Relevant BNF section: 7.3.1
A combined oral contraceptive (COC) containing the progestogen drospirenone (pronounced dro-spi-re-known) plus the oestrogen ethinylestradiol (▼Yasmin - Schering Health Care) is now available in the UK. Company advertising claims that Yasmin is "truly different", as reliable and safe as other COCs and is "the pill for well-being", with "no associated weight gain" and "a demonstrable positive effect" on premenstrual symptoms and skin condition. Such claims have also appeared in the lay media.1 Are they justified?
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Relevant BNF section: 7.3.1
Taken correctly, COCs are very effective contraceptives. Around 0.1 pregnancies occur per 100 women-years in those taking COCs "correctly and consistently", and 6-8 per 100 women-years as typically used.2
Common unwanted effects with COCs include break-through bleeding (menstrual bleeding outside the 'pill-free' week), nausea, weight changes, fluid retention, breast discomfort, acne, depression and changes in libido.3 These effects often prompt women to stop their COC or seek an alternative product. Weight gain is one of the effects that women in the UK worry about most.4 Rare, potentially life-threatening unwanted effects of COCs include venous thromboembolic disease, stroke and myocardial infarction. The rate of venous thromboembolic disease has been estimated at around 15 per 100,000 women-years for those taking COCs containing less than 50µg ethinylestradiol plus levonorgestrel or norethisterone ('second-generation' pills) and about 25 per 100,000 women-years for those taking COCs containing desogestrel or gestodene ('third-generation' pills).5
What is Yasmin?
Each Yasmin pill contains 30µg ethinylestradiol plus 3mg drospirenone (a derivative of spironolactone). Like other COCs, Yasmin inhibits ovulation by suppressing the hypothalamic-pituitary axis. The administration schedule and guidance for users in the event of missed pills are identical to those of other standard-strength monophasic COCs.3,6 As drospirenone is new, Yasmin cannot be classified as either a second- or third-generation COC. In-vitro and animal experiments show that drospirenone has anti-androgenic activity (like progesterone) and antimineralocorticoid activity (unlike most other progestogens).7 Ethinylestradiol is believed to interact with the renin-angiotensin-aldosterone system, causing fluid retention. Drospirenone could, in theory, counteract this effect by inducing diuresis, and so help prevent fluid retention, weight gain and increases in blood pressure.
Two published non-blinded randomised controlled trials conducted in western Europe (involving a total of 2,998 women aged 18-35 years) have compared Yasmin with Marvelon (desogestrel 150µg + ethinylestradiol 30µg).8,9 Eligible women included those switching directly from another oral contraceptive (around 60-70% of the women) as well as women who had not previously used an oral contraceptive. In one of the studies, 2,098 women were randomised to receive Yasmin (1,680 women) or Marvelon (418 women) for 1 year.8 In the other trial, 900 women were randomised in equal numbers to receive Yasmin or Marvelon for 2 years.9 Both trials were primarily designed to evaluate cycle control and so the primary outcome measure was the occurrence of intermenstrual bleeding.
Cycle control and contraception
In the 1-year trial, the rates of intermenstrual bleeding with Yasmin and with Marvelon were similar (around one-third of women in each group), and decreased after the initial cycles.8 There were 10 pregnancies among women randomised to Yasmin (a rate of 0.71 per 100 women-years) and 1 in the Marvelon group (0.28 per 100 women-years). The authors considered that 1 of the pregnancies in the Yasmin group was due to product-failure, the others being due to factors such as missed pills or diarrhoea. They calculated an adjusted pregnancy rate of 0.07 per 100 women-years for product-failure alone. In the 2-year trial, there was again no significant difference between the rate of women experiencing at least 1 intermenstrual bleed in the two groups.9 There were 3 pregnancies in each group (0.41 per 100 women-years), none of which were considered to be due to product-failure.
Discontinuation rates in both trials were similar with Yasmin and Marvelon (around 20-30%).8,9 The reasons most frequently cited for discontinuation (by around 7-11% of women randomised) were adverse events, mainly bleeding problems, headaches, nausea/vomiting and weight gain.
At baseline, mean body mass index of women in the two trials was 22-23kg/m. In the 1-year trial, weight (a secondary outcome measure) fell slightly in both groups, but by marginally more with Yasmin (by a mean of 0.46kg vs. 0.19kg with Marvelon, p<0.0072).8 No figures for overall mean weight change are given in the published report for the 2-year trial.9 It is not clear from either trial report whether the results are only for women who completed the studies or whether women who dropped out of the trial because of weight gain were excluded from the results. Since during the studies the women themselves measured their weight at home, and knew which COC they were on, bias was possible.
Other evidence comes from a small randomised controlled trial (involving women aged 18-34 years with a mean baseline body weight of 58-62kg) that primarily investigated the effects on the renin-angiotensin-aldosterone system of various progestogen + ethinylestradiol combinations, including Yasmin and the COC Microgynon 30 (levonorgestrel 150µg + ethinylestradiol 30µg).10 Weight was a secondary outcome, monitored by the women themselves. By the end of the study (after 6 cycles), the 20 women randomised to Yasmin had lost a mean of 0.78kg, while the 20 women on Microgynon 30 had gained a mean of 0.68kg. The difference between the two groups was statistically significant.
At the start of the 1-year study comparing Yasmin with Marvelon, each woman's skin was assessed for acne and seborrhoea (secondary outcome measures), by questioning her and using a standard grading scale.8 Acne (undefined in the report) was stated to have improved similarly with both COCs (from a rate of 21.5% to 7.8% with Yasmin vs. 20.1% to 8.2% with Marvelon), as was seborrhoea (from 11.7% to 2.8% with Yasmin and from 11.9% to 2.5% with Marvelon). No statistical analysis of these figures appears in the trial report.
One randomised controlled trial has suggested that Yasmin is as effective as Dianette (cyproterone acetate 2mg + ethinylestradiol 35µg), in reducing lesion count in women with mild-to-moderate facial acne.11 However, Dianette is only licensed for the treatment of women with severe acne and/or moderately severe hirsutism. Whether Yasmin has an effect on skin any different from that of other COCs is not known.
In the 2-year trial comparing Yasmin with Marvelon, a similar number of women in each group (around 18%-20%) reported possible premenstrual symptoms.9
Quality of life
Of the women in the two randomised trials comparing Yasmin with Marvelon,8,9 just under a quarter (680) were sent a questionnaire (about 8 weeks after the trial ended) to assess their wellbeing. How the survey subgroup was chosen is not clear. Completed questionnaires were received from 287 women (under 10% of those randomised).12 Women who had taken Yasmin were reported to have "felt significantly worse with respect to before and during menses, body weight, skin and hair, once the trials had ended, i.e. they felt better while taking" Yasmin. The company's claim that Yasmin is a "pill for well-being" is based on this survey (and another uncontrolled trial), even though the report authors state that there was no significant change in overall wellbeing. Furthermore, the women surveyed knew what pill they had been taking during the trials, which may have biased the survey results.
The summary of product characteristics for Yasmin states that it is not yet known how the drug influences the risk of venous thromboembolic disease compared with other COCs. There have been reports of venous thromboembolism and of stroke among women taking Yasmin.13,14
In the 1-year randomised trial comparing Yasmin with Marvelon (in 2,098 women), mean systolic and diastolic blood pressure (secondary outcome measures) fell by less than 2mmHg in both the groups.8 In a much smaller randomised controlled trial (20 women in each group) lasting around 6 months, systolic and diastolic blood pressure (secondary outcome measures) fell by a mean of around 2-3mmHg with Yasmin; these changes differed significantly from the 1-2mmHg rises with Microgynon 30.10
Evidence suggests that, with Yasmin, serum HDL-cholesterol concentration rises (by 9% vs. a 12% fall with Microgynon 30 in one study10) as does serum triglyceride concentration (by 47% vs. no change with Microgynon 3010). Whether and how such changes affect absolute cardiovascular risk is not known.
Contraindications and precautions
Due to the antimineralocorticoid effect of drospirenone 3mg (equivalent to a 25mg dose of spironolactone15), Yasmin might increase serum potassium concentrations if used concurrently with drugs with the same potential (e.g. ACE inhibitors, angiotensin-II receptor antagonists, potassium-sparing diuretics, long-term NSAID therapy). In practice, the concomitant administration of these drugs (except NSAIDs) with Yasmin is unlikely. Otherwise, warnings and drug interactions for Yasmin are the same as for other COCs.
The approximate drug cost to the NHS of 12 cycles of Yasmin (£59) is higher than for all other COCs (£7 to £38).
▼Yasmin, which contains ethinylestradiol plus the new progestogen drospirenone, appears to have similar contraceptive efficacy to other standard-strength combined oral contraceptives (COCs). There is no compelling published evidence to suggest that Yasmin offers any advantages over other, longer-established, COCs with regards to weight gain, skin condition or premenstrual symptoms. Furthermore, we believe that the claim that Yasmin "is the pill for well-being" is unjustified and misleading and should be withdrawn. Yasmin's effects on cardiovascular risk (including venous thromboembolic disease) have not been quantified.
Given that Yasmin has no proven superiority over, and costs more than, other COCs, we cannot recommend it.
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