In accordance with paragraph 8 of Section IV of the Procedure for Expert Evaluation, the applicant must amend the instructions for medical use of the medicinal product upon receipt of new data, including bringing the instructions for medical use into line with the approved instructions for medical use of the original (reference) medicinal product, and ensure that the information on the medicinal product corresponds to current scientific knowledge.
The previous publication can be found at the linkhttps://www.dec.gov.ua/materials/komitet-z-oczinky-ryzykiv-u-farmakonaglyadi-prac-rekomenduye-novi-zahody-z-bezpeky-shhodo-unyknennya-vplyvu-likarskyh-zasobiv-shho-mistyat-topiramat-topiramate-pid-chas-vagitnosti-2/?role=applicant
Changes to the relevant sections of the instructions for medical use
Note: These changes to the relevant sections of the instructions for medical use are the result of a referral procedure.
Amendments to the relevant sections of the instructions for medical use
[For all relevant medicinal products, the existing instructions for medical use should be amended (adding, replacing, or deleting text, as appropriate) to reflect the agreed wording, as indicated below].
- Medicinal products containing topiramate (single-component)
Reporting of suspected adverse reactions
Reporting adverse reactions after the registration of a medicinal product is of great importance. It allows continued monitoring of the benefit/risk balance of this medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Section "Posology and method of administration"
- Medicinal products containing topiramate (single-component)
[This section should contain the following wording. The wording in angle brackets applies depending on whether the medicinal product is indicated for patients under 18 years of age and adults, or the medicinal product is indicated only for adults].
<Female children and women> <Women> of reproductive potential
Treatment with topiramate should be initiated and supervised by a physician experienced in the treatment of epilepsy or migraine.
For <female children and> women of childbearing potential, alternative therapy options should be considered. The need for treatment with topiramate for patients in these groups should be reviewed at least once a year (see the sections “Contraindications,” “Special warnings and precautions for use,” and “Use during pregnancy or breastfeeding”).
- Medicinal products containing topiramate/phentermine
[This section should contain the following wording].
Women of childbearing potential
Treatment with topiramate/phentermine must be initiated and supervised by a physician experienced in weight management.
For women of reproductive potential, alternative treatment options should be considered. The need for treatment with topiramate/phentermine in patients of this category should be reviewed at least once a year (see the sections “Contraindications,” “Special warnings and precautions for use,” and “Use during pregnancy or breastfeeding”).
Section «Contraindications»
- Medicinal products containing topiramate (single-component)
[Any existing information on pregnancy and women of reproductive potential in the “Contraindications” section should be replaced with the following].
Migraine prevention:
- during pregnancy (see sections “Special warnings and precautions for use” and “Use during pregnancy or breastfeeding”);
- in women of childbearing potential who do not use highly effective methods of contraception (see the sections “Special warnings and precautions for use,” “Interaction with other medicinal products and other forms of interaction,” and “Use during pregnancy or breastfeeding”).
Epilepsy:
- during pregnancy, if there is no suitable alternative treatment (see sections “Special warnings and precautions for use” and “Use during pregnancy or breastfeeding”);
- in women of childbearing potential who are not using highly effective contraception methods. The only exception is a woman for whom there is no suitable alternative treatment but who is planning a pregnancy and is fully informed of the risks of using topiramate during pregnancy (see the sections “Special warnings and precautions for use,” “Interaction with other medicinal products and other forms of interaction” and “Use during pregnancy or breastfeeding”).
- Medicinal products containing topiramate/phentermine
[Any existing information on pregnancy and women of reproductive potential in the “Contraindications” section should be replaced with the following].
<Name of the medicinal product> is contraindicated:
- during pregnancy (see sections “Special warnings and precautions for use” and “Use during pregnancy or breastfeeding”);
- women of childbearing potential who do not use highly effective methods of contraception (see the sections “Special warnings and precautions for use”, “Interaction with other medicinal products and other forms of interaction” and “Use during pregnancy or breastfeeding”).
“Special precautions for use” section
- Medicinal products containing topiramate (single-component)
[Any existing information on women of childbearing potential in the section “Special precautions for use” should be replaced with the following text. Note that any existing results of studies regarding pregnancy should be removed].
Pregnancy Prevention Program
The use of topiramate during pregnancy can cause serious congenital malformations and fetal growth retardation.
Some data indicate an increased risk of neurodevelopmental disorders in children exposed to topiramate in utero, while other data do not indicate such an increased risk (see the section “Use during pregnancy or breastfeeding”).
Women of childbearing potential
Women of reproductive potential should have a pregnancy test before starting treatment with topiramate.
The patient must be fully informed and understand the risks associated with the use of topiramate during pregnancy (see sections “Contraindications” and “Use during pregnancy or breastfeeding”). This includes the need to consult a specialist if a woman is planning a pregnancy, in order to discuss switching to alternative treatments before stopping contraception, as well as to contact a specialist immediately if she has become pregnant or thinks she may be pregnant.
[The text below in angle brackets should be added only for medicinal products indicated for use in patients under 18 years of age].
<Female children
Physicians should ensure that parents/guardians of female children taking topiramate understand the need to consult a specialist as soon as the child reaches menarche. At that time, the patient and 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 as soon as this becomes relevant. The need to continue topiramate therapy should be reviewed, and alternative treatment options should be considered>.
Educational materials on these measures are available to health care professionals and patients (or parents/guardians). The patient guide must be provided to all women of reproductive potential who take topiramate, as well as to the parents/guardians of female children. The patient card is provided together with the packaging of <Name of the medicinal product>.
- Medicinal products containing topiramate/phentermine
[Any existing information on women of childbearing potential in the “Special warnings and precautions for use” section should be replaced with the following text].
Pregnancy Prevention Program
The use of topiramate during pregnancy can cause serious congenital malformations and fetal growth retardation.
Some data indicate an increased risk of neurodevelopmental disorders in children exposed to topiramate in utero, whereas other data do not indicate such an increased risk (see the section “Use during pregnancy or breastfeeding”).
Women of childbearing potential
Women of reproductive potential should have a pregnancy test before starting treatment with topiramate.
The patient must be fully informed and understand the risks associated with the use of topiramate/phentermine during pregnancy (see the sections “Contraindications” and “Use during pregnancy or breastfeeding”). This includes the need to consult a specialist if a woman is planning a pregnancy, in order to discontinue treatment with topiramate/phentermine and discuss the need for alternative treatment before stopping contraception, as well as to contact a specialist immediately if a woman becomes pregnant or believes she may be pregnant.
Training materials on these measures are available for healthcare professionals and patients. The Patient Guide must be provided to all women of reproductive age who take topiramate/phentermine. The Patient Card is provided with the package of <Name of the medicinal product>.
Section "Interaction with other medicinal products and other forms of interaction"
- Medicinal products containing topiramate (single-component)
[Any existing text of the section “Interaction with other medicinal products and other forms of interaction” relating to contraceptives should be reviewed and restated in the following wording. Please note that the subheading should be titled “Hormonal contraceptives for systemic use” (if the current subheading is titled “Oral contraceptives”, it should be reviewed)].
Hormonal contraceptives for systemic use
[…] The clinical significance of the observed changes is unknown. The possibility of reduced contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking hormonal contraceptives for systemic use together with <Name of the medicinal product>. Patients should be asked to report any changes in the pattern of bleeding. The effectiveness of contraception may be reduced even in the absence of breakthrough bleeding. Women using hormonal contraceptives for systemic use should also be advised to use a barrier method.
- Medicinal products containing topiramate/phentermine
[Any existing text of the section "Interaction with other medicinal products and other forms of interaction" relating to contraceptives should be replaced with the following wording. Please note that the subheading should be titled "Hormonal contraceptives for systemic use" (if the current subheading is titled "Oral contraceptives", it should be reviewed)].
Hormonal contraceptives for systemic use
Concomitant use of multiple doses of <Name of the medicinal product> 15 mg/92 mg once daily with a single dose of an oral contraceptive containing 35 mcg of ethinylestradiol (estrogen component) and 1 mg of norethisterone (progestogen component) in healthy volunteers with obesity reduced ethinylestradiol exposure by 16% and increased norethisterone exposure by 22%. The possibility of reduced contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking systemic hormonal contraceptives together with <Name of the medicinal product>. Patients should be asked to report any changes in the pattern of bleeding. Contraceptive efficacy may be reduced even in the absence of breakthrough bleeding. Women using systemic hormonal contraceptives should be advised to also use a barrier method.
Section “Use during pregnancy or breastfeeding”
- Medicinal products containing topiramate (single-component)
[Any existing information on pregnancy and women of childbearing potential in the section “Use during pregnancy or breastfeeding” should be replaced with the following.]
Pregnancy
Risk associated with epilepsy and antiepileptic medicinal products (AEMPs) in general
Women of reproductive potential, and especially women planning pregnancy and pregnant women, should receive specialist counseling on the potential risks to the fetus caused by both seizures and AED treatment. The need for AED treatment should be reviewed if a woman plans to become pregnant. Women receiving AED therapy should avoid abruptly stopping it, as this may lead to epileptic seizures, which may have serious consequences for the woman and the fetus. Where possible, monotherapy should be preferred, since therapy with several AEDs may be associated with a higher risk of congenital malformations than monotherapy, depending on the concomitant AEDs.
Risks associated with topiramate
Topiramate is teratogenic in mice, rats, and rabbits (see Preclinical safety data). In rats, topiramate crosses the placental barrier.
In humans, topiramate crosses the placenta, and similar concentrations were found in the umbilical cord and maternal blood.
Clinical data from pregnancy registries indicate that newborns with in utero exposure to topiramate as monotherapy have:
Serious congenital malformations and fetal growth restriction
- Increased risk of congenital malformations (in particular, cleft lip/palate, hypospadias, and anomalies involving various body systems) due to the use of topiramate during the first trimester. Pregnancy data from the North American Antiepileptic Drug Pregnancy Registry for topiramate monotherapy showed an approximately 3 times higher prevalence of major congenital malformations (4,3%) compared with the reference group not taking antiepileptic medicinal products (1,4%). Data from an observational population-registry-based study conducted in the Nordic countries showed a 2-3 times higher prevalence of major congenital malformations (up to 9,5%) compared with the reference group not taking antiepileptic medicinal products (3,0%). In addition, data from other studies indicate that, compared with monotherapy, there is an increased risk of teratogenic effects associated with the use of antiepileptic medicinal products as part of combination therapy. The risk was reported to be dose-dependent; effects were observed with all doses. In women who took topiramate and gave birth to a child with congenital malformations, there is an increased risk of malformations in subsequent pregnancies if they were exposed to topiramate.
- Increased incidence of births of low-weight infants (<2500 grams) compared with the control group.
- Increased prevalence of low birth weight for gestational age (SGA is defined as birth weight below the 10th percentile adjusted for gestational age, stratified by gender). In the North American registry of pregnant women taking AEDs, the risk of SGA in children of women who used topiramate was 18% compared with 5% in children of women without epilepsy who did not take AEDs. The long-term consequences of SGA could not be determined.
Neurodevelopmental disorders
- Data from two observational population-registry studies conducted on the basis of almost the same dataset in the Nordic countries indicate that the prevalence of autism spectrum disorders, intellectual disability or attention deficit hyperactivity disorder (ADHD) in almost 300 children exposed to topiramate in utero may be 2-3 times higher than in children of mothers with epilepsy who did not take AEDs. A third observational cohort study conducted in the USA did not find an increased cumulative incidence of these outcomes up to 8 years of age 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 take AEDs.
Indication Epilepsy
- Topiramate is contraindicated during pregnancy, except in cases where there is no suitable alternative treatment (see sections “Contraindications” and “Special warnings and precautions for use”).
- A woman must be fully informed about the risks of using topiramate during pregnancy and understand them. This includes a discussion of the risks of uncontrolled epilepsy for the course of pregnancy.
- If a woman plans to become pregnant, measures should be taken to switch to an appropriate alternative treatment before contraception is discontinued.
- If a woman becomes pregnant while taking topiramate, she should immediately contact a specialist to review the topiramate treatment and consider alternative treatment options.
- If topiramate is used during pregnancy, the patient should be referred to a specialist for evaluation and counseling regarding the pregnancy. Careful prenatal monitoring should be performed.
Indications Migraine prophylaxis
Topiramate is contraindicated during pregnancy (see the sections “Contraindications” and “Special warnings and precautions for use”).
Women of reproductive age (all indications)
Topiramate is contraindicated in women of reproductive age who are not using highly effective contraception. The only exception is a woman with epilepsy for whom there is no suitable alternative, but who is planning a pregnancy and is fully informed about the risks of using topiramate during pregnancy (see sections “Special warnings and precautions for use”, “Interaction with other medicinal products and other forms of interaction”, and “Use during pregnancy or breastfeeding”).
During treatment and for at least 4 weeks after discontinuation of treatment with <name of the medicinal product>, at least one highly effective method of contraception (for example, an intrauterine device) or two additional methods of contraception, including a barrier method, should be used (see the sections “Contraindications”, “Special warnings and precautions for use”, and “Interaction with other medicinal products and other forms of interaction”).
For women of reproductive potential, alternative treatment options should be considered.
Before starting treatment with topiramate, women of reproductive potential should have a pregnancy test.
The female patient must be fully informed and understand the risks associated with the use of topiramate during pregnancy. This includes the need to consult a specialist if a woman is planning a pregnancy, and to contact a specialist immediately if she has become pregnant or believes she may be pregnant and is taking topiramate.
For women with epilepsy, the risks of uncontrolled epilepsy during pregnancy should also be considered (see the sections "Contraindications" and "Special warnings and precautions for use").
[The text below in angle brackets should be added only for medicinal products intended for use in patients under 18 years of age].
<For female children (see section “Special warnings and precautions for use”)>.
- Medicinal products containing topiramate/phentermine
[Any available information on pregnancy and women of childbearing potential in the section “Use during pregnancy or breastfeeding” must be replaced with the following].
Pregnancy
<active substances/name of medicinal product> are contraindicated in pregnancy (see sections “Contraindications” and “Special warnings and precautions for use”).
Topiramate is known to be teratogenic in animals (see preclinical safety data) and humans. In humans, topiramate crosses the placenta, and similar concentrations have been found in the umbilical cord and maternal blood.
Clinical data from pregnancy registries indicate that newborns exposed in utero to topiramate monotherapy have:
Serious congenital malformations and fetal growth restriction
- Increased risk of congenital malformations (in particular, cleft lip/palate, hypospadias, and anomalies involving various body systems) due to the use of topiramate during the first trimester. Pregnancy data from the North American Antiepileptic Drug Pregnancy Registry for topiramate monotherapy showed an approximately 3 times higher prevalence of major congenital malformations (4,3%) compared with the reference group not taking antiepileptic medicinal products (1,4%). Data from an observational population-registry-based study conducted in the Nordic countries showed a 2-3 times higher prevalence of major congenital malformations (up to 9,5%) compared with the reference group not taking antiepileptic medicinal products (3,0%). In addition, data from other studies indicate that, compared with monotherapy, there is an increased risk of teratogenic effects associated with the use of antiepileptic medicinal products as part of combination therapy. The risk was reported to be dose-dependent; effects were observed with all doses. In women who took topiramate and gave birth to a child with congenital malformations, there is an increased risk of malformations in subsequent pregnancies if they were exposed to topiramate.
- Increased incidence of births of low-weight infants (<2500 grams) compared with the control group.
- Increased prevalence of low birth weight for gestational age (SGA is defined as birth weight below the 10th percentile adjusted for gestational age, stratified by gender). In the North American registry of pregnant women taking AEDs, the risk of SGA in children of women who used topiramate was 18% compared with 5% in children of women without epilepsy who did not take AEDs. The long-term consequences of SGA could not be determined.
Neurodevelopmental disorders
- Data from two observational population-registry studies conducted on the basis of almost the same dataset in the Nordic countries indicate that the prevalence of autism spectrum disorders, intellectual disability or attention deficit hyperactivity disorder (ADHD) in almost 300 children exposed to topiramate in utero may be 2-3 times higher than in children of mothers with epilepsy who did not take AEDs. A third observational cohort study conducted in the USA did not find an increased cumulative incidence of these outcomes up to 8 years of age 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 take AEDs.
Women of childbearing potential
Topiramate/phentermine is contraindicated in women of childbearing potential who do not use highly effective methods of contraception. During treatment and for at least 4 weeks after discontinuation of treatment with <name of the medicinal product>, 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 (see the sections “Contraindications”, “Special warnings and precautions for use”, and “Interaction with other medicinal products and other forms of interaction”).
For women of reproductive potential, alternative treatment options should be considered.
A pregnancy test should be performed in women of reproductive age before starting treatment with topiramate/phentermine.
The patient must be fully informed and understand the risks associated with the use of topiramate/phentermine during pregnancy. This includes the need to consult a specialist if a woman is planning a pregnancy, as well as the need to contact a specialist immediately if she has become pregnant or thinks she may be pregnant and is taking topiramate/phentermine.
List of medicinal products containing topiramate and authorized for medical use in the territory of Ukraine (according to the State Register as of 30.11.2023).
To analyze the published information, the applicant must use the original text available at the links
