Topiramate “and the combination of topiramate/phentermine”: new restrictions to prevent exposure during pregnancy

Topiramate <and the combination topiramate/phentermine>: new restrictions to prevent exposure during pregnancy

Dear healthcare professional!

This letter was prepared in agreement with the European Medicines Agency (EMA) and {the National Regulatory Authority} in order to inform you about the implementation of the pregnancy prevention program for medicinal products containing topiramate.

Brief overview

• The use of topiramate (topiramate) during pregnancy may cause serious congenital malformations and fetal growth retardation. Recent data also indicate a possible increased risk of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, and attention deficit hyperactivity disorder (ADHD), after the use of topiramate (topiramate) during pregnancy.
• <For monocomponent medicinal products containing topiramate> ^≠ The new contraindications concern the treatment of epilepsy:
  • pregnancy, except when there is no appropriate alternative treatment;
  • a woman of childbearing potential who is not using highly effective methods of contraception. The only exception is a woman for whom there is no suitable alternative treatment but who is planning a pregnancy and is fully informed about the risks associated with the use of topiramate (topiramate) during pregnancy.
• Topiramate (topiramate) <single-component medicinal products> for migraine prophylaxis <and combination medicinal products containing topiramate/phentermine (topiramate/phentermine) for weight control> are already contraindicated during pregnancy and in women of childbearing potential who are not using highly effective methods of contraception.
• Treatment of female children* and women of childbearing potential must be initiated and supervised by a physician experienced in the treatment of epilepsy or migraine <or weight control for combination medicinal products>. The need for treatment should be reviewed at least once a year.
• Due to a potential interaction, women using systemic hormonal contraceptives should also be advised to use a barrier method.
• For women of reproductive potential taking topiramate <or topiramate/phentermine>, treatment should be re-evaluated to confirm adherence to the pregnancy prevention program.

* The recommendation requires adjustment at the national level, since the use for migraine prevention is approved only for adults in some EU member states, and in others for patients over 12 years of age.

^≠ The clarification “monocomponent medicinal products” should be added to the document only if the combination medicinal product is also registered, in order to emphasize which parts relate to which medicinal products. If only the monocomponent medicinal product is registered, there is no need to add the clarification “monocomponent medicinal products” to topiramate.

Background information on safety issues

Monocomponent medicinal products containing topiramate (topiramate), indicated as:

• Monotherapy for the treatment of adults, adolescents, and children aged 6 years and older with partial-onset seizures with or without secondary generalization and with primary generalized tonic-clonic seizures.
• Adjunctive therapy for the treatment of adults, adolescents, and children aged 2 years and older with partial seizures with or without secondary generalization, or with primary generalized tonic-clonic seizures, and treatment of seizures associated with Lennox-Gastaut syndrome.
• Prevention of migraine attacks (in adults/patients aged 12 years and older) after careful consideration of alternative treatment options. Topiramate is not recommended for the treatment of acute conditions.

<Combination medicinal products containing topiramate/phentermine, indicated as:

• an adjunct to a reduced-calorie diet and physical activity for patients with obesity (BMI ≥ 30 kg/m²) or overweight patients (BMI ≥ 27 kg/m²) with weight-related comorbidities such as hypertension, type 2 diabetes, or dyslipidemia.>

Data from two observational (non-interventional) population-based register studies (1, 2), conducted on the basis of the same data set in the Nordic countries, indicate that the prevalence of autism spectrum disorders, intellectual disability or attention deficit hyperactivity disorder (ADHD) in nearly 300 of the children of mothers with epilepsy who were exposed to topiramate in utero may be 2-3 times higher than in the children of mothers with epilepsy who did not receive antiepileptic medicinal products (AEMPs).

A third observational (non-interventional) cohort study (3), conducted in the USA, did not find an increased cumulative incidence of these outcomes up to 8 years in approximately 1000 children of mothers with epilepsy who were exposed to topiramate in utero, compared with children of mothers with epilepsy who did not receive antiepileptic medicinal products.

It is already well known that the use of medicinal products containing topiramate during pregnancy can cause serious congenital malformations and fetal growth restriction:

• infants exposed in utero to topiramate monotherapy have an approximately 3-fold increased risk of major congenital malformations, including cleft lip/palate, hypospadias, and malformations of various body systems, compared with a reference group not exposed to antiepileptic medicinal products. The absolute risk of major congenital malformations due to exposure to topiramate ranges from 4,3% (1,4% in the reference group) to 9,5% (3% in the study group) (4);
• data from pregnancy registries indicate a higher prevalence of low birth weight (< 2 500 g) and of small for gestational age (SGA; defined as birth weight below the 10th percentile adjusted for gestational age, stratified by sex) with topiramate monotherapy. In the North American registry of pregnant women taking AEDs, the risk of SGA in the children of women who took topiramate was 18%, compared with 5% in the children born to women without epilepsy who did not receive AEDs (5).

For women of childbearing potential who use topiramate <or topiramate/phentermine>, the treatment should be re-evaluated to ensure that they comply with the pregnancy prevention program (described below).

Key elements of the pregnancy prevention program

For female children and women of reproductive potential

• treatment with topiramate <or topiramate/phentermine> should be initiated and supervised by a physician experienced in the treatment of epilepsy or migraine <or weight control, respectively>;
  • alternative treatment options should be considered;
• the need for treatment with topiramate (topiramate) in these populations should be reviewed at least once a year.

For women of reproductive potential

• topiramate for migraine prophylaxis <and topiramate/phentermine for weight control> is contraindicated:
  • in pregnancy;
  • for women of reproductive potential who do not use highly effective methods of contraception.
• topiramate (topiramate) for the treatment of epilepsy is contraindicated:
  • during pregnancy, if there is no suitable alternative treatment;
  • to women of childbearing potential who are not using highly effective methods of contraception. The only exception is women for whom there is no suitable alternative treatment but who are planning a pregnancy and are fully informed of the risks associated with the use of topiramate during pregnancy.
• A pregnancy test should be performed before starting treatment.
• The patient should be fully informed and should understand the potential risks associated with the use of topiramate (topiramate) during pregnancy. This includes the need to consult a specialist if a woman is planning a pregnancy, and to see a doctor immediately if she has become pregnant or thinks she may be pregnant.
• During treatment and for at least 4 weeks after discontinuation of treatment, at least one highly effective method of contraception (for example, an intrauterine device) or two complementary methods of contraception, including a barrier method, should be used. Women using systemic hormonal contraceptives should also be advised to use a barrier method.
• If a woman plans to become pregnant, consideration should be given to switching to appropriate alternative treatment <of epilepsy or migraine> before discontinuing contraception, <treatment with topiramate (topiramate)/phentermine> should be discontinued>. In the treatment of epilepsy, the woman should also be informed about the risks of uncontrolled epilepsy for the pregnancy.
• If a woman taking topiramate for the treatment of epilepsy becomes pregnant, she should be referred immediately to relevant specialists to review topiramate therapy and consider alternative treatment options, as well as for careful antenatal monitoring and counseling.
• If a woman who is taking topiramate (topiramate) for migraine prophylaxis <and topiramate (topiramate)/phentermine for weight management> becomes pregnant, treatment should be stopped immediately. The woman should be referred to a specialist for careful antenatal monitoring and counseling.

For female children (only for the treatment of epilepsy <and migraine>)

• Physicians must ensure that parents/guardians of female children taking topiramate understand the need to consult a specialist as soon as the child reaches menarche.
• Until then, the patient and her parents/guardians should be given comprehensive information on the risks associated with intrauterine exposure to topiramate, as well as on the need to use highly effective methods of contraception.

Training materials

In order to help healthcare professionals and patients avoid exposure to topiramate during pregnancy and to provide information on the risks of its use during pregnancy, educational materials will be created, including:

• a guide for healthcare professionals providing medical care to women taking topiramate (or topiramate/phentermine), including a risk awareness form to be completed (and signed) at the start of treatment and at each annual review of treatment with topiramate;
• a patient guide that should be provided to all female children or their parents/guardians and to women of childbearing potential who take topiramate <or topiramate/phentermine>;
• a patient card (enclosed in the package or attached to it) to ensure that the patient receives it each time the medicinal product is dispensed.

A text warning <and a graphic image> about the teratogenic risk will be added to the outer packaging of all medicinal products containing topiramate <and topiramate/phentermine>.

Reporting adverse reactions

Any suspected adverse reactions should be reported to the following address (insert the details of the national spontaneous reporting system, e.g., name, postal address, fax number, website).

Company contact person

(Details of the contact person for access to additional information, including the relevant website address(es), telephone numbers and postal address).

References

¹Bjørk M, Zoega H, Leinonen MK, et al. Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability. JAMA Neurol. Published online May 31, 2022. doi:10.1001/jamaneurol.2022.1269.

²Dreier JW, Bjørk M, Alvestad S, et al. Prenatal Exposure to Antiseizure Medication and Incidence of Childhood- and Adolescence-Onset Psychiatric Disorders. JAMA Neurol. Published online April 17, 2023. doi: 10.1001/jamaneurol.2023.0674. Online ahead of print. PMID: 37067807.

³Hernandez-Diaz S, Straub L, Bateman B, et al. Topiramate During Pregnancy and the Risk of Neurodevelopmental Disorders in Children. (2022), In: ABSTRACTS of ICPE 2022, the 38th International Conference on Pharmacoepidemiology and Therapeutic Risk Management (ICPE), Copenhagen, Denmark, 26–28 August, 2022. Pharmacoepidemiol Drug Saf, 2022; 31 Suppl 2:3-678, abstract 47.

⁴Cohen JM, Alvestad S, Cesta CE, et al. Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations. Ann Neurol. 2023; 93(3):551-562.

⁵Hernandez-Diaz S, McElrath TF, Pennell PB et al. Fetal Growth and Premature Delivery in Pregnant Women on Anti-epileptic Drugs. North American Antiepileptic Drug Pregnancy Registry. Ann Neurol. 2017 Sept;82 (3):457-465. doi:10.1002/ana.25031. PMI:28856694.

The full (original) text of the communication to healthcare professionals on the safety of use of medicinal products containing topiramate <or topiramate/phentermine can be found at the links: