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At the heart of general practice since 1960

Make removing a patient painless (for you at least)

Dr Anne Szarewski details the latest developments in her field

The COC and venous thromboembolism (VTE)

Numerous changes have been made to guidelines on how GPs should prescribe COCs for women who may be at risk of thromboembolism. In 1999, following a Medicines Commission Appeal, the Department of Health announced an end to the 1995 restrictions on prescribing third-generation pills.

In 2002, the High Court dismissed a test case bought by 100 women again three manufacturers of third-generation combined pills. Mr Justice Mackay ruled there was no increased relative risk by the third-generation oral contraceptives compared with second-generation products containing levonorgestrel.

GPs are now urged to assess a woman's individual risk of VTE when prescribing pills. In the last few years evidence has emerged that obesity and smoking are significant risk factors for VTE in women taking the COC. Women with a BMI over

30 have a two- to six-fold increase in the risk of VTE.

Since we now have a large variety of contraceptives (such as the progestogen-only methods described below), which are at least as effective as the COC without increasing the risk of venous thrombosis, it will be increasingly difficult to justify prescribing the COC to women with a BMI over 301.

Increased use

of Dianette

There has been a recent change in the summary of product characteristics for Dianette, mainly because of concerns about VTE risk. Dianette is actually licensed as a treatment for acne and hirsutism, rather than a contraceptive. With regard to VTE risk, there is limited data and prescriber bias must play a large role. After all, Dianette is specifically used in women with polycystic ovary syndrome, who are generally obese and therefore have a significantly increased risk of VTE due to their obesity.

Generally, Dianette is recommended for use as long as the acne or hirsutism persist: in most women it should be possible to change to another brand after between one and three years, but if symptoms are still a problem, it may be continued for longer. Otherwise, Dianette could be continued until the acne improves, and the patient then switches to either to Yasmin (see right), Cilest or one of the other skin-friendly COCs. I would advise that an individual woman should be assessed according to her BMI and other risk factors for VTE, rather than worrying purely about the use of Dianette.

I suggest to women the risk of VTE with all combined pills is around 30 to 40 per 100,000 women per year (including Dianette). This figure takes into account the published studies to date on VTE risk for all COCs.

Yasmin

This is a new combined pill containing 30µg ethinylestradiol and 3mg of a new progestogen, drospirenone. Drospirenone appears to have a pharmacological profile

almost identical to natural progesterone and is therefore unique among synthetic progestogens in having antimineralocorticoid activity.

It is well documented that ethinylestradiol tends to cause water retention, and some women do complain of bloating when they take COCs. Drospirenone, which is related to spironolactone, counteracts this by having a natriuretic effect. Trials suggest Yasmin is as effective as Dianette for mild to moderate acne, and it may be particularly suitable for those who suffer bloating and breast tenderness on other pills.

There has been considerable adverse publicity about Yasmin recently but this was purely to do with an advert, which was considered inappropriate. There is nothing inherently wrong with Yasmin, though it is more expensive than other pills.

Evra

This is a contraceptive patch containing 20µg of ethinylestradiol and 150µg of norgestimate, launched in the UK in 2003.

Each patch is worn for a week, and can be placed on the buttocks, abdomen, the back or the upper arm. Showering, bathing and swimming do not appear to affect adherence. In the clinical trials, some 20 per cent of women experienced mild to moderate application site reactions, although only 2 per cent discontinued the method for this reason. Efficacy was high, with a failure rate of only 0.7-1.2 per 100 women years overal · 2,3. Cycle control was good and comparable with that of Mercilon (approximately 10-15 per cent having spotting or bleeding in the third cycle).

The main side-effect was transient breast tenderness in the first couple of months, experienced by 18 per cent of users. Evra may be particularly suitable for young women, who find it hard to remember their pills ­ and they can sign up to a service that sends them a mobile text message reminder.

NuvaRing

This vaginal ring contains 15µg of ethinylestradiol and 120µg of etonogestrel (3-ketodesogestrel). The ring is flexible and transparent. It is made of ethylene vinylacetate (EVA) copolymers, with an outer diameter of 54mm and a cross-sectional diameter of 4mm. Each ring is used for three weeks, followed by a one-week ring-free interval.

Like the Evra patch, NuvaRing can be inserted and removed by the woman herself. In a large multicentre tria · 4 the method failure was 0.77 per 100 women years, and the user failure rate was 1.18 per 100 women years. NuvaRing has good cycle control and is well tolerated.

It is hoped it may be available in

the UK in 2005 but has been available in the US and parts of Europe (including Eire) for some time, which means UK GPs may come across women using it.

Progestogen only contraception (POC)

This has gained popularity in the last few years, especially as we now have a new pill that is ideal for older women or those who should not take oestrogens because of smoking or other contraindications.

There is no age limit for POC,

even in smokers, and it can be used during lactation, and for women at risk of VTE.

Cerazette is a new progestogen-only pill (75µg of desogestrel daily) designed to inhibit ovulation. A study comparing Cerazette with Microval showed that only 1.7 per cent of cycles were ovulatory in Cerazette users, compared with 40 per cent in Microval users5.

In a randomised trial of Cerazette vs Microval, the Pearl Index was

0.17 (method failure) and 0.5 (user failure) for Cerazette compared with 1.4 (method failure) and 1.9

(user failure) for Microval in non-breast-feeders6.

Although the bleeding pattern in Cerazette users is more variable than with Microval, there is a greater tendency towards infrequent bleeding and amenorrhoea by the end of the first year.

In June this year, the Medicines Healthcare and Products

Regulatory Agency granted Cerazette a licence with a 12-hour missed-pill window, rather than the three hours normally advised for conventional POPs.

This, combined with its higher efficacy, should make it a much more attractive proposition for many women.

Doubling the daily dose of conventional POPs has been suggested as a policy in women who weigh over 70kg.

There is, however, no evidence relating to the POP itself7, rather this is an extrapolation from data on a couple of other methods: a progestogen-only vaginal ring (which was not marketed) and an early version of Norplant (not the one marketed in the UK).

The efficacy of Implanon does

not appear to be affected by

weight.

There seems little justification for such a policy for the POP. But in the case of young women using conventional POPs, it might be reasonable to err on the side of caution in view of the already higher failure rate.

It would appear this will not be necessary with Cerazette, since blood levels, as with Implanon, are high enough to withstand any effect of increased weight.

Progestogen-only emergency contraception (Levonelle-2)

Recent data from a WHO randomised tria · 8 suggests Levonelle can be taken as a stat dose, rather than split into two doses 12 hours apart. There was no difference in the efficacy of the two regimens, with 1,356 women in each group.

This stat dose regimen is licensed and new packaging has been available since January 2004. It is likely that a single tablet version will become available in the near future.

There is a trend towards advance prescribing of the emergency pill, particularly for women known to be at higher risk (eg those using condoms as their contraceptive method).

Levonorgestrel -releasing intra-uterine system (Mirena)

The Mirena releases 20µg of levonorgestrel per day and is now licensed for five years. Its mechanism of action is mainly related to atrophy of the endometrium, and the majority of women will ovulate at least occasionally after the first year of use.

Its use results in a major reduction in menstrual flow and dysmenorrhoea, prompting suggestions that it is a viable alternative to hysterectomy and endometrial ablation in women with menorrhagia (for which it now has a licence).

The Mirena is also proving useful for perimenopausal women who still need contraception, as it also provides the progestogen part of HRT.

It has just been granted a licence for use solely in HRT.

And on its way....

four things that the future holds

1 Mifepristone

is a potentially new and extremely effective emergency contraceptive, even at a very low dose (10mg). Nausea and vomiting appear to be less common than with the Yuzpe regimen (PC4), but there is likely to be a delay in the onset of menstruation, which may limit the acceptability of the method.

2 Lunelle

is a promising injectable progestogen and oestrogen combination that is currently being devloped, but has to be given monthly which could affect its popularity.

3 A subcutaneous version of Depo Provera

is being researched, which could be self-administered and enable women to take more control over their family planning.

4 A male hormonal contraceptive

is still on the horizon. There appear to be two successful approaches: one consists of a testosterone implant coupled with Depo Provera injections, while the other consists of an etonorgestrel implant (similar to Implanon) coupled with testosterone injections. Both have been successful in trials so far, with few side-effects.

Useful websites and further reading

www.ffprhc.org.uk

www.fpa.org.uk

Szarewski A, Guillebaud J.

Contraception: a User's Handbook.

OUP 3rd ed revised March 2002

References

1 Szarewski A. The Combined Pill and VTE, Thrombus,

Winter 2002, Vol 6 (4):5-6

2 Smallwood GH et al. Efficacy and safety of a transdermal contraceptive system. Obstet Gynecol. 2001; 98: 799-805

3 Audet M et al. Evaluation of contraceptive efficacy and cycle control of a transdermal: Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive. JAMA 2001; 2347-54

4 Dieben TOM et al. Efficacy, cycle control and user acceptability of a novel combined contraceptive vaginal ring. Human Reproduction 2002; 100 (3): 585-93

5 Rice C et al. A comparison of the inhibition of ovulation achieved by desogestrel 75µg and levonorgestrel 30µg daily. Human Reprod. 1999; 14(4): 982-985

6 Korver T for collaborative group. A double-blind study comparing the contraceptive efficacy, acceptability and safety of two progestogen-only pills containing desogestrel 75µg /day or levonorgestrel 30µg /day.

Europ J Contraception and Reprod Health Care 1998; 3: 169-178

7 Vessey M. Oral contraceptive failures and body weight: findings in a large cohort study. Journal Family Planning & Reprod Health Care 2001; 27 (2): 90-1

8 Von Hertzen H et al for the WHO Research group on post-ovulatory methods of fertility regulation.Low-dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial.

Lancet 2002; 360:1803-10

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