As part of Health Canada's efforts to minimize health risk factors to Canadians, a safety review was initiated to evaluate the currently available information regarding the potential risk of blood clots with DIANE-35. The review was prompted by a French medicines regulatory agency announcement on January 30th, 2013 indicating its intention to suspend the marketing authorizations for DIANE-35 and its generics for acne treatment in France within 3 months. The French decision was triggered by reports of deaths caused by blood clots associated with the use of DIANE-35 in France.Footnote 1 The Health Canada review includes the consideration of strategies that would minimize potential risks to Canadians with the use of DIANE-35.
DIANE-35 and its generics are approved in Canada for the treatment of severe acne with accompanying symptoms of androgenisation (male characteristics) including excessively oily skin as well as facial and body hair growth, after topical therapy or systemic antibiotic treatments have failed. It is to be used only after other acne treatments have not worked. In discussion with a woman's health care provider, the use of these medicines should be discontinued when signs of acne have cleared.
Blood clots are a rare but well-known side effect associated with the use of DIANE-35 and other hormonal products containing progestins and estrogens. The risk of blood clot formation is less common in young, healthy, non-pregnant women than in those on hormonal products. Other issues that may increase a woman's chance of developing a clot include older age, smoking, obesity and periods of immobility such as those associated with long-distance travel or hospitalization. Some evidence indicates that the chance of developing clots may be higher during the first year of use with hormonal products. The risk of blood clots is outlined in the product information available to the public.
To assess the available evidence that dealt with a woman's chance of developing a blood clot while taking DIANE-35. The evidence considered Canadian patient reports, scientific and medical literature, and what is known about the use of this medicine both in Canada and internationally. The currently existing strategies to minimize this risk were also considered, including a review of the product information available to health care professionals and patients.
Health Canada estimates the number of prescriptions for DIANE-35 and generics to be stable over the last five years at approximately 450,000 prescriptions per year, which corresponds to about 40,000 women using this drug each year in Canada. The major reason for prescribing this medicine is for the treatment of severe acne, but the data also indicates its usage as a means of birth control (estimated at 35-40% of prescriptions given by general practitioners and obstetrician/gynecologists), which is considered an unapproved use of this drug. However, due to the relatively low number of overall prescriptions for DIANE-35 in Canada, these figures on use as a means of birth control can only be used as guidance for estimation.
The Canada Vigilance database was searched for reports that implicated both cyproterone acetate and ethinyl estradiol products and a blood clot-related incident or any report of death. Reports from the point of DIANE-35 becoming available in Canada, in 1998, up to May 1, 2013, were collected. The search retrieved 95 unique reports. A total of 12 reports of death were identified and were further investigated. In 10 out of the 12 cases, the likelihood of the drug causing the death was considered to be at least "possible," with the other two reports containing not enough information to determine whether or not the drug caused the death. However, in nine out of these possible 10 cases, the patients had additional risk factors that would predispose or make it possible for them to have blood clots, such as obesity, smoking, previous trauma and decreased mobility. The case reports do not indicate a change in the known safety profile of DIANE-35 for blood clots in Canada.
The review considered the scientific and medical literature. Several scientific studies addressed the risk of blood clots with different types of hormonal products such as DIANE-35 and birth control pills. The risk of blood clots with these products was compared to the risk of blood clots in women that do not use these products. It was found that the occurrence of blood clots in users of DIANE-35 was higher than non-users but similar to some of the hormonal birth control products currently available on the Canadian market. It was concluded that this information does not point to a higher risk of blood clots than what is already known about DIANE-35 and outlined in the product information.
It was important to determine how DIANE-35 was being used in other countries to better understand the French medicines regulatory agency's decision. At that time, the approved use of the drug in France was for treating acne, potentially exposing a greater number of French patients to the risk of blood clots than in Canada. In comparison, the approved use in the United Kingdom is similar to Canada: for treatment of moderate to severe acne and after used topical therapy or systemic antibiotic treatments have failed.
The current prescribing information for DIANE-35 already contained warnings about the risk of blood clots. This information is supported by evidence from key scientific studies. Considering the current evidence and discussions that have taken place internationally, Health Canada is adopting a precautionary approach and has updated the prescribing information to provide further clarity regarding this rare but known risk. The completion of the review was communicated in the form of an advisory, to inform the public and health care professionals about the safe use of this product in the appropriate patient population. Health Canada's review of the safety of the anti-acne medication DIANE-35 has found that the drug's benefits continue to outweigh the risks, when used as authorized.
Full review reports are available upon request to Marketed Health Products Directorate. These reports are subject to redactions of personal and confidential information.
Bayer Inc. Official Canadian Product Monograph for DIANE-35 (dated June 17, 2010)
Bird ST, et al. (2013) Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis. CMAJ 185(2):E115-E120
Hansson PO, Sorbo J and Eriksson H. (2000) Recurrent venous thromboembolism after deep vein thrombosis: Incidence and risk factors. Arch Intern Med;160:769-774.
Heinemann LAJ and Dinger JC. (2007) Range of published estimates of venous thromboembolism incidence in young women. Contraception 75:328-36.
Heit JA, et al. (2005). Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 143:697-706.
Johnson JV, et al. (2008) Effects of oral and transdermal hormonal contraception on vascular risk markers: a randomized controlled trial. Obstet Gynecol 111:278-84.
Lidegaard O, et al. (2011) Risk of venous thromboembolism from use of oral contraceptives containing different progestogenes and oestrogen doses: Danish cohort study, 2001-2009. BMJ. 343:d6423.
Lidegaard O, et al. (2009) Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ; 339:b2890
Lidegaard O, et al. (2002) Oral contraceptives and venous thromboembolism: a five-year national case-control study. Contraception 65:187-196.
Middeldorp S, et al. (2000) Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a crossover study. Thromb Haemost 84:4-8.
Nast A, et al. (2012) European Evidence-Based (S3) Guidelines for the Treatment of Acne. J Eur Acad Dermatol Venereol 26(S1):1-29.
Rosendaal FR. (1999) Venous thrombosis: a multicausal disease. Lancet 353:1167-73.
Seaman HE, et al. (2004) Venous thromboembolism associated with cyproterone acetate in combination with ethinyloestradiol (DIANEtte«): observational studies using the UK General Practice Research Database. Pharmacoepidemiol Drug Saf 13:427-436.
Silverstein MD, et al. (1998) Trends in the incidence of deep vein thrombosis and pulmonary embolism: A 25-year population- based study. Arch Intern Med 158:585-593.
Tans G, et al. (2000) A randomized cross-over study on the effects of levonorgestrel- and desogestrel-containing oral contraceptives on the anticoagulant pathways. Thromb Haemost 84:15-21.
Tchaikovski SN and Rosing J. (2010) Mechanisms of estrogen-induced venous thromboembolism. Thromb Res 126:5-11.
Thiboutot D, et al. (2009) New insights into the management of acne: An update from the Global Alliance to improve outcomes in acne group. J Am Acad of Dermatol 60(5) S1:pp.S1-S50.
UK Summary of Product Characteristics for DIANEtte updated 19 March 2012 http://www.medicines.org.uk/emc/medicine/1814/SPC
van Hylckama Vlieg A, et al. (2009) The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 339:b2921.
Vasilakis-Scaramozza C and Jick H. (2001) Risk of venous thromboembolism with cyproterone or levonorgestrel contraceptives. Lancet 358:1427-29.
DIANE-35 was re-instated in France in January 2014.