Health Concerns for Diane-35: Drug advertised widely to teens and doctors in Canada despite health warnings

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by Barbara Mintzes with Women and Health Protection

The young girl on the ad in Healthy Woman magazine looks 15 or 16. She has beautiful, flawless skin and a glowing smile. “Diane-35. Ask your doctor or your dermatologist,” says the caption. In the accompanying television ad, young girls prance and preen in front of a mirror, twirling umbrellas to bouncy pop music.

Diane-35 (cyproterone acetate and ethinyl estradiol) is one of a handful of prescription drugs that has been widely advertised to the Canadian public in spite of laws prohibiting such advertising.

Diane-35 is a combination product consisting of two hormones: cyproterone acetate and ethinyl estradiol. Cyproterone acetate is a progestin which counters the effects of male hormones. Higher doses are used to treat prostate cancer. Ethinyl estradiol is the estrogen component of most birth control pills.

Although prescription drug advertising is illegal in Canada, with the exception of postings of “name, price and quantity,” Diane-35 has been heavily advertised in television commercials, on bus shelter billboards and posters in women's washrooms at colleges and universities, and in magazines distributed in doctors' waiting rooms.

In the one-year period from September 1999 to September 2000, Diane-35 showed a 45% growth in prescribing volume. Promotional campaigns aimed at health professionals and the public are likely to have contributed to this rapid increase.

Health concerns for Diane-35
Diane-35 was approved in Canada in 1998; it has never been approved in the US. A similar product with a higher dose of estrogen was first approved in Europe in 1978; Diane-35, was approved in Europe in 1985, and has also been marketed in Asian and Latin American countries both for birth control, and as an acne treatment.

In late 1994, the German drug regulatory agency carried out a safety review of Diane-35 after a woman who had used the drug for birth control for 14 years died of liver cancer. Following this review, Diane-35 was restricted first in Germany, then in the rest of Europe, and in Malaysia, to second-line use for severe acne in women with signs of a hormonal imbalance (“androgenization” or excess male hormones).

The German authorities had not found definitive evidence that Diane-35 could cause liver cancer, but animal and laboratory studies supported the hypothesis, and cyproterone was known to be toxic to the liver in humans, especially at higher doses and with longer duration of use.

In Canada, Diane-35's approved use is similar to the European restriction: the drug has only been approved as a second line treatment for severe acne, accompanied by signs of excess male hormone, and only when the patient has not responded to other acne treatments such as oral antibiotics.

More recent concerns about the safety of Diane-35 have focussed not on liver toxicity or potential cancer risks, but on the drug's ability to cause potentially fatal blood clots, or venous thromboembolism (VTE). These are blood clots that usually occur in the leg, and can travel to the lung, where they become dangerous.

VTE is a rare harmful effect of all combined estrogen-progestin products, including those used for birth control. However, several studies have found Diane-35 to be riskier than the most commonly used birth control pills. As a result, regulatory agencies in the UK, Australia, New Zealand, and Canada have sent out safety advisories about these risks.

Advertising to doctors
Berlex, the manufacturer, cannot legally advertise Diane-35 to physicians as a contraceptive, as it is not approved in Canada for this use. However, Berlex provided an “unrestricted educational grant” to authors of a report distributed to Canadian doctors; this report, “Diane-35 – is it an oral contraceptive?” affirms that Diane-35 is as effective for birth control as other estrogen-progestin combination pills available in Canada. The other key message in the report is a reassurance on safety issues: a statement that Diane-35 has “no significant teratogenic effect” [i.e. does not cause birth defects], that it may have beneficial effects on the liver, and that there is no evidence it causes liver cancer, even following longer-term use. The report clearly conveys the message that this product may be used for birth control. And while it was published in October of 2002, after two regulatory agencies had sent out warnings about risks of blood clots for Diane-35, nowhere in the report are these risks mentioned.

Health Canada, the federal agency responsible for the enforcement of the Food & Drugs Act, has not effectively prevented this type of promotional message from reaching health professionals, nor the types of advertising campaigns aimed at the public described above.

The regulation of advertising is one part of “post-market surveillance,” or follow-up of medicines once they have been approved for marketing. Very few resources – less than one full-time staff position — are devoted to this activity by Health Canada; most activities are delegated to industry self-regulation.

In January 2003, a CBC television documentary raised concerns about the safety of Diane-35, Berlex's promotional campaign, and the widespread use of the product for birth control, an unapproved use. This documentary sparked considerable controversy, including charges of media alarmism.

However, in late December 2002, a few days after the CBC had interviewed Health Canada staff for the documentary, the agency posted the first safety advisory on Diane-35. In April 2003, Health Canada required Berlex to send out a “dear health professional” letter to all physicians in Canada, warning them of the risks of VTE for Diane-35. In addition, a consumer advisory was posted on Health Canada's website. The timing of the documentary in relation to these safety advisories suggests that media attention may have contributed to the decision to take regulatory action.

Women's health groups had previously raised similar concerns to Health Canada, with much less success. In late 1999, when Berlex began to promote Diane-35 on billboards in Montreal, DES Action Canada made a complaint to Health Canada and the Pharmaceutical Advertising Advisory Board. It led to an investigation, some meetings and correspondence, and changes to Berlex's website. However, in spite of receiving a letter from Health Canada saying that the problem had been solved, DES Action staff noted that the Diane-35 billboards continued to be displayed at Montreal bus shelters. In early 2000, DES Action held a press conference at a bus shelter. Soon after, the billboards were removed from Montreal bus shelters, although they continued to run in other cities.

Women and Health Protection sent a second letter of complaint to the Deputy Minister of Health in March 2001, following Berlex's launch of a new national billboard, television and cinema ad campaign for Diane-35. This complaint led to no perceptible regulatory action and the Diane-35 ad campaign continued. Print ads continued to run in Healthy Woman, a Canadian magazine commonly found in the waiting rooms of family physicians and gynaecologists, with the latest ad (to date) appearing in September 2003.

Thus, Canadian laws prohibiting direct-to-consumer advertising and complaints from women's groups proved largely ineffective in preventing or limiting advertising campaigns that targeted adolescent girls and young women and promoted sales of a potentially hazardous product.

For a more detailed investigation of Diane-35, visit: www.whp-apsf.ca or call: 1-888-818-9172.