Following its review of retinoid medicines, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has recommended that pregnancy prevention measures be updated and that they include a warning on the possible risk for neuropsychiatric disorders, such as depression, anxiety, and mood changes.
Retinoids are a class of medications that includes the active substances acitretin, adapalene, alitretinoin, bexarotene, isotretinoin, tazarotene, and tretinoin. They are taken orally or applied as creams or gels to treat a number of skin conditions, including acne and psoriasis. Some retinoids are also used to treat certain cancers.
The PRAC launched a review of retinoids in July 2016 because of concerns that pregnancy prevention programs (PPPs) and product information about the risk for neuropsychiatric disorders are inconsistent and inadequate. On the basis of its review, the PRAC made several recommendations at its February meeting.
For Pregnancy Prevention
The PRAC confirmed that when taken orally during pregnancy, all retinoids can have harmful effects on the fetus and therefore must not be used during pregnancy. In addition, the oral retinoids acitretin, alitretinoin, and isotretinoin should not be taken by women of childbearing age unless the conditions of a PPP are met. Although PPPs for these retinoids are already in place in some EU member states, the PRAC has now “updated and harmonized the PPP to ensure it is optimal to support the discussion between the doctor and the patient on the risks of these medicines, and that it is followed in practice,” the EMA explained in a statement.
The new PPP includes assessment of patients regarding the likelihood of becoming pregnant; requirements around pregnancy testing and the need for effective contraception before, during, and after treatment; and a requirement that patients and prescribers complete an “acknowledgement form” to confirm that appropriate advice has been given. Educational materials for physicians and a reminder card for patients will also be provided.
In addition, the PRAC wants companies that market acitretin, alitretinoin, and isotretinoin to conduct a study and a survey to assess the effectiveness of the updated measures and, in particular, to check on whether the PPP has been implemented.
For the oral retinoids bexarotene and tretinoin, a PPP is not necessary because these medicines, which are used to treat certain cancers, are used in a very different patient population under strict medical supervision. The current measures are considered appropriate for pregnancy prevention, the PRAC concluded.
For topical retinoids, the amount of active substance absorbed from the skin is “extremely low,” and therefore it is unlikely that these products will cause harm to the developing fetus, the PRAC said. However, because excessive use or skin lesions may increase absorption, “as a precaution,” the committee recommended that topical retinoids not be used during pregnancy or by women planning to become pregnant.
Neuropsychiatric Disorders
Although warnings about the possible risk for neuropsychiatric disorders such as depression, anxiety, and mood changes are already included in the product information for some oral retinoids, the PRAC reviewed the extent and nature of these warnings to ensure that they reflect the available evidence and that they are applied consistently.
The PRAC concluded that it could not be clearly established that oral retinoids posed a risk, owing to limitations of the available data. However, they recognized that patients with severe skin conditions may be more vulnerable to neuropsychiatric disorders, owing to the nature of the disease.
The committee therefore recommended that the prescribing information for all oral retinoids include a warning about this risk and that the warning include signs and symptoms patients and their families should be aware of, such as changes in mood or behavior.
For topical retinoids, the available data are “extremely limited” but suggest that these medicines do not carry a risk for psychiatric side effects. The PRAC therefore concluded that no additional warnings need to be added to the prescribing information.
These updated recommendations will be sent to EMA’s Committee for Medicinal Products for Human Use, which will determine a final opinion.
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