Safety advisory on cyproterone acetate/ethinylestradiol

HSA, in consultation with its Product Vigilance Advisory Committee (PVAC), has completed its benefit-risk assessment on cyproterone acetate/ethinylestradiol (CPA/EE). New restrictions will be imposed to limit the use of this product so as to mitigate the risks of venous and arterial thromboembolism in view of the modest benefit derived from treatment with CPA/EE for conditions such as androgenetic alopecia and mild acne.

CPA/EE has been licensed in Singapore since 1990 for the treatment of androgen-dependent diseases in women, such as acne (especially pronounced forms and those which are accompanied by seborrhoea or by inflammation or formation of nodes), androgenetic alopecia, and mild forms of hirsutism (Diane-35®, Bayer (South East Asia) Pte Ltd). It is also available as generic products Estelle-35® or Estelle-35ED® (Apex Pharma Marketing Pte Ltd).

Background

In January 2013, the French health authority (ANSM) initiated a suspension of the marketing authorisations of CPA/EE in France.1 This decision followed its review which found that the effectiveness of these products in treating acne was only moderate. Furthermore, the ANSM took the view that these products were being widely used off-label for contraception although their efficacy as a contraceptive had not been established. The ANSM considered that the benefit-risk ratio of CPA/EE was unfavourable since its modest efficacy did not outweigh the risk of thromboembolic events and unwanted pregnancies.

At the request of ANSM, the European Medicines Agency (EMA) conducted a review on the risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) associated with CPA/EE. In May 2013, the EMA concluded that the benefits of CPA/EE continue to outweigh its risks, provided that several measures were taken to minimise the risk of thromboembolism.2 These included stipulating that CPA/EE should only be used for the treatment of acne when alternative treatments (such as topical therapy or systemic antibiotic treatment) have failed, the removal of indication for the treatment of alopecia, and strengthening of the safety information in the package inserts (PI) of CPA/EE-containing products.

Similarly, Health Canada and the Australian Therapeutic Goods Administration (TGA) also concluded that the benefits of CPA/EE continue to outweigh its risks when used as authorised for acne and hirsutism.3,4

HSA's benefit-risk assessment

HSA's review took into consideration the efficacy of CPA/EE in its locally authorised indications, expert opinions from dermatologists, O&G specialists and family physicians, local ADR reports associated with the use of CPA/EE, related scientific literature on VTE and ATE, and actions taken by other regulatory agencies.

HSA, together with its PVAC, concluded that there remains a place in therapy for CPA/EE, particularly for moderate to severe acne where conventional treatment (e.g., systemic antibiotics, topical therapy) has failed, as well as in the treatment of mild hirsutism. However, there was insufficient data to demonstrate its benefit in treating androgenetic alopecia compared with the risk of thromboembolism. In view of the increased risks of VTE and ATE associated with CPA/EE, additional warnings and restrictions will be put in place in the labelling to mitigate the risks of such events.

HSA's regulatory decision and advisory

The indications for CPA/EE will be restricted and its safety information in the local PIs will be strengthened as follows:

  • CPA/EE is indicated for the treatment of moderate to severe acne related to androgen-sensitivity (with or without seborrhoea) and/or mild forms of hirsutism in women of reproductive age
  • When used for the treatment of acne, CPA/EE should only be used after topical therapy or systemic antibiotic treatments have failed
  • CPA/EE is no longer indicated for the treatment of androgenetic alopecia
  • CPA/EE should not be prescribed for the purpose of contraception alone
  • The need to continue treatment should be evaluated periodically by the treating physician
  • The use of CPA/EE carries an increased risk of VTE compared with no use. The excess risk of VTE is highest during the first year a women starts CPA/EE or when restarting or switching after a pill-free interval of at least a month

In addition, the contraindications and warnings will be strengthened to increase awareness of the risk and risk factors of thromboembolism in relation to the use of CPA/EE.

Although no local cases of thromboembolic events associated with CPA/EE have been reported, healthcare professionals are reminded to screen patients for risk factors, such as increasing age, smoking and obesity, as well as counsel them on the signs and symptoms of VTE and ATE. Patient selection and counselling are vital in ensuring that the benefit-risk profile of CPA/EE remains positive.

Healthcare professionals are also encouraged to report adverse reactions suspected to be associated with the use of CPA/EE to the Vigilance Branch of HSA.

References

  1. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/01/news_detail_001703.jsp&mid=WC0b01ac058004d5c1
  2. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Cyproterone_and_ethinylestradiol_containing_medicinal_products/human_referral_prac_000017.jsp&mid=WC0b01ac05805c516f
  3. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/29283a-eng.php
  4. http://www.tga.gov.au/safety/alerts-medicine-diane-35-130205.htm
Healthcare professional, Industry member, Therapeutic Products
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