CWHN Writes the Minister of Health Re: Diane-35 Drug Ads
Honourable Ujjal Dosanjh,
Minister of Health
House of Commons
Ottawa, Ontario K1A 0A6
February 17, 2004
Honourable Minister
We are petitioning you to act immediately to stop the airing of a direct-to-consumer television advertisement for the prescription drug Diane-35 (cyproterone and estradiol) which poses serious risks to public health as well as being in contravention of the Food & Drugs Act. This ad has begun to air in February 2005 on a variety of Canadian channels, including MuchMusic, Global TV, and CTV.
Diane-35 increases the risk of venous thromboembolism (potentially fatal blood clots) as compared to other similar hormone combinations. There are at least six reported deaths in Canada of young women for which Diane-35 was the suspected cause.
Diane-35 was the subject of two safety advisories in Canada. The first was a reposting of a UK safety advisory in December 2002; the second was a 'dear health professional letter' that Health Canada required the manufacturer, Berlex, to send to all Canadian physicians and pharmacists. This dear health professional letter warned of the increased risk of venous thromboembolism and advised doctors not to prescribe Diane-35 for two unapproved (off-label) uses: for birth control and for mild acne. The UK, Australian and New Zealand governments have sent out similar safety advisories.
Diane-35 has only been approved for a restricted indication in Canada: treatment of severe acne in women who have failed to respond to other acne treatments such as oral antibiotics and have signs of hormonal imbalance. When it was approved, an internal Health Canada memo stated that the aim of this restricted indication was to limit population exposure. In addition to the risk of venous thromboembolism, one ingredient, cyproterone, is associated with liver toxicity and causes changes to liver cell DNA. A potential link to liver cancer remains an open question.
Health Canada failed to take any noticeable regulatory action in response to two previous direct-to-consumer advertising campaigns for Diane-35 in 1999 and 2001, in spite of complaints. These ads promoted widespread use of the product and ran for many months.
Berlex's current television ad promotes the use of Diane-35 for the two unapproved uses Health Canada and Berlex warned physicians against in the April 2003 'dear health professional' letter: mild acne and birth control.
Mild acne is promoted as an indication through the use of images of young girls with flawless skin preening in the mirror and the message to 'Ask your doctor or your dermatologist' at the end of the ad. The addition of dermatologist is a clear hint of the indication. Anyone who had severe acne that had failed to respond to previous treatment would not have the flawless skin of these models, either before or following treatment. Someone with the occasional pimple or who would like more beautiful skin would look much more like these models (i.e. with mild acne not requiring medical treatment). Birth control is promoted as an indication through the image of the pill package which appears in the closing shot of the ad, and which looks likes birth control pill packaging. The ad targets a vulnerable population: adolescent girls.
This is a television commercial for a prescription - i.e. Schedule F - drug. Prescription drug advertising is illegal in Canada, with the exception of price advertising, as outlined in Section C.01.044 of the Food & Drugs Act: "Where a person advertises to the general public a Schedule F [prescription-only] Drug, the person shall not make any representation other than with respect to the brand name, proper name, common name, price and quantity of the drug."
The TV ads for Diane-35 are not price advertisements. They contravene Section C.01.044 as they include representations other than name, price and quantity, among others:
- the models who are preening, twirling umbrellas, walking;
- the statement to 'Ask your doctor or your dermatologist';
- the image of the pill packet;
Ironically, in the United States, with its less restrictive laws on direct-to-consumer advertising than in Canada, this advertisement would be considered illegal. It would be considered a full product advertisement (with regulatory requirements for risk information) rather than a 'reminder' ad, because a medical specialty, dermatology, is mentioned in order to hint at the drug's approved use.
The airing of this ad will stimulate additional prescriptions for Diane-35. These prescriptions can be expected to lead to avoidable, unnecessary harm to previously healthy young women. Three to 10 extra cases of venous thromboembolism occur per 10,000 women taking Diane-35 per year, as compared to the rate of venous thromboembolism in users of low dose oral contraceptive pills. (See the enclosed summary of scientific evidence on venous thromboembolic risks and liver toxicity.)
Acne is not a life-threatening event, and a range of approved contraceptives exist with better safety profiles than Diane-35. There is no scientific evidence that Diane-35 is any more effective than a range of prescription and over-the-counter acne treatments available in Canada, either when used as a second-line treatment in the population for which it has been approved, or in any other population groups.
The health of young women in Canada deserves to be protected through proper, timely enforcement of the Food & Drugs Act. We ask you to take immediate action to stop the airing of this commercial in all Canadian media, and to prevent similar future ad campaigns.
Sincerely,
Barbara Mintzes, PhD, Centre for Health Services and Policy Research, UBC
Anne Rochon Ford, Coordinator, Women and Health Protection
Madeline Boscoe, Executive Director
& Abby Lippman, PhD, Chair, Canadian Women's Health Network
cc
- Diane Gorman, HPFB
- Anne Szutke-Fournier, MHPD
- Deanna St.Prix-Alexander, Bureau of Women's Health and Gender Analysis
References
Baraldi R, Marcelis C. , DES Action Canada Berlex advertising campaign for Diane-35 in Montreal, May 1999
Bassett K, Ford AR, Fuller C et al. letter to Diane Gorman, Assistant Deputy Minister, Health Canada, concerning direct-to-consumer advertising of Diane-35 (cyproterone/estradiol), March 13, 2001
Chaudhuri AK, Leroux AM, Matula T. Division of Endocrinology, Metabolism and Allergy. Health Canada. Review of Additional Data- Safety Submitted on April 22, 1997. Memo to M Carmen, Director, Bureau of Pharmaceutical Assessment. 9427-874-1-38. July 15, 1997
Committee on Safety of Medicines (UK CSM). Cyproterone acetate (Dianette);
risk of venous thromboembolism (VTE). Current Problems in Pharmacovigilance
2002; 28(Oct):9-10. Available at: www.mca.gov.uk/ourwork/monitorsafequalmed/currentproblems/currentproblems.htm
European Agency for the Evaluation of Medicines. EMEA Committee for Proprietary Medicinal Products (CPMP). Combined oral contraceptives and venous thromboembolism. London: Sept 28, 2001. Ref: EMEA/CPMP/2201/01/en/Final
Health Canada. Health Products and Food Branch and Therapeutic Products Directorate. Important safety concerns on the use of Diane-35. Ottawa. December 19, 2002
MedSafe. Letter to health professionals doctors/midwives/pharmacists about VTE with cyproterone-containing oral contraceptives. Wellington: March 2002.
Stril J-L, Berlex Canada and Health Canada, Health Products and Food Branch. Important Drug Safety Information about Diane-35 and the risk of venous thromboembolism. 'Dear Health Professional' letter. Pointe-Claire, Quebec: April 10, 2003
Diane-35 (cyproterone/estradiol)
An unacceptable risk profile
(excerpted from : "Evaluation Report on Diane-35 (cyproterone and estradiol) efficacy and safety" [unpublished]. Women & Health
Protection and Therapeutics Initiative, December 2004)
Venous thromboembolism (potentially fatal blood clots, including deep vein thrombosis and pulmonary embolism)
Eight case-control studies have examined risks of venous thromboembolism (VTE) with Diane-35 in a variety of settings and user groups. Women with acne or polycystic ovary syndrome had over twice the risk of VTE as women with the same diagnoses using oral contraceptives: odds ratio=2.2 (95% CI 1.4-3.6, age-adjusted); absolute risk increase =4.3 per 10,000 exposed women per year (95% CI 0.9-7.8 per 10,000). In a subgroup analysis that requires confirmation in further studies, women ³ 30 had an absolute risk increase of 20.4 per 10,000 (95% CI 7.2-33.6) exposed women per year. (Seaman et al, 2003)
Several studies compared the risk of VTE in Diane-35 to risks in users of levonorgestrel-containing combined oral contraceptives, a commonly-used type of birth control pill, which is associated with relatively low risks of VTE. They found between twice and five times the risk of venous thromboembolism: Vasilakis- Scaramozza and Jick (2001) odds ratio=3.9 (95% CI 1.1-13.4); Pini et al. (1996) odds ratio=4.5 (95% CI 1.1-20.6); Farley/WHO (1995), odds ratio= 5.1 (95% CI 1.3-20.3); Farmer et al. (2000), odds ratio=2.3 (95% CI 1.1-4.8). In absolute terms, the increases ranged from around 3 to 10 extra cases per 10,000 exposed women per year.
A second study by Farmer et al. (2000), carried out in the UK Medi-Plus database, failed to find a significant difference between Diane-35 and levornorgestrel-containing pills: odds ratio=0.7 (95% CI 0.2-3.0). However, there were only four cases among 8090 women exposed to Diane-35 . Unlike the studies above, researchers were aware what drug women had used when they assessed health outcomes; thus the methodology was less robust. This study also failed to find a significant difference between different types of oral contraceptives (2nd vs 3rd generation), unlike most other case-control studies. (Walker, 1998)
A recent New Zealand study has compared the rate of hospitalizations for VTE with rates of population use of oral contraceptives and Diane-35. (Heuser et al, 2004) The authors similarly found an increased risk with Diane-35. However, the study methodology was weaker than in the studies listed above.
Two studies only examined the risk of Diane-35 in comparison to non-users of oral contraceptive. In a Danish study, Lidegaard et al (2002) found a tripling of probability of VTE: odds ratio =3.3 (95% 1.4-7.6). Parkin et al. used death certificates to examine risks of fatal pulmonary embolism in women of reproductive age in New Zealand: odds ratio=17.6 (95% CI 2.7-113) among Diane-35 users.
Liver toxicity and possible risks of cancer
There is evidence of dose-related liver toxicity with the progestin component of Diane-35, cyproterone, and ongoing questions remain about potential liver carcinogenicity. Laboratory studies have found that cyproterone causes DNA adducts to form in rat and human liver cells, a potential sign of genotoxicity, and there is evidence of liver tumour development in pre-market rodent studies. (Brambilla and Martelli, 2002) A 1994 case report of the death from hepatocellular carcinoma of a woman who had used Diane-35 for 14 years for birth control prompted further investigation, given the rarity of this cancer and her lack of other risk factors. (Anon, 1995).
One case-control study of hepatocellular cancer failed to find a relationship between exposure to Diane-35 or other progestins with a similar chemical structure and development of liver cancer (MILTS, 1997) However, few women were exposed to Diane-35 and cyproterone, most outcomes were grouped, and there is evidence of genotoxicity with cyproterone, unlike the other included progestins, such as medroxyprogesterone. A second case-control study examining all types of liver toxicity, from altered liver enzymes to fatal and non-fatal serious liver disorders. (Seaman, 2003a) The authors failed to find a significant difference between Diane-35 users, and users of conventional oral contraceptives: odds ratio =2.2 (95% CI 0.9-4.8), p=.09, NS. The absolute rate of liver disorder on Diane-35 was 3.8 (95% CI 1.5-6.0) per 10,000 women-years, versus 2.2 (95% CI 1.4-3.0)/10,000 women-years on conventional oral contraceptives.
References
Anonymous. Germany's cyproterone warning. Lancet 1995; 345 (8955):979
Brambilla G, Martelli A. Are some progestins genotoxic liver carcinogens? Mutation Research 2002; 512: 155-163
Carcinogenicity Assessment Committee. Bureau of Pharmaceutical Assessment. Diane-35 (cyproterone acetate 2mg + ethinyl estradiol 35 ug). Ottawa: Minutes of Meeting, October 16, 1996. [obtained through Access to Information]
Farley TMM, Meirik O, Chang CL et al. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995; 346(8990):1582-1588
Farmer RDT, Lawrenson RA, Todd JC et al. Oral contraceptives and venous thromboembolic disease.
Analysis of the UK General Practice Research Database and the UK MediPlus Database. Human Reproduction Update 1999; 5:688-706
Heuser P, Tonga K, Hopkins R et al. Specific oral contraceptive use and venous thromboembolism resulting in hospital admission. New Zealand Medical Journal 2j004; 117 (1206):1-6
Lidegaard O, Edstrom B, Kreiner S. Oral contraceptives and venous thromboembolism: a five-year national case-control study. Contraception 2002; 65: 187-196
MILTS Project Team. Oral contraceptives and liver cancer. Results of the Multicentre International Liver Tumor Study. Contraception 1997; 56:275-284.
Parkin L, Skeg DCG, Wilson M et al. Oral contraception and fatal pulmonary embolism. Lancet 2000; 2133-2134
Rudiger T, Beckmann J, Wueisser W. Hepatocellular carcinoma after treatment with cyproterone acetate combined with ethinyloestradiol. Lancet 1995; 345(8947):452-453
Seaman HE, de Vries CS, Farmer RDT. The risk of liver disorders in women prescribed cyproterone acetate in combination with ethinyloestradiol (Dianette): a nested case-control study using the GPRD. Pharmacoepidemiology and Drug Safety 2003a; 12:541-550
Seaman HE, deVries CS, Farmer RDT. The risk of venous thromboembolism in women prescribed cyproterone acetate in combination with ethinyl estradiol: a nested cohort analysis and case-control study. Human Reproduction 2003; 18(3):522-526
Topinka J, Andrae U, Schwarz LR, Wolff T. Cyproterone acetate generates DNA adducts in rat liver and in primary rat hepatocyte culture. Carcinogenesis 1993; 14(3):423-427
Topinka J, Binkova B, Schwarz LR, Wolff T. Cyproterone acetate is an integral part of hepatic DNA adducts induced by this steroidal drug. Carcinogenesis 1996; 17(1);167-169
Vasilakis-Scaramozza, Jick H. Risk of venous thromboembolism with cyproterone or levonorgestrel contraceptives. Lancet 2001; 358(9291):1427-1429
Walker AM. Newer Oral Contraceptives and the Risk of Venous Thromboembolism. Contraception 1998;57; 169-181
Wooltorton E. Diane-35 (cyproterone acetate): safety concerns. CMAJ 2003; 168(4):455-6
