OXCARBAZEPINE EVALUATION Produced by the UK Medicines Information Pharmacists Group NEW MEDICINES ON THE MARKET Evaluated information for the NHS YASMIN Summary · Yasmin (ethinylestradiol 30mcg / drospirenone 3mg) is a combined oral contraceptive. · It has similar contraceptive efficacy and cycle control to other combined oral contraceptives. Contrary to initial claims by the manufacturer, there is no compelling evidence that its effects on skin, premenstrual symptoms, and feelings of well being are any different to standard combined oral contraceptives. A clinically important effect on weight gain has not been demonstrated. · Yasmin is generally well tolerated. The frequency and type of adverse event reported in clinical trials are typical of those observed with other combined oral contraceptives. · The risk of venous thromboembolic events (VTE) and arterial disease with Yasmin cannot be quantified from current evidence and is unknown. · Yasmin costs significantly more than other combined oral contraceptives. It offers no proven advantages to warrant the increased cost. Date Published May 2003 Monograph Number 4/03/02 Marketed: April 2002 Region of Origin to whom queries should be directed: Newcastle The information contained in this document will be superseded in due course. Not to be used for commercial purposes. May be copied for use within the NHS. Copyright MIPG 2003 Web site http://www.ukmi.nhs.uk/Med_info/stage4.asp YASMIN Approved Name: Ethinylestradiol and drospirenone Brand Name Yasmin (Manufacturer): (Schering Health) Presentation: Oral tablet containing ethinylestradiol 30 mcg and drospirenone 3 mg. BNF Therapeutic Class: Combined oral contraceptive (BNF 7.3.1) Licensed Indications: Oral contraception. Dosage and Administration: One tablet daily for 21 days; subsequent courses repeated after 7-day tablet free interval (during which withdrawal bleeding occurs) Sector of Use: Hospital [Y ] Primary Care [Y] Therapeutic Comment: Yasmin has similar contraceptive efficacy and cycle control to other combined oral contraceptives. It offers no proven advantages to warrant the increased cost. Cost and Course Details: Cost for 3 x 21 days £14.70 Treatment Alternatives: Cost for 3 x 21 days Marvelon £6.70 Femodene £6.84 Ovranette £2.46 Microgynon 30 ED £2.56 Microgynon 30 86p (From MIMS March 2003) Page 2 of 6 YASMIN INTRODUCTION Drospirenone: Drospirenone is absorbed within two hours of oral administration of Yasmin (absorption is Approaches to developing new oral contraceptives slowed by food). Serum drospirenone concentrations include reducing the dose of oestrogen and were increased in women with moderate renal progestogen used and using progestogens with a more impairment. Prior to elimination (which is both faecal favourable pharmacological profile.1 Most combined and renal), drospirenone is extensively metabolised in oral contraceptives contain ethinylestradiol in the liver, the two main metabolites found in the plasma combination with progestogens derived from the 19- are pharmacologically inactive.4 nortestosterone i.e. levonorgestrel, norethisterone, desogestrel or gestodene. At doses commonly used in oral contraceptives these progestogens do not have the EFFICACY anti-mineralocorticoid activity of natural progesterone, There are two open label comparative studies with which compensates for the oestrogen-induced salt and water retention.1 The ideal progestogen would have the Marvelon, a formulation that contains the same antimineralocorticoid activity similar to that of natural oestrogen combined with desogestrel, a third- progesterone.2 generation progestogen (see Table 1). In the first study lasting for 26 cycles (n=887) there were three pregnancies in each group and all were thought to be PHARMACOLOGY due to user rather than method failure.2 In the second Yasmin contains ethinylestradiol and the progestogen study 2069 women were randomised in a ratio of 4:1 to drospirenone. Drospirenone is derived from 17 - either Yasmin or Marvelon for 13 cycles.1 There were spirolactone and is an analogue of the aldosterone 10 pregnancies in the Yasmin group compared with antagonist, spironolactone. Its pharmacological one in the Marvelon group. No level of statistical properties are similar to those of natural progesterone. difference is given. Of these 11 pregnancies only one, The contraceptive effect of Yasmin is based on the in the Yasmin group, was considered by the authors to interaction of various factors, including the inhibition of be due to method failure. When corrected for other ovulation and the changes in the endometrium.3 factors (missed tablets, diarrhoea, etc) the number of pregnancies per 100 women-years use was 0.07 with Yasmin and 0.28 with Marvelon.1 This is reported to PHARMACOKINETICS be similar to other oral contraceptives.4 Ethinylestradiol: Ethinylestradiol is absorbed within two hours of oral administration of Yasmin (absorption The frequency and pattern of intermenstrual bleeding, is slowed by food). It is rapidly metabolised, primarily withdrawal bleeding, amenorrhoea and premenstrual by conjugation and aromatic hydroxylation via the symptoms were similar in recipients of Marvelon and hepatic cytochrome P450 (CYP) 3A4 isoenzyme, and is Yasmin in both studies. excreted in urine and faeces.4 Page 3 of 6 YASMIN Weight Drug and Therapeutics Bulletin in August 2002, which In the 13 cycle study mean weight loss during treatment argued that there was no compelling published was statistically significantly greater with Yasmin than evidence that Yasmin offered any advantages over with Marvelon although the difference was very small other, longer established combined oral contraceptives (0.46 kg vs. 0.19 kg p<0.0072).1 In the 26 cycle study with regards to weight gain, skin condition or the authors report a significant difference between the premenstrual symptoms.8 two groups although no actual figures are presented.2 The results from both studies included all women who ADVERSE EFFECTS received some treatment, including those who dropped out of the study due to weight gain. In both studies Discontinuation rates were similar between groups and most women maintained a stable body weight (+/- 2 were around 20%1 and 30%2 for each of the two kg).1,2 efficacy studies. 9% of women withdrew due to adverse events, most frequently headache, menstrual disorders, In both studies women measured their own weight at nausea / vomiting and weight gain.1 home and knew which preparation they were taking. There have been reports of venous thromboembolism In a small (n=80) double blind study a significant but among women taking Yasmin.9 The absolute risk of small difference on weight was observed after 6 cycles thromboembolism in users of combined oral between women taking Microgynon 30 (levonorgestrel contraceptives is very low (15/100,000 or 25/100,000 150 mcg, ethinylestradiol 30 mcg) compared with for second and third generation respectively). This is Yasmin (+ 0.68 kg vs ­ 0.78 kg).5 considerably less than the risk during pregnancy (60/100,000). No thrombotic events were reported Skin back from comparative trials.1,2 Yasmin has been on In the 13 cycle study the incidence and severity of acne the European market since November 2000 giving an was reduced in both groups from 21.5% to 7.8% in the estimated 2 million women-years of use. The Yasmin group and from 20.1% to 8.2% in the observational reporting rate of VTE is currently Marvelon group.1 6.5/100,000 women years of use. These are In a double blind randomised comparative study over 9 spontaneous reports and the likelihood of under cycles in 128 women with mild to moderate acne, the reporting should be considered.10 median total acne lesion count decreased to a similar extent in women receiving Yasmin 62.5% and those CONTRAINDICATIONS AND receiving Dianette 58.8% (cyproterone 2 mg and PRECAUTIONS (see SPC) ethinylestradiol 35 mcg).6 The SPC gives a comprehensive list of conditions when combined oral contraceptives should not be used and In November 2002, Schering withdrew its promotional where there are special precautions for use. material for Yasmin following a request from the MCA.7 This followed an article that appeared in the Page 4 of 6 YASMIN REFERENCES 1. Huber J, Foidart J.M, Wuttke W, et al. Efficacy and tolerability of a monophasic oral contraceptive containing ethinylestradiol and drospirenone. The European Journal of Contraception and Reproductive Health Care 2000;5:25-34. 2. Foidart JM, Wuttke W, Bouw GM, et al. A comparative investigation of contraceptive reliability, cycle control and tolerance of two monophasic oral contraceptives containing either drospirenone or desogestrel. The European Journal of Contraception and Reproductive Health Care 2000;5:124-134. 3. Yasmin Summary of Product Characteristics. Schering Health Care Limited May 2002. 4. Keam SJ and Wagstaff AJ. Ethinylestradiol/Drospirenone. A review of its use as an oral contraceptive. Treatment of Endocrinology 2003;2(1):49-70. 5. Oelkers W, Foidart JM, Dombrovicz N et al. Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism. The Journal of Clinical Endocrinology and Metabolism 1995;80:1816-21. 6. van Vloten WA, van Haselen CW, van Zuuren EJ, et al. The effect of 2 combined oral contraceptives containing either drospirenone or cyproterone acetate on acne and seborrhoea. Cutis 2002;69(suppl 4):2-15. 7. Anon. Yasmin advert withdrawn ­ why and how. Drug and Therapeutics Bulletin 2002;41:17-8. 8. Anon. Is Yasmin a truly different pill? Drug and Therapeutics Bulletin 2002;40:57-9. 9. Sheldon T. Dutch GPs warned against new contraceptive pill. British Medical Journal 2002;324:869. 10. Personal communication, Schering Health Care Ltd., April 2003. Page 5 of 6 YASMIN Table 1 ­ Comparative studies of two oral contraceptives containing either drospirenone or desogestrel. Ref Design of Study Treatments Assessed Primary Outcome Results and Comments No Measures 1. Multi-centre , Yasmin (n=1657) and Contraceptive efficacy Assessment Yasmin Marvelon randomised, open- Marvelon (n=412) for 13 (analysed using the Pearl Pearl index 0.07 0.28 label cycles, follow up for 6 weeks. index), cycle control, skin Both preparations were taken condition, blood pressure and Cycle control No significant differences ­ good with low incidence of orally for 21 consecutive days, body weight and adverse intermenstrual bleeding followed by a tablet free interval events of 7 days. Acne Reduced from 21.5% to Reduced from 20.1% to 7.8% 8.2% Seborrhoea Reduced from 11.7% to Reduced from 11.9% to 2.8% 2.5% Physical Mean systolic and diastolic pressure slightly lower than findings baseline but not significant Body weight Mean weight loss 0.46kg Mean weight loss 0.19kg (1lb) (0.4lbs) Adverse 38.5% 32.3% events Typical of those associated with an oral contraceptive 2. Multi-centre , Yasmin (n=442) and Marvelon Contraceptive efficacy Assessment Yasmin Marvelon randomised, open- (n=445) for 26 months, follow up (analysed using the Pearl Pearl Index 0.41 0.4 1 label for 3 months. Both preparations index), cycle control, blood were taken orally for 21 pressure and body weight and Cycle control No significant differences ­ good with low incidence of consecutive days, followed by a adverse events intermenstrual bleeding tablet free interval of 7 days. Physical A statistical difference between the two groups, although findings no actual figures are presented. Premenstrual No significant difference syndrome Blood Mean systolic and diastolic pressure slightly lower than pressure baseline but not significant Adverse 42.5% 42.0 % events Typical of those associated with oral contraceptive Pearl index = The number of pregnancies per 100 woman years. (If out of 100 women using a contraceptive over a period of one year, one woman becomes pregnant the Pearl index is 1.0.) Page 6 of 6 Document Outline Produced by the NEW MEDICINES ON THE MARKET Evaluated information for the NHS Summary INTRODUCTION PHARMACOLOGY PHARMACOKINETICS EFFICACY Weight Skin ADVERSE EFFECTS CONTRAINDICATIONS AND PRECAUTIONS (see SPC) REFERENCES Assessment Body weight