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ProjTitle.icon P.II.B.7. Risk Minimization Measures

In the area of pregnancy and breastfeeding, the objective of risk minimization measures (RMM) generally is to reduce any risk to the child as much as possible given the need for appropriate treatment for the mother. In this area, strategies for RMM include those aiming at:

•  Avoiding unintentional exposure in utero (e.g. by pre-conception counselling, discontinuing a specific medicine when the wish for child exists or avoiding pregnancy through effective contraception), considering teratogenic properties and the half-life of the medicinal product (see P.II.B.7.2.);

•  Mitigating the risk in the event of unplanned pregnancy by switching or discontinuing the medicinal product where possible (which may require specialist consultation) and intensified monitoring of the pregnancy; 

•  Modifying medication before or during pregnancy, e.g. by changing the dosage or route of administration or adapting treatment to the physiological changes in pregnancy for example in the case of medicines with a narrow therapeutic window; 

•  Where harm to the embryo or foetus by transfer through semen is an identified safety concern, minimizing exposure via male partners exposed to the medicine by use of barrier contraception and informing the physician if the partner becomes pregnant; 

•  Minimizing exposure through breast milk by optimized timing of medicine intake, short treatment duration, discontinuation of medication or if minimizing exposure is not feasible or acceptable, avoiding breastfeeding. If the decision is taken to breastfeed whilst continuing maternal medicine intake and there is a (potential) risk for the child, the infant should be carefully monitored and breastfeeding discontinued in the case of the adverse signs and symptoms; 

•  In breastfeeding women, depending on the therapeutic context and the availability of therapeutic alternatives, avoiding use of medicines that significantly reduce breast milk production. 

When serious risks of a medicinal product with use in pregnancy have been identified, a set of stringent RMM should be implemented aiming at avoiding exposure in utero, including sometimes a PPP (see P.II.B.7.2.). For less serious risks, the emphasis will be on ensuring that healthcare professionals and patients have information available supporting them making informed decisions regarding the most appropriate choice in the individual case.

P.II.B.7.1. Educational materials

Materials targeted at healthcare professionals and/or women of childbearing potential, pregnant or breastfeeding women may be warranted as part of the RMP (see P.II.B.1.) if there are important identified or potential risks and routine RMM is not considered sufficient. The guidance in GVP Module XVI and its Addendum I as well as section P.II.B.6. applies. Appropriate educational materials may cover:

•  Information regarding the risks and/or uncertainties in relation to exposure in utero or through breastfeeding, the risks of the underlying medical conditions, considerations for women of child bearing potential to use adequate contraceptive measures, advice about dosing, switching or discontinuation of treatment, monitoring of the foetus/child or other RMM;

•  Information for healthcare professionals to support their communication about risks and RMM with female patients (or their parents/care giver); 

•  Information for women considering using the product that explains the risks and the need to consult their healthcare professional to establish the most appropriate treatment and monitoring options for them individually; 

•  Encouragement of healthcare professionals and pregnant women to report exposure and pregnancy outcomes or suspected adverse reactions in a breastfed child to, as appropriate, a pregnancy registry (possibly with follow-up into breastfeeding), or marketing authorization holder;

•  Information on the need for pregnancy testing before the start of treatment and, as applicable, during and after treatment.

The target healthcare professional population for educational material needs to be agreed in each particular case, taking into account the characteristics of the medicinal product and the disease as well as the situation that different healthcare professionals may be involved in the care of long-term conditions during pregnancy. Different educational materials may be appropriate for different healthcare professional types and specialties.

Patient alert/reminder cards should provide succinct messages on the potential for harm, the need for contraception, action to take in the event of an unplanned pregnancy and action to take if planning a pregnancy, as applicable.

P.II.B.7.2. Advice on effective contraception

In cases where pregnancy should be avoided during the use of a product (according to section 4.3 or 4.6 of the summary of product characteristics (SPC)), women of childbearing potential must be advised, through the patient information leaflet and possibly in addition through educational materials (P.II.B.7.1.), to use effective contraception. The decision on the contraceptive method should be an individual informed choice and may depend on a variety of factors including the duration of the indicated treatment.

Contraceptive methods have different efficacy as well as ‘perfect use’ and ‘typical use’ failure rates, due to different potential and rates of incorrect or inconsistent use or effects of interacting medicines. Risk of user error is higher for daily methods than for long-acting methods and is highest for methods used at time of sexual intercourse. Instructions should specify that pregnancy must be excluded before treatment initiation and each repeat prescription and for how long pregnancy must be avoided, taking into account the half-life of the product and/or its metabolites, the pharmacological effect, and for some genotoxic products, spermatogenesis and/or folliculogenesis.

For highly teratogenic substances, the potential of exposure through semen should be considered and if an identified safety concern for exposure through semen exists, the recommendation to use barrier methods needs to be made.

P.II.B.7.3. Pregnancy prevention program

When a medicinal product with known teratogenic effect is intended for use in women of childbearing potential, implementing a pregnancy prevention program (PPP) may be appropriate. Scenarios when a PPP may be needed include chronic conditions where treatment may be started long before the patient becomes of child-bearing potential or is considering pregnancy.

When considering the need for a PPP, the following should be taken into account:

•  The level of scientific evidence for the teratogenic potential of a medicinal product, including the evidence on the magnitude and nature of the teratogenic effect

•  The likelihood of the use of the medicinal product in women of childbearing potential, especially, its potential use under the clinical conditions for which the product is authorized. 

The nature of the PPP will depend on the indication, the duration of use of the medicine, and whether or not alternatives to the medicine are available (e.g. delaying pregnancy, delaying treatment or using an alternative medication or other kind of treatment). The guidance to be followed for PPPs is provided in GVP Module XVI.

In relation to evaluating the effectiveness of PPPs, the following applies in addition to GVP Module XVI: In the case of a pregnancy occurring during the use of medicinal product for which a PPP is in place, the reasons for the occurrence of the pregnancy should be evaluated, where feasible, for the continuous improvement of the PPP. A formal root cause analysis should be considered if substantial failures are identified. These efforts, and any action resulting from them, need to be reported routinely in the PSUR.​

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