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Focus on Diane-35®

ABSTRACT

Diane-35®, known as Dianette® in some countries, is a combination of cyproterone acetate 2 mg and ethinyl estradiol 0.035 mg. It has recently received regulatory clearance in Canada, but has not yet been approved by the US FDA. The Canadian indication is for the treatment of women with severe acne that is unresponsive to oral antibiotics and other available treatments, and is associated with symptoms of androgenization including seborrhea and mild hirsutism.1 When Diane-35® is used in a cyclic manner it also functions as an oral contraceptive.1

Key Words: Diane-35, Dianette, contraceptive, acne

Some of the early studies of cyproterone combined with ethinyl estradiol utilized Diane®, which is a preparation containing 0.050 mg of ethinyl estradiol. Studies have shown that compared to Diane, Diane-35® with the estrogen component reduced to 0.035 mg of ethinyl estradiol, is as effective in treating acne and hirsutism, and is as reliable as a contraceptive. As well, it has the added advantage of a 30% reduction in the amount of estrogen it contains.2,3

Pharmacology

Some experts believe that in female acne, hypersensitivity of the target tissue is related to an excessive conversion of androgen precursors to active metabolites and of ovarian or adrenal hyperandrogenism. This topic remains a matter of debate. Others believe that in both women and men, there may be a hypersensitivity of the end organ to androgens. This is related to an increase in the activity of 5α-reductase type 1 which converts testosterone into active dihydrotestosterone. The production and the plasma transport of androgens may also be involved.4 Cyproterone acetate is antiandrogenic, (i.e., blocking androgen receptors) and antigonadotrophic, (i.e., inhibiting the hypothalamopituitary ovarian axis reducing androgen synthesis). In addition, the estrogen component increases the level of sex hormone binding globulin, which in turn reduces the plasma level of free androgens. These actions reduce the androgen stimulated increase in sebum associated with seborrhea.5 Sebaceous gland activity decreases over a period of three to six months, leading to diminution and even clearance of the acne.

Cyproterone can produce unwanted side effects including menstrual irregularities, but the presence of the estrogen circumvents this problem. Cyproterone also has progestogenic activity. When the cyproterone-estrogen combination is taken as recommended, it provides reliable contraception, but should not be prescribed solely for this purpose.1

Clinical studies

In 144 women, most of whom were suffering from moderately severe androgenization, six cycles of Diane-35® significantly improved or healed their acne and seborrhea. After 12 treatment cycles, the treatment success rate was almost 90%.7 In another study of 26 women, acne was in remission in 82% of patients after three cycles. As well, seborrhea was reduced in 86% of the women after three cycles and in 96% after six cycles.8 Between 1968 and 1995, 143 women were treated with Cyproterone 50 mg (combined with estrogen in most cases). The results for acne were good or very good in more than 90% of patients.9

Adverse effects

Diane-35® has many properties in common with estrogen/progestogen combination oral contraceptives, and the same contraindications, warnings and precautions should be considered. In a prospective, two year follow-up study in 35 of the 143 patients mentioned above9, hematological, clinicochemical, and metabolic parameters before and after, suggest that cyproterone acetate, with or without ethinyl estradiol, is an effective and safe long term treatment of hirsutism and/or acne in women.

Practical experience with Diane-35*

A panel of experts in the treatment of acne was questioned about their experiences using Diane-35®. The questions they were asked, and their responses are summarised below:

  1. If the patient fails to respond to antibiotics, would a hormonal combination such as Diane-35® be your treatment of choice?

    If it was only tetracycline that was used, one could try minocycline before trying a hormonal combination such as Diane-35®.10 However, when patients have failed to respond to antibiotics, most11-15 of our panel advise the use of this hormonal combination. This is true, epecially if the symptoms are not severe enough to consider prescribing isotretinoin, and when contraception is indicated or already being taken.14

    Not everyone agrees. One of the panel members feels that used alone, hormonal combinations are not sufficiently effective.16 Another stated that after antibiotic treatment fails, he uses isotretinoin, unless the patient wants birth control long term.17

    We should remember that women with SAHAsyndrome (seborrhea, acne, hirsutism and possibly also androgenetic alopecia) require the hormonal combination rather than antibiotics to clear their acne. Also, 30-35 year old females with persistent acne may also exhibit dysmenorrhea. In such instances, using Diane-35® would be helpful, especially as polycystic ovary disease (PCO) is often an underlying disease in these cases.18
  2. For what period of time should hormonal treatment be continued for acne, and what percentage of patients relapse when treatment is discontinued?

    Use Diane-35® for three months and then review.10,13,16 Usually, clinical improvement will be clearly visible after about three18 to six months. For the longer term, when such treatment proves to be appropriate, some advisors prescribe hormonal combinations for months15 to years.11,12,17 The percentage of patients whose acne relapses when treatment is discontinued depends on the age of the patient, the severity of the disease and the duration of treatment.18 Some felt that there was insufficient data to accurately answer the question.10-12 One panel member believed that the percentage of patients who relapse, is lower than that seen following discontinuation of birth control pills with a higher estrogen content.12 Estimates of relapse ranged from 3%14, to 60-70% on a long term basis13,15, to more than 90%.16
  3. Has the occurrence of any side effects limited the usefulness of such treatment?

    Most of the side effects are also seen with standard oral contraceptives.10 All of the side effects are minor and uncommon and rarely necessitate discontinuation of treatment.17

    Side effects that have been reported include dysmenorrhea (including breakthrough and premature bleeding in 1-2% of cases),14 some breast tension and hardness found in 10-15% of cases,14 and very sporadic reports of headache16,14 and nervousness.18,14

    Other reports include possible or occasional chloasma15 which may become more of a problem in countries with greater sun exposure.18 There are some reports of depression14 and decreased libido,18 however, increased libido and decreased depression have also been noted.14,18
  4. Does the monthly cost of the medication create a problem for patients?

    The answer was a unanimous NO! Many other acne treatments are more expensive.17
  5. Do you usually recommend the use of topical anti-acne medications in combination with hormonal therapy?

    The majority of our panel said yes, although one would only use topical anti-acne medications during the initial phase of treatment.12 Unlike the isotretinoin treatment for acne, complete clearing is unusual with hormonal combinations, and additional topical therapy may be helpful.17 The choice of product depends on whether the acne is inflammatory or comedonal.10 A sebostatic drug may cause skin dryness, and this can confuse women used to seborrheic skin.18 They may be helped by skin cleaning products which help maintain the skin’s water content.

Product Diane-35® Ortho Tri-cyclen

Dosage

First treatment course: 1 tablet daily for 21 days; subsequent courses consist of 21 days on and 7 days off.

21-Pill Pack: 21 active pills taken daily for 3 weeks followed by no pills for 1 week.
28-Pill Pack: 21 active pills taken daily for 3 weeks and then 7 “reminder” pills with no hormones taken for 1 week.

Supplied

Blister pack units consisting of 21 tablets; each tablet contains 2mg cyproterone acetate and 0.035mg ethinyl estradiol.

Each tablet contains ethinyl estradiol 0.035mg. The white tablets contain 0.18mg of norgestimate; the light blue tablets contain 0.215mg of norgestimate; the green tablets contain inert ingredients.

Cost

$19.00 (CDN)
£5.52 (UK)

21-Pill Pack: $28.70 (US), $18.26 (CDN)
28-Pill Pack: $28.85 (US), $18.26 (CDN)



Ortho Tri-cyclen®, a combination of ethinyl estradiol with norgestimate, one of the newer less androgenic progestins, was approved by the US FDA in December, 1996, and the Canadian HPB in March, 1998. The indication is for the treatment of moderate acne vulgaris in women with no known contraindications to oral contraceptive therapy. Ortho Tri-cyclen® was reviewed in a focus article in the Skin Therapy Letter, Volume 2, Number 3.

References

  1. Diane-35® Canadian product monograph
  2. Fugere P, Percival-Smith RK, Lusier-Cacan S et al. Cyproterone acetate/ ethinyl estradiol in the treatment of acne. A comparative dose-response study of the estrogen component. Contraception 1990; 42: 225-234.
  3. Vermeulin A, Rubens R. Effects of cyproterone acetate plus ethinyl estradiol low dose on plasma androgens and lipids in mildly hirsute or acneic young women. Contraception 1988; 38: 419-428.
  4. Beylot C, Doutre MS, Beylot BM et al. Oral contraceptives and cyproterone acetate in female acne treatment. Dermatology 1998; 196: 148-152.
  5. Yamada-AhSue M., Berlex. Personal communication. November, 1998.
  6. Kaiser E. Clinical experience with Diane-35, currently the lowest dose antiandrogenic hormonal ovulation inhibitor, in mild to moderate androgenization in the female. Geburtshilfe Frauenheilkd 1986; 46: 738-742.
  7. Marianowski L, Cyganek A, Grzechocinska B. Clinical treatment results of treating androgenization symptoms in women with preparation Diane-35. Wiad Lek 1994; 47: 745-746.
  8. van Wayjen RG, van den Ende A. Exp Clin Endocrinol Diabetes 1995; 103: 241-251.
  9. Cunliffe WJ. Personal communication. February, 1999.
  10. Arndt KA. Personal communication. February, 1999.
  11. Bergfeld WF. Personal communication. February, 1999.
  12. Christophers E. Personal communication. February, 1999.
  13. Degreef H. Personal communication. February, 1999.
  14. Shalita AR. Personal communication. February, 1999.
  15. Wolff K. Personal communication. February, 1999.
  16. Lebwohl M. Personal communication. February, 1999.
  17. Orfanos CE. Personal communication. February, 1999.

In this issue:

  1. Focus on Diane-35®
  2. Psoriasis Treatments Under Development
  3. Update on Drugs and Drug News - Number 4 1999