Diane-35: Reconsidering the risks

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Publication Date: 
Thu, 2013-08-01

By Holly Grigg-Spall

A young woman admires her flawless skin in her bathroom mirror; smiling to herself she is pleased with what she sees in the reflection. Then, she climbs through the mirror and into a better life, one filled with friends, dancing, fashion, fitness regimes, transparent umbrellas—she’s got nothing to hide—and a good-looking, happy boyfriend. As the young woman jumps back into her bathroom seemingly thrilled with the lifestyle her clear skin has provided, a brightly colored packet of pills that closely resemble oral contraceptives appears in the foreground. “Diane 35: Ask your doctor or dermatologist” is the accompanying message.

Diane-35 is comprised of synthetic anti-androgen cyproterone acetate and synthetic estrogen ethinyl estradiol, making it as effective at preventing pregnancy as all birth control pills, although it has never been approved as a contraceptive. Since its release in Canada in 1998, Diane-35 has only been approved by Health Canada for cases of severe acne with a stipulation that women take the drug for just a few months and only if other possible treatments have been tried and failed.

‘Was a problem waiting to happen’

Prior to the widespread distribution of the commercial campaign described above, Health Canada had issued two warnings informing women and their doctors that Diane-35 held a risk of causing blood clots four times higher than the risk associated with other birth control pills. A number of women’s groups collaborated to register a complaint with Health Canada about the nature of the advertisements that were shown in movie theatres, on television, on billboards and in public washrooms. This was in the same year that CBC aired its investigation of the potential dangers, A Hard Pill To Swallow.

Since its release in Canada in 1998, Diane-35 has only been approved by Health Canada for cases of severe acne with a stipulation that women take the drug for just a few months and only if other possible treatments have been tried and failed. See the Globe & Mail article April 8, 2014 about the recent review of Diane-35.

“The CBC documentary showed that the pharmaceutical company actively pursued prescription of this drug as a form of birth control, and so for extended use by women,” says Dr. Barbara Mintzes, a drug policy researcher and assistant professor at the University of British Columbia. “Diane-35 is an example of regulatory failure. This was a problem waiting to happen.” 

Mintzes was among those associated with the women’s health groups, including Women and Health Protection in Canada, that protested the marketing campaign used to promote Diane-35. “There isn’t good evidence that this is something anyone needs. Evidence suggests all birth control pills have some effect against acne and there isn’t a clear advantage to this one,” she says. “This drug has never actually been tested within the population it is approved for—those suffering severe acne. Diane-35 was one of the first medications to be marketed to the public in Canada aggressively and illegally.”

Off-label prescription of the drug by doctors for birth control combined with the marketing strategy by Berlex, now Bayer, saw 800,000 women prescribed Diane-35 in 2002, the majority of whom were using it for birth control and so taking the drug for long periods of time despite the warnings from Health Canada. Although the CBC documentary may be credited with lowering the number of users for a short time, prescriptions for Diane-35 continued to grow from 2003 onwards for women in their teens through menopause.

Health Canada review

In February 2013, Health Canada undertook a review of the drug, prompted by the decision by the regulatory body in France, ANSM, to stop sales of Diane-35. ANSM made this decision while conducting its own review into four reported deaths of young women in France that were linked to Diane-35. Health Canada, faced with 11 reported deaths of otherwise healthy women related to Diane-35 since its release in Canada in 1998, had little choice but to reconsider the risks. Three months later, with little discussion of the process that occurred in the interim, Health Canada announced its conclusion that the benefits of Diane-35 outweigh the risks within the boundaries of its approved use. The European Medicines Agency—the Europe-wide regulatory body—echoed this statement, but the ANSM in France (at the time of writing this article) has maintained the suspension of Diane-35 prescriptions, although the decision is under review.

For some, Health Canada’s decision is questionable considering that the widespread off-label prescribing of Diane-35 as a contraceptive and the flouting of recommended restrictions is what brought the agency to this point of review. 

The benefit of this drug, according to Health Canada’s description, is the alleviation of a non-life-threatening but quality-of-life threatening issue: severe acne. The risk of this drug is a life-threatening blood clot (venous thromboembolism).  Health Canada, nonetheless chose to allow continued use, as stated in this warning from the agency: 

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. In Canada, Diane-35 is approved for the temporary treatment of severe acne—with associated symptoms of high levels of male hormone, including seborrhea (oily skin) and mild hirsutism (excessive body hair)—in women who are unresponsive to other available treatments. It should not be used in patients with a history that puts them at risk for blood clots, and is not approved for use as an oral contraceptive.”

Diane-35 contains a particularly high level of synthetic estrogen in comparison to other birth control pills on the market. It is believed that this is what creates the heightened risk of venous thromboembolism, a blood clot that forms in a vein due to blood coagulation that moves around the body and causes a life-threatening pulmonary embolism, or blockage in a main artery of the lung. When Diane-35 was originally released onto the market, the level of estrogen was similar to other pills containing a pairing of synthetic estrogen and synthetic progesterone.

Several assumptions underpin Health Canada’s chosen path in this case. The agency assumes that Diane-35 is an effective treatment for severe acne, which available research has not shown. Although the drug alleviates or moderates the severity of acne it does not treat its cause. Health Canada also assumes that the treatments currently offered by most doctors—pharmaceutical drugs and creams—are the only effective treatments available. This fails to recognize the evidence showing positive outcomes from lifestyle changes and complementary (non-pharmaceutical) acne treatments. Additionally, it is assumed that doctors will adhere to the rules outlined by Health Canada when prescribing this medication to women from here on. This remains to be seen. Lastly, there is the suggestion that venous thromboembolism is the only adverse effect worthy of concern; this ignores the fact that a powerful medication able to cause such a serious health problem is likely to have other adverse effects on the body.

“Diane-35 has been over-prescribed but this is just an extension of a wider problem. People barely think of the pill as a drug. It’s just become part of normal life. The advertising targets young teens like birth control pills are an accessory, like it’s the same as any other thing you would find in a young woman’s bedroom or purse.”

Some women are known to be more at risk of developing blood clots than others, including those who are overweight, older, who smoke, drink alcohol excessively, or have a genetic predisposition. Women with no other risk factors might be more likely to make the connection between a sudden serious health problem and their use of Diane-35. It is likely that the 11 deaths reported in Canada are not the total sum of injuries and deaths caused by the drug in this country but that there are a number going unreported every year due to lack of awareness.

Adrienne Shnier is a doctoral candidate at York University in Toronto, studying Health Policy & Equity in the School of Health Policy and Management. Shnier believes the causes of over-prescription are numerous and complex.

“Typically, if a patient knows what drug they want and describes their symptoms to their doctor, perhaps with a commercial or an online diagnosis quiz in mind, the physician will prescribe that drug within less than five minutes,” reports Shnier.  “There is no time for effective patient history discussion there or consideration of lifestyle factors that might make a doctor reconsider a prescription.”

When discussing an issue like acne, patients may insist on their own self-diagnosis of “severe” acne if their experience of the condition is causing enough anxiety. Couple that with a doctor who has been encouraged by drug sales representatives and marketing materials to prescribe this pill and you have a recipe for over-prescription.

Shnier’s work focuses on issues of conflicts of interest within the medical industry. Aside from the advertising directed at young women, doctors are also the targets of the drug company’s product promotion. “Studies have shown that something as simple as a pen given by a drug representative can make a doctor feel more favorably towards a medication,” says Shnier. Adding to this situation is that doctors rarely see or read all of the information available about the potential risks of a drug. They not only have little time to read everything that is available, but some of that information is not made available at all. “We have seen that pharmaceutical companies will suppress, lock away or destroy data that arises in research which presents their drug in an unfavourable light. Sometimes this information will only come out during litigation as a function of a trial,” Shnier says. “At the very minimum doctors need all of the data that comes from the research. Health Canada needs all of that data. Otherwise no one is making an informed decision.”

Unites States and France

Barbara Mintzes is intrigued by the United States’ Food and Drug Administration’s decision not to approve Diane-35. Her theory is that this seemingly unusual choice was caused by a possible connection between the Diane-35 component cyproterone acetate and liver cancer, a disease that is unlikely to be definitively linked back to the drug because it takes a long time to develop in the body and is not widely known to be a possible adverse effect.  Mintzes is critical of the lack of transparency behind Health Canada and the FDA’s approaches to drug regulatory decisions. Direct-to-consumer advertising is essentially banned in Canada, but there are few resources to deal with the pharmaceutical industry’s tenacity at getting around laws in order to reach potential customers

A US FDA appraisal in 2012 concluded with a decision to keep all drospirenone-containing pills on the market—the benefits again cited as outweighing the risks—despite accusations of conflicts of interest on the appraisal board, and a questionable process. Board members voted 15 to 11 in favour when asked, “Do you believe that, in the general population of women who desire contraception, the benefits of the (DRSP)-containing oral contraceptives for prevention of pregnancy outweigh their risks?”

Considering there are other safer options available to prevent pregnancy, this decision is questionable at the very least. 

In France, where sales of Diane-35 are still suspended, the regulatory body underwent an overhaul in response to the scandal surrounding another controversial drug: Mediator. Like Diane-35, this drug was marketed off-label with deadly results. Mediator was approved for diabetes and marketed off-label for weight loss. The head of the pharmaceutical company that produced Mediator, which caused the deaths of up to 2,000 people, is now on trial for involuntary manslaughter. In most countries, including Canada, members of medical regulatory bodies and the pharmaceutical industry are protected from such prosecution.

Acne treatments

Founder of the Edmonton-based Justisse Healthworks for Women, Geraldine Matus, argues that we must admit all hormonal contraceptives are prescribed off-label whether it is to “regulate” periods or prevent PMS. Matus does not believe, whether evidence is available or not, that Diane-35 or any hormonal birth control should be given to women suffering with acne. “I am appalled that for something like acne we give young women such a powerful endocrine disrupter. It’s like repairing a Swiss watch with a jackhammer. It is total overkill. The birth control pill in any form never cures anything. It only alters the symptoms.”

The cause of acne can be hormonal imbalance, but Diane-35, and any hormonal contraceptive, only suppresses and replaces the natural hormone cycle with a constant stream of synthetic hormones whilst suppressing the entire endocrine system. The pills do not rectify the imbalance. Metabolic issues, dietary problems, and allergies can also provoke acne. Matus believes for many women a small intervention such as restricting unhealthy foods or increasing zinc intake can make a big difference.

“The birth control pill suppresses immunological function and so can in fact aggravate acne by worsening underlying issues like poor gut health,” Matus explains. As Diane-35 is not a cure, when women come off they are likely to find their acne returns. Non-pharmaceutical treatment of acne such as lifestyle changes including diet and exercise are unlikely to be addressed in the doctor’s office when doctors, and perhaps patients themselves, almost always prefer the quick fix.

“Most acne patients are told by their dermatologist that diet has nothing to do with acne, despite research to the contrary,” explains Toronto naturopath Pamela Frank, “Every acne patient I have ever had has identified food triggers for the condition. The pill is only appropriate, I believe, if women are either unaware of the better, safer, more natural options or unwilling to make the effort to change their diet, exercise daily, and reduce their stress level. Correcting the root cause leads to greater overall health.”

Polycystic ovary syndrome

Thirty-two year old Canadian clinical social worker, Shannon Tessier, took Diane-35 for 10 years; “I was prescribed [Diane-35] at 20 years old, at my own request. I was really upset with my acne and had tried every prescription known to ‘cure’ it. After seeing several adverts in the women’s washrooms at my university, I went on the drug company website. I then made an appointment with my doctor. He asked me no questions, he just said, ‘Okay let’s give it a try.’ That was it. There was no discussion of side-effects or risks. No one ever mentioned there was a time limit to how long I could use this drug. My skin was completely clear, but I basically had no sex drive. Some 12 years later, after learning about the female hormone system, I believe Diane-35 masked what were PCOS [polycystic ovary syndrome] symptoms and worsened the underlying issue of my hormonal imbalance.”

A study conducted at the University of Virginia School of Medicine and published by the Canadian Medical Association Journal in 2012 found that for women with PCOS taking any birth control pill could double their risk of deep vein thrombosis. So, potentially, women with PCOS are facing the heightened risk caused by their condition plus that caused by oral contraceptives generally, as well as the risk specific to Diane-35 if that is what they are prescribed for their symptomatic severe acne. At least one study suggests as many as 83 per cent of women with severe acne have underlying PCOS, although it often goes undiagnosed.

Amy Medling is the founder of online community PCOS Diva. She used the birth control pill for 10 years to suppress PCOS symptoms. “When I came off to have my children I realized I had just been slapping a band-aid over my symptoms. I now take a holistic approach with a low carbohydrate, nutrient-rich, whole foods diet and doing the right kinds of exercise to stay fit and lower stress hormones. On the pill I had extreme moodiness and irritability with no libido. I felt like the drug had hijacked my body. The nutritional deficiency and negative metabolic impact aggravated my PCOS. I share my own treatment methods on my website and they appear to work for the majority of women.”

Another route of treatment

Dr. Jerilynn Prior is director of the Centre for Menstruation and Ovulation Research within the University of British Columbia. On the CEMCOR website Prior addresses the use of Diane-35 to treat acne in the “Ask Jerilynn” patient Q&A section. Prior recommends that instead of this drug someone suffering with acne as a result of PCOS—which Prior prefers to call “anovulatory androgen excess” to be specific about its physiological root—should try a combination therapy of oral bioidentical progesterone taken during the second half of the monthly cycle and spironolactone, which is similar to the anti-androgen in Diane-35 but, she believes, does not have the adverse effects of blood clotting and liver damage.

“I have treated somewhere between 100 and 200 women with that combination and it has worked very well for them. It brings their own hypothalamus, pituitary glands, and ovaries into balance and drops the male hormones that cause acne. The imbalance isn’t an irreversible issue. You can break the cycle and restore normal health. Suppressing your own system with Diane-35 or any birth control pill is not a good thing; it is suppressing the production of hormones that are essential to life,” says Prior.

“There’s a lot of stigma around acne and women get desperate enough that they will use a harmful drug to get relief. If they get relief from Diane-35 they won’t want to go back to the acne and will want to stay on it. They aren’t made aware of the other options,” she says.  Prior suggests that in addition to the bioidentical progesterone and spironolactone for even quicker skin-clearing results it is possible to add to the routine a highly effective topical medication containing retinoic acid and Stievamycin.

The term bioidentical is much disputed with some believing it to be a relatively meaningless description as there is no way to reproduce a synthetic version of women’s hormones that are exactly the same as those produced by the body. On a molecular level they are the same as the body’s hormones and the body responds to them as though they were the same, but little is known as to how they are changed once metabolized.

Prior believes that some doctors, once aware of the risks of Diane-35, may opt to swap their patients to Yaz or Yasmin. These two birth control brands contain the synthetic progestin drospirenone but a lower amount of synthetic estrogen and are approved for the treatment of moderate acne. Yaz or Yasmin, also produced by drug company Bayer, are at the centre of a large civil law suit in the United States with hundreds of Canadian women recently taking the same action with the support of law firm Siskinds LLP. Yaz and Yasmin also hold a higher risk of causing blood clots, around three times higher than other birth control pills.

Drospirenone and depression

Shannon Tessier was switched to Yaz on the recommendation of her doctor after years of taking Diane-35. In line with the anecdotal evidence provided by women who have gone online to share the negative psychological and emotional effects of this drug, Shannon describes her experience, “I just didn’t feel ‘right.’ I felt uncomfortable in my own skin. So, I booked another appointment and asked to be put back on Diane-35. Now though, I can see we are over-reliant on the pill as the answer and this prevents us from accessing other treatments.”

Diane-35 has also been linked to depression. Although the insert states this adverse effect would be only “mild” if present, women on Diane-35 have reported severe depression leading to suicidal thoughts. The Medications and Healthcare Products Regulatory Agency in the United Kingdom conducted a review in 2006 on the basis of these reports.  The women detailed doctors prescribing anti-depressants rather than considering that the change could be caused by the pill. The review also highlighted the length of time most of the women involved had been on Diane-35 (sold as Dianette in the UK), which was far longer than the approved period. The MHRA advised doctors to be vigilant but also suggested they could withdraw the medication only to prescribe it again if the acne returns which, as mentioned, is likely to happen.

Amy Sedgwick is the co-founder of the Toronto-based Red Tent Sisters organization. She counts among her clients many women who have decided to stop using hormonal birth control as a contraceptive or as a medication for any number of issues for which it is prescribed, including acne and PCOS. She coaches these women through the transition, tutoring them in body literacy and fertility awareness.

“The pill isn’t prescribed the way other drugs are prescribed. There’s an assumption that every young woman should be on it.  We assume the pill is safe and no big deal partly because it is everywhere,” asserts Sedgwick, “Diane-35 has been over-prescribed but this is just an extension of a wider problem. People barely think of the pill as a drug. It’s just become part of normal life. The advertising targets young teens like birth control pills are an accessory, like it’s the same as any other thing you would find in a young woman’s bedroom or purse.”

Sedgwick admits that none of her clients feel they were properly informed of the potential risks of the pill when it was prescribed, nor were they warned of what they may experience when they stopped taking it. “The only way the benefits would outweigh the risks in prescribing this drug is if there were no other options, but there are,” says Sedgwick. “We need to make sure there are supports in place …  Perhaps women would choose differently if they knew that there were alternatives.”

Just a month after the Health Canada decision on Diane-35, as this article is readied for publication, the aforementioned contraceptive pills Yaz and Yasmin that double as acne-treatment hit the headlines again with reports of an estimated 23 deaths of young women in Canada. This news is a stark reminder of the danger of prescribing powerful drugs with serious harmful effects when there are viable and safer alternatives available.  

As for Diane-35, its off-label use continues despite Health Canada warnings, and the manufacturer Bayer stands behind all three of its products despite the deaths and lawsuits.

We need a sea change in thinking about the overall safety of oral contraceptives. With stories like those of Diane-35 and Yaz/Yasmin, isn’t it high time we make this discussion more public?

Holly Grigg-Spall is a women’s health writer and activist. Her book, Sweetening the Pill or How We Got Hooked on Hormonal Birth Control will be published by Zero Books on September 27, 2013 (www.sweeteningthepill.com).

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