Medicines and Healthcare products Regulatory Agency (MHRA) announces that a review of the risks of major congenital malformations and of adverse neurodevelopmental outcomes for antiepileptic drugs by the Commission on Human Medicines (CHM) has confirmed that lamotrigine (Lamictal) and levetiracetam (Keppra) are the safer of the medicines reviewed during pregnancy.
In the context of the known harms with valproate, the CHM has reviewed available safety data relating to the use of other key antiepileptic drugs in pregnancy for the risk of major congenital malformations, neurodevelopmental disorders and delay, and other effects on the baby. The key antiepileptic drugs were selected for the review on the basis of their place in United Kingdom clinical practice.
Clinicians should use this information when discussing treatment options with women with epilepsy at initiation and at routine recommended annual reviews and with women who are planning to become pregnant.
The key review findings are:
Major congenital malformations
MHRA’s review of risk of major congenital malformations assessed data from meta-analyses of epidemiological studies and other large epidemiological studies. The studies reviewed include comparisons of pregnancy outcomes between women given antiepileptic drug monotherapy and women without epilepsy or women with epilepsy who were not treated with antiepileptic drugs. The results from these meta-analyses and other studies show that:
- A large amount of data exists for lamotrigine (more than 12,000 pregnancies exposed) and levetiracetam (more 1,800 pregnancies exposed) and these data do not suggest an increased risk of major congenital malformations when these antiepileptic drugs are used at the usual maintenance doses.
- For lamotrigine, studies investigating the effect of dose have shown conflicting results; one study using data from EURAP showed a statistically significant increase in the rate of major congenital malformations when doses of lamotrigine higher than 325mg per day were compared with doses of lamotrigine 325mg per day or lower.
- Other studies do not suggest dose-response effect on the risk of major congenital malformations: data for carbamazepine (around 9,000 pregnancies exposed), phenobarbital (around 1,800 pregnancies exposed), phenytoin (around 2,000 pregnancies exposed), and topiramate (around 1,000 pregnancies exposed) demonstrate that they are associated with an increased risk of major congenital malformations compared with that seen in the general population and women with epilepsy not on an antiepileptic drug; the risk of major congenital malformations with carbamazepine, phenobarbital, and topiramate is dose-dependent; the available data for pregabalin suggest it may be associated with a slightly increased risk of major congenital malformations, but these data include emerging findings that are currently under review and further evaluation is needed to reach definitive conclusions; due to limitations of the data for gabapentin, oxcarbazepine, and zonisamide, the risk remains uncertain; the possibility of an increased risk of major congenital malformations can neither be confirmed nor ruled out.
Neurodevelopmental disorders and delay
The review also considered meta-analyses and epidemiological studies that investigated the risk of adverse effects on neurodevelopmental outcomes including measures of intelligence, developmental outcomes, and symptoms or diagnoses of autism spectrum disorders in children exposed in-utero to antiepileptic drugs. These data support the following conclusions:
- For carbamazepine, lamotrigine, and levetiracetam, data do not suggest an increased risk of neurodevelopmental disorders or delay, however, due to the limitations of these data the possibility of an increased risk cannot be definitively ruled out.
- For phenobarbital and phenytoin, although the clinical studies report inconsistent findings, the totality of the data show the possibility of adverse effects on neurodevelopment.
- Some recent data raise concerns that topiramate use during pregnancy may be associated with poorer developmental outcomes, however, the numbers in the available studies remain limited and further data are needed to reach firm conclusions.
- For gabapentin, oxcarbazepine, pregabalin, and zonisamide the data are either lacking, extremely limited, or have limitations, and the risks remain uncertain.
Other effects during pregnancy
The available meta-analyses and epidemiological studies also provide data on the risk of fetal loss, prenatal growth restriction, and preterm birth associated with antiepileptic drug use during pregnancy. These studies support that:
- Use of lamotrigine or levetiracetam during pregnancy is not associated with an increased risk of fetal loss, prenatal growth restriction, or preterm birth.
- Use of phenobarbital, topiramate, and zonisamide during pregnancy is associated with an increased risk of intrauterine growth retardation (small for gestational age).
- For carbamazepine, gabapentin, oxcarbazepine, and pregabalin, the risks associated with use during pregnancy remain uncertain.
Monitoring and dosing advice in pregnancy:
For any antiepileptic drug that is used during pregnancy, it is recommended to use monotherapy treatment and the lowest effective dose, where possible. Physiological changes during pregnancy (and post-partum) can affect concentrations of antiepileptic medicines, particularly for lamotrigine and phenytoin. For details of the key issues of individual drugs, please refer to the website in MHRA. Prescribers should consult advice from the Summary of Product Characteristics (SmPC) and relevant clinical guidance for dosing and monitoring recommendations of any antiepileptic drugs in pregnancy.
Summary of key conclusions of review:
- Lamotrigine – Studies involving more than 12,000 pregnancies exposed to lamotrigine monotherapy consistently show that lamotrigine at maintenance doses is not associated with an increased risk of major congenital malformations.
- Levetiracetam – Studies involving more than 1,800 pregnancies exposed to levetiracetam do not suggest an increased risk of major congenital malformations.
- For both lamotrigine and levetiracetam, the data on neurodevelopmental outcomes are more limited than those for congenital malformations. The available studies do not suggest an increased risk of neurodevelopmental disorders or delay associated with in-utero exposure to either lamotrigine or levetiracetam; however, the data is inadequate to rule out definitively the possibility of an increased risk.
- For the other key antiepileptic drugs, data show: an increased risk of major congenital malformations associated with carbamazepine, phenobarbital, phenytoin, and topiramate use during pregnancy; the possibility of adverse effects on neurodevelopment of children exposed in utero to phenobarbital and phenytoin; an increased risk of fetal growth restriction associated with phenobarbital, topiramate, and zonisamide use during pregnancy.
Actions for prescribers:
- At initiation and as part of the recommended annual review for patients with epilepsy, specialists should discuss with women the risks associated with antiepileptic drugs and with untreated epilepsy during pregnancy and review their treatment according to their clinical condition and circumstances.
- Urgently refer women who are planning to become pregnant for specialist advice on their antiepileptic treatment.
- All women using antiepileptic drugs who are planning to become pregnant should be offered 5mg per day of folic acid before any possibility of pregnancy.
- For lamotrigine, levetiracetam or any antiepileptic drugs that can be used during pregnancy, it is recommended to use monotherapy whenever possible; use the lowest effective dose.
Please refer to the following website in MHRA for details:
http://www.gov.uk/drug-safety-update/antiepileptic-drugs-in-pregnancy-updated-advice-following-comprehensive-safety-review
In Hong Kong, there are registered pharmaceutical products containing lamotrigine (26 products) and levetiracetam (27 products). All products are prescription-only medicines. So far, the Department of Health (DH) has received adverse drug reaction related to lamotrigine (2 cases) and levetiracetam (6 cases), but these cases are not related to congenital malformations and neurodevelopmental outcomes.
The risk of major malformations and impairment of neurodevelopment associated with the use of antiepileptic drugs (such as lamotrigine and levetiracetam) during pregnancy is documented in overseas reputable drug references such as the “Martindale: The Complete Drug Reference”. The DH will remain vigilant on safety update of the drugs issued by other overseas drug regulatory.
Ends/Friday, Jan 8, 2021
Issued at HKT 18:00
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