratio for lamotrigine monotherapy could be interpreted as:

• no increased risk of oral clefts for lamotrigine


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• equal increase in risk for oral clefts and for all other non chromosomal defects combined following lamotrigine exposure .

However, as several large AED pregnancy registries have failed to report any substantial increase in the overall risk of all major congenital defects or any additional signals for specific malformation types, the latter explanation is unlikely.

This is the first large scale case control study using EUROCAT data to assess the risk of a specific malformation in relation to drug exposure. As such, the results of the validation study confirming the known association of valproate and spina bifida are very encouraging regarding the ability of this dataset to detect AED specific effects.

The EUROCAT dataset captured 3.9 million births, yet only observed two lamotrigine monotherapy exposures among the non syndromic oral cleft cases and 38 exposures among the controls. This illustrates the difficulty in testing hypotheses generated through pregnancy registries where both the outcome and exposure are rare. The EUROCAT dataset was the largest GSK was able to identify: 40 lamotrigine exposures in cases and controls versus only 5 lamotrigine exposures in the database of the United States based Slone Centre which is considered expert in this case control methodology ( personal communication), yet was only powered to detect an odds ratio of 5. However, given the initial hypothesis generated by NAAED postulating a relative risk of 17 for isolated oral clefts, this data source was adequately powered to prove or refute such a magnitude of association.

2.5. Conclusions

These data do not support the hypothesis of a substantially increased risk of non-syndromic oral clefts (or cleft palate alone) associated with lamotrigine exposure.

3. UPDATE ON FINDINGS ON IN UTERO EXPOSURE TO LAMOTRIGINE MONOTHERAPY IN ANTI-EPILEPTIC DRUG PREGNANCY REGISTRIES

As part of GSK’s ongoing commitment to monitoring AED pregnancy registry data with respect to lamotrigine exposure and major birth defects, updates have been secured from the following AED registries:

• The International Lamotrigine Pregnancy Registry

• The UK Epilepsy and Pregnancy Register

• EURAP Updates were not available from:

• The North American Anti-Epileptic Drug (NAAED) Pregnancy Registry

• Swedish Medical Birth Register


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• Danish Multi-Centre Registry

The most current data available to GSK from all ongoing registries are summarised in Table 5 below. Changes from the December 2006 report are highlighted in Table 6.

NB All first trimester monotherapy exposures in Table 5 represent analysable denominators. The analysable denominator includes live infants without birth defects plus all birth outcomes with defects. Pregnancy losses and induced abortions without reported defects are not included in the denominator due to inconsistent ascertainment of birth defects in those situations. All investigators provided analysable denominators apart from the UK registry which provided a denominator of all prospectively registered first trimester lamotrigine exposures irrespective of birth outcome (n=1051). We have calculated the analysable denominator using the numerator of all major birth defects and reported first trimester risk for lamotrigine.


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Table 5 Summary of current data on major birth defects (MBDs) from AED pregnancy registries

Registry (Cut off date)

Number of 1st trimester

monotherapy exposures

Risk of all MBDs

(95% CI)

Number of infants with isolated oral

clefts

Number of infants with anencephaly

International Lamotrigine Registry

(March 2007) [GlaxoSmithKline

International Pregnancy Registry,

2007]

1053 2.6% (1.7% - 3.8%)

1 cleft palate* 1 cleft lip/palate

3 cases (all induced abortions)

UK Epilepsy and Pregnancy Registry

(March 2007) 2007]

1000 2.7% (1.8% - 3.9%)

1 cleft lip/palate None But

1 acrania 1 microcephaly

1 porencephalic cyst within brain

EURAP (May 2007)

2007]

717 4.0%§ (3.1% - 6.3%)

1 cleft lip (type unspecified)

None BUT 1 reduction deformity of the brain in a live born

infant 1 craniosynostosis

1 agenesis of corpus callosum in

spontaneous abortion No update for

NAAED (January 2006) [Holmes, 2006]

564 2.6% (1.2% - 4.9%)

3 cleft palate 2 cleft lip (1 identified on ultrasound)

1 case**

Swedish Medical Birth Register

(End 2005) PC; GlaxoSmithKline

International Pregnancy Registry,

2007]

347 4.0%δ (2.3% - 6.8%)

1 cleft palate* 2 cleft lip/palate

None

Danish Multicentre Registry

(End 2000) [Sabers, 2004]

51 0% None None

* Confirmed duplicate case of cleft palate **Confirmed duplicate of one of the cases reported from the International Lamotrigine Registry matched on maternal age, lamotrigine dose and date of induced abortion. §Includes chromosomal and some minor abnormalities (5 cases Down Syndrome, one autosomal abnormality) δIncludes major and minor malformations


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Table 6 Summary of changes since previous update (December 2006)

Registry New 1st trimester monotherapy

exposures

No. new isolated oral clefts

No. new anencephaly cases

International Lamotrigine Registry

145 None None

UK Epilepsy and Pregnancy Registry

150 None Previously reported single orofacial cleft case confirmed as cleft lip with palate

None BUT 3 defects affecting

head/brain not previously described in

detail EURAP 272 None None BUT

1 reduction deformity of brain in live born infant

1 craniosynostosis 1 agenesis of corpus

callosum in spontaneous abortion

3.1. International Lamotrigine Pregnancy Registry

As of March 31st, 2007, data were available on 1053 first trimester monotherapy exposures. The risk of major birth defects among the 1053 exposures was 2.6% (95% CI 1.7% - 3.8%). In the corresponding registry report, the Scientific Advisory Committee notes that the milestone of 1000 exposures has been reached and that assuming a baseline risk of major birth defects in the general population of 2% (Metropolitan Atlanta Congenital Defects Program (MACDP) data estimate risk of 2.1% of major defects ascertained at birth) the upper bound of the lamotrigine monotherapy risk estimate now excludes a two fold increase in risk of all major birth defects. The committee consensus statement therefore concludes that the registry has met its primary objective and that there is no signal for a substantial increase in the overall risk of all major defects, though increases in the risk of specific defects cannot be ruled out [GlaxoSmithKline International Pregnancy Registry, 2007].

There were no new reports of oral clefts since the previous update to agencies (December 2006) leaving one report of an isolated cleft palate and one report of an isolated cleft lip with palate. The former is a confirmed duplicate of the cleft palate reported in the Swedish Medical Birth Registry. There were no new cases of anencephaly in this report leaving three cases.

3.2. UK Epilepsy and Pregnancy Registry

Data as of the end of March, 2007, were shared by the UK Epilepsy and Pregnancy Registry. The observed risk of major birth defects among 1000 analysable first trimester lamotrigine monotherapy exposures was 2.7% (95% CI 1.8% - 3.9%) 2007].


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There were no new cases of isolated oral clefts since the last update with a single case of cleft lip with palate being reported among the 1000 exposures.

This Registry reported no cases of anencephaly, though across the life of the registry one case of acrania, one case of microcephaly and one case of a porencephalic cyst within brain were observed.

3.3. EURAP

As of the end of May 2007, EURAP had analysable data on 717 first trimester exposures to lamotrigine monotherapy. The observed risk of major birth defects was 4.0% (95% CI 3.1% - 6.3%) 2007]. This risk is higher than that reported by other registries, but will reflect the longer infant follow up (up to one year versus mainly at birth in the International Lamotrigine Registry and three months after birth for the UK Registry) as well as the inclusion of chromosomal abnormalities (six of the reported birth defects) that are excluded from risk calculations in other registries.

Among the 717 exposures, there was one report of a cleft lip (type unspecified), one report of a reduction deformity of the brain in a live born infant, one report of craniosynostosis and one report of agenesis of the corpus callosum in a spontaneous abortion.

3.4. NAAED

The risk of major defects (2.6%, 95% CI 1.2% - 4.9%) summarised above represents data from January 2006 previously published in abstract form [Holmes, 2006]. Among the 564 first trimester monotherapy exposures five cases of oral cleft (three cleft palate and two cleft lip) and one case of anencephaly were observed. The case of anencephaly is believed to be a duplicate of one of the cases observed in the International Lamotrigine Registry. The principal investigator of NAAED confirmed that these cases were matched on mother’s age, lamotrigine dose and date of induced abortion.

Although, more recent data to August 2006 have been included in a draft manuscript, the authors will not allow GSK to share these data with regulators until the manuscript is in press. The manuscript was initially submitted for publication in September 2006. However, several unsuccessful submissions have delayed these conditions being met. The latest information provided to GSK states that the manuscript has been re-submitted, following referees’ comments, to the journal Neurology. Final acceptance is expected in October 2007. GSK expects to be able to share these new data with the regulators at that time.

This situation is frustrating and regrettable, but extensive correspondence with the NAAED investigators has failed to resolve this issue.

3.5. Swedish Medical Birth Register and Danish Multi-Centre Registry

A previous update from the Swedish Medical Birth Register was received by GSK in November 2006 [ PC; GlaxoSmithKline International Pregnancy Registry, 2007].


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As this Register no longer receives formal government funding the investigator is unable to provide updates more frequently than on a yearly basis. Further information was sought on the case cleft of palate with renal dysplasia. While the principal investigator did not provide additional clinical descriptions of the case, it was confirmed that this was very unlikely to be a syndromic cleft case such as Meckel Grueber syndrome.

The data from the Danish multi-centre registry represents a unique analysis and as such new data will not become available from this source [Sabers, 2004].

4. CONCLUSIONS

Since the previous report to regulatory agencies in December 2006, new data have been provided on exposure to lamotrigine during pregnancy from the International Lamotrigine Pregnancy Registry, the UK Epilepsy and Pregnancy Register and EURAP. Two of these registries have passed the milestone of 1000 first trimester monotherapy exposures and hence have reached their primary objective of being powered to detect a signal of major teratogenicity. Neither the International nor the UK registry reported a signal for a substantial increase in all major birth defects.

There is growing consistency across three large registries in the observed risk of all major defects following first trimester monotherapy exposure (2.6% in the International Lamotrigine Registry, 2.6% in the North American Anti-Epileptic Drug (NAAED), 2.7% in the UK Epilepsy and Pregnancy Registry). The higher risks reported through the Swedish Register (4.0%) and EURAP (4.0%) reflect the inclusion of chromosomal and minor defects in estimates as well as the longer term follow up of infants in the latter registry.

No new cases of isolated oral clefts or anencephaly were reported in 438 new exposures reported through these three registries. The one oral cleft observed within the UK Registry was confirmed as a case of cleft lip with palate and several defects relating to the head or brain of the newborn were reported (acrania, microcephaly and porencephalic cyst within the brain). An additional case of a brain reduction deformity within a liveborn infant was reported from EURAP.

Additional data are now available on lamotrigine and the risk of non syndromic oral clefts from a case control study within the EUROCAT network. The study was reassuring in providing no evidence of a substantially increased risk of oral clefts associated with lamotrigine.

These new data continue to increase our knowledge of the risks associated with exposure to lamotrigine in pregnancy.


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5. REFERENCES

Becker M, Svensson H, Kallen B. Birth weight, body length, and cranial circumference in newborns with cleft lip or palate. Cleft Palate Craniofacial Journal. 1998; 35: 255-61.

Bille C, Skytthe A, Vach W et al. Parent’s age and the risk of oral clefts. Epidemiology. 2005; 16: 311-16.

Christensen K. The 20th century Danish facial cleft population – epidemiological and genetic-epidemiological studies. Cleft Palate Craniofacial Journal. 1999; 36: 96-104.

Croen LA, Shaw GM, Wasserman CR et al. Racial and ethnic variations in the prevalence of orofacial clefts in California, 1983-92. Am J Med Genetics. 1998; 79: 42-47.

Das S, Runnels R Jr, Smith J et al. Epidemiology of cleft lip and cleft plalate in Missississippi. South Med J. 1995; 88: 437-42

DeRoo LA, Gaudino JA, Edmonds LD. Orofacial cleft malformations. Associations with maternal and infant characteristics in Washington state. Birth Defects Research (A). 2003; 67: 637-42.

GlaxoSmithKline International Pregnancy Registry. Interim report 1 September 1992 – 31 March 2007.

Harville EW, Wilcox AJ, Lie RT et al. Cleft lip and palate versus lip only: are they distinct defects? Am J Epidemiol. 2005; 162: 448-53.

Hashmi SS, Waller DK, Langlois P, et al. Prevalence of non-syndromic oral clefts in Texas: 1995-1999. Am J Med Genetics. 2005; 134(A): 368-72.

Holmes LB, Wyszynski, DF, Baldwin EJ et al. Increased risk for non-syndromic cleft palate among infants exposed to lamotrigine during pregnancy (abstract). Birth Defects Research Part A: Clinical and Molecular Teratology 2006;76(5)318..

Data from the Swedish Medical Birth Registry. Personal communication.

Kallen B. Maternal drug use and infant cleft lip/palate with special reference to corticoids. Cleft Palate Craniofacial Journal. 2003; 40(6): 624-8.

Meijer WM, Cornel MC, Dolk H, De Walle HEK, Armstrong MC, de Jong van-den Berg LTW. The potential of the European network of congenital anomoly registers (EUROCAT) for drug safety surveillance: a descriptive study. Pharmacoepi Drug Safety. 2006; 15: 675-82.

Menegotto BG, Salzano FM. Epidemiology of oral clefts in a large South American sample. Cleft Palate Craniofacial Journal. 1991; 28: 373-77.


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Morrow J, Russell A, Guthrie E, Parsons I, Robertson I, Waddell R et al. Malformation risk of anti-epileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol. Neurosurg, Psychiatry. 2006; 77: 193-98.

Data from the UK Epilepsy and Pregnancy Register May 2007. Personal communication.

Robert E, Kallen B, Harris J. The epidemiology of orofacial clefts. 1. Some general epidemiological characteristics. J Craniofacial Genetics Developmental Biology. 1996; 16: 234-41.

Sabers A et al. Epilepsy and pregnancy: lamotrigine as main drug used. Acta Neurol Scand. 2004; 109: 9-13.

Stoll C, Alembik Y, Dott B et al. Associated malformations in cases with oral clefts. Cleft Palate Craniofacial Journal. 2000; 37: 41-47.

Teconi R, Clementi M, Turolla L. Theoretical recurrence risks for cleft lip derived from a population of consecutive newborns. J Med Genetics. 1988; 25: 243-46.

Tolarova MM, Cervenka J. Classification and birth prevalence of orofacial clefts. Am J Med Genetics. 1998; 75: 126-37.

Data from EURAP May 2007. Personal communication.

Vallino-Napoli LD, Riley MM, Halliday J. An epidemiologic study of isolated cleft lip, palate or both in Victoria, Australia from 1983-2000. Cleft Palate Craniofacial Journal. 2004; 41: 185-94.


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APPENDIX 1: Protocol WEUKSTV2169/EPI40486 EUROCAT case control study


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CONFIDENTIALGlaxoSmithKline Research and Development – Worldwide Epidemiology

Title Page

Title:

LAMOTRIGINE AND OROFACIAL CLEFTS – A case control study using the EUROCAT network

Date of Protocol : 05/01/2007

Epidemiology Project/Protocol Number: WEUKSTV2169/EPI40486

Principal investigator(s) and center(s) involved in the study (as appropriate): EUROCAT,

Dates of observation: 1995 - 2005

Database source (if appropriate): EUROCAT – European network of congenital malformation registries

Copyright Statement: Copyright GlaxoSmithKline Group of Companies 2000. All rights reserved. Unauthorised copying or use of this information is prohibited.

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TABLE OF CONTENTS

Page1. SUMMARY OF PROTOCOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

2. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

3. OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

4. RATIONALE OR CONTRIBUTION TO GSK. . . . . . . . . . . . . . . . . . . . . . . . 23

5. TARGET AUDIENCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

6. METHODOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236.1. Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236.2. Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246.3. Outcome definition and measures . . . . . . . . . . . . . . . . . . . . . . . . . . . 246.4. Exposure definition and measures . . . . . . . . . . . . . . . . . . . . . . . . . . . 256.5. Covariate definition and measures . . . . . . . . . . . . . . . . . . . . . . . . . . 256.6. Adverse drug experience/event measures . . . . . . . . . . . . . . . . . . . . 256.7. Data collection and management . . . . . . . . . . . . . . . . . . . . . . . . . . . 266.8. Validation procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266.9. Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266.10. Sample size and power calculations . . . . . . . . . . . . . . . . . . . . . . . . 266.11. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

7. STUDY MANAGEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287.1. Ethical approval and subject consent . . . . . . . . . . . . . . . . . . . . . . . . 287.2. Subject confidentiality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287.3. Reporting of adverse drug events . . . . . . . . . . . . . . . . . . . . . . . . . . . 287.4. Study closure/uninterpretability of results . . . . . . . . . . . . . . . . . . . . . 287.5. Study milestones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287.6. Study Advisory Committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287.7. Study reporting and publications . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287.8. Resourcing needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

8. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

9. TABLES AND FIGURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30


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1. SUMMARY OF PROTOCOL

This is a case control study to test the hypothesis that first trimester lamotrigine monotherapy exposure is associated with an increased risk of isolated oral clefts. As lamotrigine represents a rare exposure, a multi-country network was sought. EUROCAT represents a European wide network of congenital malformation registries. Data on cases of isolated oral clefts will be extracted from EUROCAT member registries meeting set inclusion criteria (around outcome and exposure data). The primary comparison group will include all non oral cleft, non chromosomal malformations as the registries do not collect data on non malformed infants. Data on exposure to anti-epileptic drugs (AEDs) during the first trimester of pregnancy will be extracted along with other key covariates including age of mother, history of epilepsy and gestational age of the infant.Primary analyses, using logistic regression, will compare the lamotrigine monotherapy versus no AED use and a secondary analysis will compare lamotrigine monotherapy versus other AED monotherapy (with and without valproate.

2. INTRODUCTION

In the most recent interim report of the Lamotrigine Pregnancy Registry of GlaxoSmithKline (July 2006), and in a meeting with GSK in Harlow Sept 13 2006, concern centred on a signal regarding higher risk of orofacial clefts following in utero exposure to lamotrigine monotherapy. Results of the North American Antiepileptic Drug (NAAED) Pregnancy Registry reported an unexpectedly high prevalence of isolated non-syndromic, cleft palate and/or cleft lip in infants exposed to lamotrigine monotherapy during the first trimester of pregnancy (Holmes et al. 2006) – 3 isolated cleft palate and 2 isolated cleft lip were identified among 564 exposed pregnancies, a rate of 8.9 per 1,000. In comparison their control population rate was 0.6 per 1,000 giving a relative risk of approx 15. The EUROCAT rate for non-chromosomal orofacial clefts is 1.4 per 1,000 (2000-2003, all full member registries). The rate of isolated oral clefts from the NAAED comparator group is recognised as low. It is suspected that this is due to the surveillance program being run by a medical geneticist leading to the exclusion of many conditions as genetic/mendelian that would not usually be identified through the routine medical practice followed by other surveillance data sources. The observation of Holmes et al was followed by an FDA alert (September 2006). Other pregnancy registries of similar size have not replicated this observation, although the Swedish register with a smaller exposed cohort also noted two cases of orofacial cleft. The GSK Lamotrigine Pregnancy Registry with 831 first trimester lamotrigine exposed pregnancies found a prevalence of major congenital anomalies of 2.8% (95% CI 1.8-4.2%), including 2 cases of orofacial cleft – one cleft soft palate, and one minor cleft of upper lip and soft palate.

It is clear that huge populations are needed for the study of drug exposures with exposure prevalence as low as anticonvulsants. The UK Epilepsy and Pregnancy Register (Morrow et al 2006) recently reported on 3607 pregnant women with epilepsy (equivalent to a total estimated population of max 700,000 births based on an epilepsy rate of max 5 per 1,000). Lamotrigine monotherapy was taken by nearly 20% of their cohort. There were 21 malformations in this group, an odds ratio of 1.4 (95% CI 0.8-2.7) compared to their baseline carbamazepine group, thus they were able to exclude an odds ratio as high as 3 for all malformations combined.

The signals regarding specific congenital anomalies should be tested in a case-control study design a more efficient approach when considering a rare outcome. EUROCAT is a network of population based congenital anomaly registries (see Appendix) covering 1.5 million births per year that has the possibility to test signals coming from Pregnancy Registries.


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3. OBJECTIVES

To investigate whether intrauterine exposure to lamotrigine monotherapy in the first trimester of the pregnancy is associated with an increased risk of isolated orofacial clefts using a case-control design, hypothesis driven.

4. RATIONALE OR CONTRIBUTION TO GSK

The North American Anti-Epileptic Drug Pregnancy Registry recently reported data indicating an elevated risk of isolated oral clefts associated with first trimester exposure to lamotrigine monotherapy. This signal has not been confirmed in other large AED pregnancy registries. Given the operation of multiple anti-epileptic drug (AED) registries with capturing substantial numbers of exposures to lamotrigine it is increasingly likely that signals around specific defects will be detected. However, the pregnancy registry design, and methodological differences between registries, makes it difficult to ascertain whether such signals represent a true association or are due to chance.

This case control study will be more appropriately powered and designed to test hypotheses that exposure to lamotrigine monotherapy during the first trimester of pregnancy is linked to isolated oral clefts.

5. TARGET AUDIENCE

Internal, regulators and physicians (neurologists, epileptologists, general practitioners, obstetricians etc.)

6. METHODOLOGY 6.1. Study Population

EUROCAT is a European network of population-based congenital anomaly registers for the epidemiologic surveillance of congenital anomalies. It started in 1979. The Central Registry has since 2001 been at the

EUROCAT aims to provide epidemiologic surveillance of congenital anomalies in Europe

EUROCAT currently has 40 members in 20 countries. Of these, 34 are full members transmitting individual level data on congenital anomalies and 6 are associate members transmitting only yearly aggregate numbers. In total, almost 1.5 million births per year are surveyed, covering 29% of the births in European Union (EU) member states and 19% of births in four non-EU countries. The central database holds a total of 375,000 cases of congenital anomalies from 1980-2004 including livebirths, stillbirths and terminations of pregnancy following prenatal diagnosis. The inclusion of terminations of pregnancy following prenatal diagnosis is now an essential component of any epidemiologic study of congenital anomalies. The standard data on each case are described in EUROCAT Guide 1.3 ( and include among others maternal diseases before and during pregnancy, and drugs taken in the first trimester of pregnancy. Not all registries record drug exposure information. Up to 2004 (birth year), registries could give up to 3 drug codes (grouped into 26 categories) as well as text information on the drug. Some registries keep text information locally only. Registries with ATC drug coding mainly keep their drug information locally, but some use both coding systems and put the ATC code in the text field. From 2005, ATC drug codes have been introduced to replace the 26 category drug codes.


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For this study all EUROCAT registry populations will be included where the registry meets the following inclusion criteria:

Antiepileptic drug exposure recorded for at least 3 per 1,000 malformed babies/foetus in the registry database for the study period (figures below this threshold would indicate issues with drug data recording).Specific drug name or complete 7 digit ATC code available for at least 80% of AED exposed babies/foetus for the study period.

Study period: From the year after start of licensing of lamotrigine in each country up to and including 2005 (year of licensing: Austria 1995, Belgium 1997, Denmark 1995, Finland 1997, France 1997, Germany 1996, Holland 1995, Ireland 1995, Italy 1998, Malta 1996, Norway 1996, Poland 1997, Spain 1995, Switzerland 1997, United Kingdom 1995).

A validation study of the database for the years 2000-2003 gives an estimate of 21 registries which meet the criteria, with annual birth coverage of 450,200. A conservative estimate for the population available for an 8 year period would be 3.5 million births. The proportion of malformed babies/foetus with recorded AED exposure in 2000-2003 was 5.2 per 1,000.

6.2. Study Design

This is an observational study using case-control surveillance methodology. Infants with isolated oral clefts will be defined as cases and two control groups will be selected including all non chromosomal abnormalities excluding isolated oral clefts and a second control group of chromosomal abnormalities (not usually considered to be associated with medication exposure). EUROCAT does not have access to data on non malformed infants due to its existence as a network of congenital malformation registries. Data on exposure to AEDs during the first trimester of pregnancy will be extracted from the registries, as will other relevant data including exposure to other medication associated with oral clefts and additional data on the pregnancy outcome e.g. gestational age, mother’s age.

6.3. Outcome definition and measures

Case definition: Livebirths, fetal deaths from 20 weeks, and terminations of pregnancy following prenatal diagnosis with: Non-chromosomal, non monogenic isolated orofacial clefts. Subanalysis for cleft palate.Isolated clefts to be classified by medical geneticist (EC). ICD9 and 10 codes as given in EUROCAT Guide 1.3.

Control definition: Livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy following prenatal diagnosis, with the following: Control group 1. All non-chromosomal, non case group defects. Despite the fact that this group MAY include other potential specific malformations related to lamotrigine exposure, such risks will be diluted in the entire control group, and this group represents the best available comparison group. All syndromic and non isolated, non syndromic clefts will also be excluded from this group.Control group 2. All chromosomal anomalies. This is being assessed as a second potential control group. In previous studies chromosomal abnormalities have been considered as the standard control group as they are not related to medication exposure during pregnancy. However, concerns


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around the comparability of this group in terms of recording of drug exposure have been voiced and need to be addressed before inclusion as a second control group. A priori criteria will be set around the evaluation of data quality and power calculations will determine whether the number of registries will valid data will provide adequately powered analyses.

6.4. Exposure definition and measures

The primary exposure group will be: exposure to lamotrigine monotherapy during the time period from first day of last menstrual period to 12th week of gestation (first trimester). The primary referent group will be defined as no exposure to any AED at any time from the first day of the LMP to the 12th week of gestation and secondary referent groups will consider any other AED monotherapy with and without valproate (latter associated with oral clefts) during the first trimester of pregnancy.

All recorded drug exposures are first trimester according to the instructions of EUROCAT Guide 1.2 and 1.3. Drugs may be recorded in text (with a general code for antiepileptics or psychotropics) or by specific ATC code. Data are recorded for exposure to up to five different drug classes during the first trimester of pregnancy (excluding folate and other vitamin supplements).

All participating registries will be asked for their source of information for AED exposure for cases and controls, as part of the validation process. Up to 2004 (birth year), registries could give up to 3 drug codes (grouped into 26 categories) as well as text information on the drug. Some registries keep text information locally only. Registries with ATC drug coding mainly keep their drug information locally, but some use both coding systems and put the ATC code in the text field. From 2005, ATC drug codes have been introduced to replace the 26 category drug code.

The quality of information on drug exposure depends on the source of that information, as discussed in Meijer et al 2006. An evaluation of drug data for three chronic diseases found a very good level of recording of maternal epilepsy and anticonvulsants, a good ascertainment of maternal diabetes but lack of specificity regarding the exact type of insulin used, but a lesser level of recording of maternal asthma and anti-asthmatics. It is therefore clear that evaluation of data quality must be done in relation to the specific drugs under investigation.

6.5. Covariate definition and measures

EUROCAT has some routinely collected information on potential confounders and risk modifiers. For this analysis, we will consider socio-demographic characteristics (age of mother), information on birth outcome (type of delivery, gestational age). Data on smoking and other medications (steroids and barbiturates) related to oral clefts is either not available or will not be extracted from the EUROCAT database. Steroid and barbiturate use is not expected to be differentially distributed between users of lamotrigine and non AED or other AED monotherapy users and should therefore not act as an important confounder of the possible relationship between lamotrigine and oral clefts.

6.6. Adverse drug experience/event measures

N/A


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6.7. Data collection and management

The standard data on each case are described in EUROCAT Guide 1.3.and includes among others maternal diseases before and during pregnancy, and drugs taken in the first trimester of pregnancy. Not all registries record drug exposure information. Up to 2004 (birth year), registries could give up to 3 drug codes (grouped into 26 categories) as well as text information on the drug. Some registries keep text information locally only. Registries with ATC drug coding mainly keep their drug information locally, but some use both coding systems and put the ATC code in the text field. From 2005, ATC drug codes have been introduced to replace the 26 category drug code.

6.8. Validation procedures

A validation study will be conducted alongside the main study to determine if the database is capable of picking up the known association between valproic acid and spina bifida. This will help in interpretation of results. Cases: non chromosomal spina bifida. Control: all nonchromosomal, non spina bifida cases. Exposure: Valproic acid monotherapy vs no AED, valproic acid polytherapy vs no AED.

Validation work concerning the completeness of records of drug exposure during pregnancy has been completed and published for AEDs (Meijer et al. 2006).

6.9. Data analysis

Standard logistic regression, controlling for registry, year of birth and age of mother will be completed. Although, other covariates will be available, due to the limited number of cases only those named above will be included in the regression model. Data for other covariates of interest will be extracted to ensure they are not differentially distributed between cases and controls.

Primary exposure comparisons: lamotrigine monotherapy vs no AED.

As epilepsy itself could be associated with adverse pregnancy outcomes, additional analyses will include:

lamotrigine monotherapy vs other AED monotherapy and

lamotrigine monotherapy vs all other AED monotherapy excluding valproic acid (known to be associated with oral clefts).

Due to lack of control non-malformed birth population with coded drug exposure, there is no possibility for finding overall odds ratio for malformation, except by additional data collection.

6.10. Sample size and power calculations

3.5 million births over the eight year period 1998-2005. Note that in some countries a longer study period will be available from the year after start of licensing.


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Rate of isolated orofacial clefts 1.0 per 1,000 births (EUROCAT Working Group 2000). Exposure rate: A validation study for 2000-2003 of EUROCAT data found an exposure rate to lamotrigine of 0.8 per 1,000, half of which was monotherapy (based on lamotrigine use as an antiepileptic only). We can expect a lower exposure rate in earlier study years.

With a population of 3.5 million births, isolated orofacial cleft rate of 1.0 per 1,000 (3500 cases), with at least 10 controls per case, exposure rate 0.4 per 1,000, power 80%, alpha 0.05, we can detect an odds ratio of 5.0 (calculated by Vanderbilt Medical Centre Power and Sample Size Calculation). With a population of 3.5 million births, isolated cleft palate rate of 3.4 per 10,000 (1190 cases), with at least 10 controls per case, exposure rate 0.4 per 1,000, power 80%, alpha 0.05, we can detect an odds ratio of 10.1 (calculated by Vanderbilt Medical Centre Power and Sample Size Calculation).

Note that estimates of population size are conservative for this study - more registries may be able to participate, and there will be more years of data available retrospectively than estimated here, but probably at a lower exposure rate.

Power calculations are based on an assumption of 10 controls per case. While this is clearly feasible for the primary control group, feasibility work is needed to confirm this for the secondary control group of chromosomal abnormalities.

6.11. Discussion

One of the strengths of the EUROCAT data is large sample size. This means that we can investigate the risk of specific malformations, which are uniformly coded among registries, with a background of years of validation of prevalence rates. If there is a prior hypothesis (previous signal as to the specific malformation of concern), the exposure rate for the malformation of concern can be compared with all other malformations. If there is no prior hypothesis as to which specific malformation is of concern, other study designs include comparing the spectrum of malformations between the new drug, and all other drugs, or no drugs. Due to lack of control non-malformed birth population with coded drug exposure, there is no possibility for finding overall odds ratio for malformation, except by additional data collection. Dose of the drug is not routinely recorded in the database, but can be obtained by going back to medical records.

It should be noted that this is not a classic case control study as no control group of non malformed infants is available for comparison. This will impact on the interpretation of data and careful consideration needs to be given in how results will be described. Unfortunately, no data source with non malformed infants was of sufficient size to allow adequate power to study the hypothesis of interest.

The potential for exposure misclassification is also particularly important given the small numbers of outcomes (distributed between LTG exposed and unexposed) and the impact misclassification could have on the resulting statistical comparisons. EUROCAT has been tasked to consider ways of testing for such misclassification prior to data extraction and analysis.


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7. STUDY MANAGEMENT 7.1. Ethical approval and subject consent

The study protocol has been reviewed and approved by the ethics committees of the and

7.2. Subject confidentiality

All patient identifiers are removed from patient records in the individual registry databases.Therefore patient confidentiality and anonymity will be assured at the time of data downloading to the central EUROCAT database.

7.3. Reporting of adverse drug events

N/A

7.4. Study closure/uninterpretability of results

N/A

7.5. Study milestones

Signing of contract agreement Mid-End Jan 2007

Reporting of validation study End May 2007

Final study report to GSK End June 2007

Submission of publication October 2007

7.6. Study Advisory Committee

N/A

7.7. Study reporting and publications

A report detailing study results will be provided to GSK by June 30th, 2007. These results will be shared in confidence with the regulators. EUROCAT will be free to publish the data and results at its discretion. A copy of any manuscript(s) will be sent to the GSK for comment 30 days in advance of submission to a journal.

7.8. Resourcing needs

N/A


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8. REFERENCES

EUROCAT Guide 1.3. 2005. Instructions for the Registration of Congenital Anomalies. Available on

Holmes LB et al. Increased risk for non-syndromic cleft palate among infants exposed to lamotrigine during pregnancy (abstract). Birth Defects Research Part A 2006; 76: 318.

Lamotrigine Pregnancy Registry. Interim Report 1 Sept 1992 through 31 March 2006. Issued July 2006. Glaxo Smith Kline.

Morrow et al. 2006 Malformation risks of antiepileptic drugs in pregnancy. A prospective study for the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 77: 193-198

Meijer WM, Cornel MC, Dolk H, de Walle HEK, Armstrong NC, de Jong-van den BergLTW for the EUROCAT Working Group. The potential of the European network of congenital anomaly registers (EUROCAT) for drug safety surveillance: a descriptive study. Drug Safety and Pharmacoepidemiology 2006 Volume 15, Issue 9 , Pages 675 - 682

EUROCAT Working Group 2000. EUROCAT and Orofacial Clefts: The Epidemiology of Orofacial Clefts in 30 European Regions

9. TABLES AND FIGURES

NONE


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APPENDICES

None


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APPENDIX 2: Summary Data received from the registries

International Lamotrigine Pregnancy Registry

Monotherapy Number of 1st trimester exposures 1053 Number major birth defects 27 Risk of MBDs (95% CI) 2.6% (1.7% – 3.8%) Number of isolated oral clefts

(specifying cleft type) 1 cleft palate

1 cleft lip and palate Number of anencephaly cases 3

Polytherapy with valproate

Number of 1st trimester exposures 139

Number major birth defects 15 Risk of MBDs (95% CI) 10.8% (6.4% – 17.5%)

Polytherapy without valproate




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Description of major defects reported among first trimester monotherapy exposures

First Trimester Lamotrigine Exposures 1 September 1992 – 31 March 2007 Lamotrigine Monotherapy 1.

Live male infant. Cleft soft palate. 40 weeks gestation. Lamotrigine 200 mg/day preconception, 300 mg/day week 37 and throughout pregnancy.

2. Live female infant. Right club foot. 40 weeks gestation. Lamotrigine 500 mg/day preconception and throughout pregnancy.

3. Live male infant. Hydronephrosis with megaureter. 41 weeks gestation. Lamotrigine 100 mg/day preconception and throughout pregnancy.

4. Induced abortion. Anencephalic fetus. 20 weeks gestation. Lamotrigine 150 mg/day preconception.

5. Live male infant. Congenital atresia of anus with recto-cutaneous fistula reaching the perineum. 33 weeks gestation. Lamotrigine 25 mg/day from the first trimester, 50 mg/day week 20 and throughout pregnancy.

6. Live male infant. Ventricular septal defect. 41 weeks gestation. Lamotrigine 250 mg/day preconception to week 22.

7. Live female infant. Fetal hydronephrosis, oligohydramnios, intrauterine growth restriction. 34 weeks gestation. Lamotrigine 250 mg/day preconception and throughout pregnancy.

8. Live male infant. Minor subpulmonic muscular ventricular septal defect. Persistent foramen ovale-no surgery/intervention required. 41 weeks gestation. Lamotrigine 300 mg/day preconception to week 6, 250 mg/day week 6-7, 200 mg/day week 7-32, 250 mg/day week 32 and throughout pregnancy.

9. Live male infant. Bilateral club feet, requiring casting. 40 weeks gestation. Lamotrigine (dose unknown) preconception and throughout pregnancy.

10. Live infant. Absent right kidney. 40 weeks gestation. Lamotrigine 12.5 mg/day preconception to week 5, 25 mg/day week 16-24, 100 mg/day week 24 and throughout pregnancy.

11. Live male infant. Transposition of great vessels, ventricular septal defect requiring surgery/intervention. 39 weeks gestation. Lamotrigine 200 mg/day preconception to week 7.

12. Live male infant. Left polycystic kidney. 39 weeks gestation. Lamotrigine (dose unknown) preconception, 500 mg/day week 1, 400 mg/day week 1, 300 mg/day week 1-2, 200 mg/day week 2, 100 mg/day week 2 and throughout pregnancy.

13.* Live female infant. Down syndrome. No malformations noted (because this is a chromosomal anomaly, it is not included in the analysis). 37 weeks gestation. Lamotrigine 225 mg/day preconception and throughout pregnancy.

14. Live male infant. Hypospadias. 34 weeks gestation. Lamotrigine 200 mg/day preconception and throughout pregnancy.

15. Live female infant. Minor cleft of upper lip and soft palate. 40 weeks gestation. Lamotrigine 100 mg/day preconception and throughout pregnancy.


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First Trimester Lamotrigine Exposures 1 September 1992 – 31 March 2007 Lamotrigine Monotherapy 16.

Live male infant. Hypoplastic left heart syndrome. The baby subsequently died. 39 weeks gestation. Lamotrigine 100 mg/day preconception and throughout pregnancy.

17. Live female infant. Hypoplasia of left ventricle of the heart. The baby subsequently died. 37 weeks gestation. Lamotrigine 400 mg/day preconception and throughout pregnancy.

18. Live male infant. “Fluid on left kidney”. 38 weeks gestation. Lamotrigine 550 mg/day preconception and throughout pregnancy.

19. Live female infant. Cortical dysplasia. 41 weeks gestation. Lamotrigine 300 mg/day preconception and throughout pregnancy.

20. Stillbirth. Diaphragmatic hernia with dislocation of abdominal organs in the thorax. 38 weeks gestation. Lamotrigine 200 mg/day preconception and throughout pregnancy.

21. Induced abortion. Anencephaly diagnosed by prenatal ultrasound. 15 weeks gestation. Lamotrigine 400 mg/day preconception, 425 mg/day week 10 and throughout pregnancy.

22. Induced abortion. Anencephaly. 19 weeks gestation. Lamotrigine 200 mg/day preconception to week 6.

23. Live female infant. Bilateral hip dislocation, treated by an orthopedist with a Pavlik harness. 39 weeks gestation. Lamotrigine 200 mg/day preconception, 300 mg/day week 19, 400 mg/day week 26 and throughout pregnancy.

24. Live male infant. Club feet, treated with casting. 39 weeks gestation. Lamotrigine 300 mg/day preconception and throughout pregnancy.

25. Live female infant. Ventricular septal defect and patent foramen ovale. 40 weeks gestation. Lamotrigine 300 mg/day preconception to week 12, 400 mg/day week 12-21, 600 mg/day week 21 and throughout pregnancy.

26. Live female infant. Transposition of the great vessels and transposition of the ventricles, requiring surgery. 40 weeks gestation. Lamotrigine 100 mg/day preconception to week 6, 100 mg/day week 15 and throughout pregnancy.

27. Live infant. Pyloric stenosis, requiring pyloromyotomy. 39 weeks gestation. Lamotrigine (dose unknown) week 6 and throughout pregnancy.

28. Live female infant. Congenital diaphragmatic hernia; pulmonary hypoplasia; complex congenital heart defect (transposition of the great arteries, tetralogy of Fallot). Infant died at 24 hours of age from refractory hypoxia. 38 weeks gestation. Lamotrigine 500 mg/day preconception and throughout pregnancy.

29.* Induced abortion. Prenatal ultrasound at approximately 19 weeks showed signs of Trisomy 21. Amniocentesis confirmed Trisomy 21 (because this is a chromosomal anomaly, it is not included in the analysis). 20 weeks gestation. Lamotrigine 250 mg/day preconception and throughout pregnancy.

*Not included in analysis as chromosomal defects are deemed very unlikely to be due to drug exposureUK Epilepsy and Pregnancy Registry


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* Analysable first trimester denominator

Monotherapy Number of 1st trimester exposures 1050 (1000)*

Number major birth defects 27 Risk of MBDs (95% CI) 2.7% (1.8% – 3.9%) Number of isolated oral clefts

(specifying cleft type) 1 cleft lip and palate

Number of anencephaly cases 1 acrania – Induced abortion at 13 weeks?

Microcephaly x1 Porencephalic cyst with little surrounding brain tissue x1


Number of 1st trimester exposures 213 (200)



Number of 1st trimester exposures 335 (335)



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Description of major defects reported among first trimester monotherapy exposures in the UK Registry

Lamotrigine Monotherapy

Major Malformations

1. Oesophageal Atresia 2. Large Umbilical Cyst - Exomphalos 3. Hypoplastic Left Heart Syndrome – Placental Abruption.

Died within approx 30 minutes of birth 4. Duodenal Atresia / small bowel obstruction – laparotomy performed 5. Transposition of the great vessels- baby died 3 days old 6. Bilateral hydrocele 7. Cleft Lip & Palate 8. Hypospadias, Hospital follow up 9. 17 weeks

Large porencephalic cyst within the brain with little brain tissue surrounding 10. ? Hydrocele & crooked fingers and toes. (Unable to obtain any further

information) 11. Right hydrocele at 8/40. Ventilated as grunting on CPAP with high CO2 for 10

hrs(35 Wks Gest) 12. Microcephaly and failure to thrive at 11 weeks 13. Cardiac murmur - VSD 14. Congenital dislocation of hip 15. Mod – severe hearing loss/ Bilateral hydronephrosis & hydroureter, obstruction

both sides on prophylactic antibiotics 16. Fallots Tetralogy 17. Bilateral talipies equinovarus - pop 18. Hydrocoele 19. Infant diagnosed with infantile spasms at 4-6 weeks, lissencephaly and

epilepsy 20. Bilateral cataracts 21. Coarctation- Emergency operation at 8 days of age 22. Cerebral Palsy, tube fed (Em C/s for meconium staining 23. 13 Weeks. PM - Acrania 24. ? small VSD awaiting cardiology review 25. Hypospadias & wide skull sutures 26. Hydrocele 27. Elective Termination at 21 weeks for spina bifida


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EURAP

Monotherapy Number of 1st trimester exposures 717 Number major birth defects 29 Risk of MBDs (95% CI) 4.0% (3.1% – 6.3%) Number of isolated oral clefts

(specifying cleft type) 1 cleft lip (type unspecified)

Number of anencephaly cases None BUT 1 reduction deformity of the

brain in live born 1 craniosynostosis

1 agenesis of corpus callosum in spontaneous abortion



Number major birth defects 24 Risk of MBDs (95% CI) 19.0% (12.8% - 27.2)



Number major birth defects 12 Risk of MBDs (95% CI) 5.7% (3.1% - 10.0%)


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Description of major defects reported among first trimester monotherapy exposures within EURAP

Live births Albinism

Cleft lip unspecified Congenital anomalies of diaphragm

Congenital anomalies of urachus; Haemangioma Congenital cataract, unspecified

Craniosynostosis Dislocation of hip, unilateral; Ventricular septal defect Dislocation of hip, unilateral; Ventricular septal defect

Down’s syndrome Down’s syndrome

Gonadal dysgenesis Haemangioma Hypospadias

Hypospadias; Hydrocele Inguinal hernia, bilateral without mention of obstruction or gangrene

Inguinal hernia, unilateral of unspecified without mention of obstruction or gangrene Inguinal hernia, unilateral of unspecified without mention of obstruction or gangrene

Other specified congenital anomalies of brain; Reduction deformities of brain Other specified congenital anomalies of kidney

Talipes equinovarus Ventricular septal defect Ventricular septal defect

Induced abortion Down’s syndrome Down’s syndrome Down’s syndrome

Hypoplastic left heart syndrome* Hypoplastic left heart syndrome

Spontaneous abortion Agenesis of corpus callosum

Still birth Other conditions due to autosomal anomalies; Dolichocephaly; Hydrops fetalis not due to

isoimmunization * Two hypoplastic left hearts in twins representing one pregnancy and one exposure


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HM2007/00278/00 CONFIDENTIAL WEUKSTV2169

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