Diane 35 is a drug indicated in the treatment of acne, the use of which has long been diverted into a contraceptive pill. In 2013, she was restricted to France, accused of being linked to the death, by thrombosis or embolism, of several women.
Diana 35 is a drug anti-acne marketed by the Bayer laboratory since July 1987 in France. This drug is indicated in the treatment of acne in women. But its composition means that it also has contraceptive properties and helps block ovulation. So even if this medicine has no never received marketing authorization (AMM) as a pill contraceptive, its use has long been misused as a contraceptive for thousands of women. Issue : a risk of venous thromboembolism (formation of a clot, risk of embolism, phlebitis, etc.) multiplied by 4 has been demonstrated in patients treated with Diane 35 (or its generics). In 25 years, these are nearly 400 women who had a thromboembolic accident under Diana 35 and 10 of them died by pulmonary embolism or cerebral thrombosis. Suspension, return to the market, restriction of use… Back to the scandal around Diane 35.
Key dates: when was Diane 35 banned in France?
► In October 1997the first warnings concerning the venous and arterial thromboembolic risk of proprietary medicinal products containing the fixed-dose ethinylestradiol + cyproterone combination (which is the case with Diane 35) have been reported to the French health authorities.
► In July 2011following the reported risks and within the framework of a systematic reassessment of the benefit/risk of medicinal products authorized before 2005, the Medicines Agency (ANSM) asked the Bayer laboratory to clarify the positioning of Diane 35 in view of its actual use and to submit data concerning its contraceptive efficacy, in order to regularize an identified off-label use.
► In December 2011Bayer laboratories provide the ANSM with a file containing the Diane 35 anti-acne and anti-ovulatory efficacy data, as well as product safety data. But according to the ANSM, Diane 35 is not intended to be prescribed as an anti-ovulatory.
► In February 2013, the Medicines Agency (ANSM) is launching a European procedure concerning the specialty Diane 35 and its generics. At the end of this revaluationthe ANSM considers that the benefit/risk ratio of Diane 35 and its generics is unfavorable in the treatment of acne And suspends the French marketing authorization as a precautionary measure. Diane 35 can no longer be prescribed.
► But a few months later, on July 25, 2013, the European Commission finally concludes with a favorable benefit/risk ratio of Diane 35 and its generics and the ANSM raises MA suspensions in January 2014. However, due to the known thromboembolic risk, the European Commission restricts the use of Diane 35 and its credits: these drugs can only be prescribed as second-line treatment of moderate to severe acne and in case of failure of the usual treatments (local treatment or oral antibiotic treatment). From now on, Diane 35 should no longer be used as a birth control pill nor should it be prescribed at the same time as another hormonal contraceptive, due to its contraceptive action.
► In 2020: sales of Diane 35 (and its generics) drop considerably and represent less than 900,000 platelets whereas they represented nearly 5 million in 2010 (see graph below)
What are the dangers of Diane 35? How many deaths?
The venous thromboembolic risk associated with the use of Diane 35 has been clearly identified, indicates theANSM in its document on the data on the venous thromboembolic risk related to the use of Diane 35. Between 1987 (date of marketing authorization for Diane 35 in France) and August 7, 2015, 347 cases of thromboembolic events associated with taking Diane 35 and its generics have been registered in the National Pharmacovigilance Database. Of these 347 cases, there were:
- 175 cases of pulmonary embolism with or without reported deep vein thrombosis
- 146 cases of deep vein thrombosis (cerebral, retinal, cellar, mesenteric, iliac, popliteal)
- 17 cases of superficial thrombosis (phlebitis) or not filled in
- 9 cases of arterial or mixed thrombosis
55% of these women recovered without sequelae, 21% of women recovered with sequelae and 10 of them died by pulmonary embolism or cerebral thrombosis. These women had on average 23 years. As of February 26, 2013, it is estimated that Diane 35 (and its generics) represented 6% of sales of all combined oral contraceptives In France. Diane 35 (and its generics) is prescribed by general practitioners, gynecologists and dermatologists with the prescribing reason for acne or contraception, distributed as in the following table:
| Reason for limitation | Acne | Contraception |
|---|---|---|
| Dermatologists | 94% | – |
| Generalists | 7% | 89% |
| Gynecologists | 5% | 77% |
The majority of prescriptions for Diane 35 (and its generics) as a pill come from general practitioners and gynecologists.
Why was Diane 35, an anti-acne, prescribed as a pill?
Some women have been prescribed this anti-acne as contraception when they had mild acne or simply oily skin.
According to medical code of ethics“within the limits set by law, the doctor is free to choose his prescriptions, which will be those he considers most appropriate in the circumstances.“. This means that a doctor can therefore prescribe an off-label drug if it seems to him to be in the interest of his patient. (and with, of course, obligations surrounding this practice: the Bertrand law reinforcing the supervision of off-label prescriptions, the Kouchner law of 2002 requiring the patient to be informed of the risks of therapy). In the case of Diane 35, some women were prescribed this anti-acne as contraception when they had mild or moderate acne or simply oily skin. Above all, some have taken it for a long time when its indication is normally limited to only 2 to 3 months. Also, word of mouth has caused some women to ask for it in consultation, seeing that this pill, taken by other women in their entourage, significantly improved the condition of the skin. “I have ladies who, when they took her, wanted the same for their daughters. They were demanding”, remember Elizabeth Paganelli, General Secretary of the National Union of French Gynecologists-Obstetricians, interviewed in 2013 by FranceInfo. This is without counting on the medical world and the governmental authorities which maintained an ambiguous and obscure relationship with Diane 35 (dosage was like a birth control pill (one pill a day for 21 days with a week off)it was reimbursed by Social Security as a pill), so even that the Bayer laboratory has never requested marketing authorization as a contraceptive.
What are the generics of Diane 35?
Diane 35 is the name of the originator drug and its generics are as follows:
- Holgyeme
- Lumalia
- Minerva
- Cyproterone acetate
- Generic Ethinylestradiol
What is the composition of Diane 35?
Diane 35 contains cyproterone acetate and ethinyl estradiol.
Sources:
– Diane 35 and its generics, Dossier ANSM, published on September 1, 2020 and updated on June 10, 2021
– Data on the venous thromboembolic risk linked to the use of Diane 35, ANSM, October 2015
– Revue Prescrire: Diane 35: return to the market in France, despite the excesses, February 2013