What is Evra?

Evra is a three-layered patch that measures around 20cm (4.5cm x 4.5cm), and contains 600µg of ethinylestradiol* and 6mg of norelgestromin (the main active metabolite of norgestimate, the progestogen in the combined pill Cilest). The patch consists of an outer polythene and polyester backing, an adhesive middle layer containing the drugs, and a clear protective polythene liner that is removed to expose the sticky surface, which is then applied to the skin. The patch delivers 20µg ethinylestradiol plus 150µg norelgestromin into the systemic circulation every 24 hours.2 After application, serum concentrations of oestrogen and progestogen plateau by around 48 hours, and remain steady for the 7 days of usage.3 With a COC, serum concentrations of the hormones vary during each 24-hour period. We know of no direct comparisons of the serum hormone concentrations achieved with Evra and Cilest.

* This new spelling reflects the use of recommended International Non-proprietary Names (rINNs) instead of former British Approved Names (BANs), as required by European law. For more information, see the British National Formulary, or http://medicines.mhra.gov.uk/inforesources/productinfo/banslist.pdf

Patch application and reapplication

The summary of product characteristics (SPC) recommends that the patch is applied to the abdomen, buttocks, outer upper arm or upper torso, but not the breasts.2 It also states that each patch should be applied for 7 days, then removed and another applied. The dosage regimen mimics the 28-day cycle used for COCs, with 21 days of hormone administration (three consecutive patch applications) and then 7 days that are patch-free. As with COCs, extending the patch-free interval beyond 7 days risks pregnancy. To help prevent local irritation, a new patch should not be placed on the site of the preceding one. If a patch detaches partially or completely, insufficient hormone delivery may occur. The SPC advises that if a patch has been detached for less than 24 hours, it can be reapplied or replaced immediately without the need for extra contraceptive protection. If the patch has been detached for more than 24 hours, or if the woman is unsure when the patch became detached, or if the replacement of a patch in the middle of the patch cycle (week 2 or 3) is delayed for more than 48 hours, the SPC advises women to start a new patch cycle immediately by putting on a new patch and using non-hormonal contraception for the next 7 days.

Women using the patch can register through the company's website for Evra-users to receive text messages reminding them when patch change is due.

Patch disposal

Around 80% of the total hormone content of the patch remains in the patch when this is removed after 7 days' use. It is now recognised that should these patches enter the sewerage system (each weekly patch being equivalent to two or three COC pills daily entering this system) they could cause water pollution. We therefore welcome the action of the European regulatory authority in highlighting this potential environmental problem, 4 such that the SPC, patient information leaflet and labelling instruct the user not to flush the patches down the toilet. Instead, the user is advised to seal the used patch with a sticky label that comes with the packaging and discard it "according to local requirements" or return it to a pharmacy.2

Clinical evidence

Effect on pregnancy rate

The Evra patch used in the published trials, and originally licensed in the EU, contained 750µg ethinylestradiol, not 600µg as currently licensed.4

In one non-blinded trial, 1,417 women aged 18-45 years were randomised to use Evra or a triphasic ethinylestradiol/levonorgestrel COC pill similar to Logynon ED, for 6 cycles (two-thirds of the women) or 13 cycles (one-third of the women).5 The overall pregnancy rate was 1.24 per 100 woman-years (95% CI 0.15-2.33) for those using Evra and 2.18 per 100 woman-years (95% CI 0.57-3.80) for the COC. This difference was not statistically significant. The reported rates of product-failure (i.e. calculated by including only those pregnancies not associated with a concurrent dosing error)* were 0.99 per 100 woman-years (95% CI 0.02-1.96) for Evra and 1.25 per 100 woman-years (95% CI 0.02-2.47) for the COC; again, this difference was not statistically significant. In a non-blinded randomised trial, published only as an abstract (and which 3 years later has still not been published in full), Evra (used by 861 women) was compared with the oral contraceptive Mercilon (ethinylestradiol 20µg plus desogestrel 150µg; taken by 656 women).8 Overall pregnancy rates were 0.88 per 100 woman-years for the patch and 0.56 per 100 woman-years for the COC; reported product-failure rates were 0.66 per 100 woman-years and 0.28 per 100 woman-years, respectively. These differences between the groups were not statistically significant. Neither of the trials was large enough to assess the relative contraceptive efficacy of the patch and the COCs.

In a non-comparative trial, involving 1,672 women (aged 18-45 years) who took Evra for 6 or 13 cycles, the overall pregnancy rate was 0.71 per 100 woman-years and the reported product-failure rate 0.59 per 100 woman-years.9 The data from the three trials5^,8^,9 have been pooled to calculate an overall pregnancy rate for Evra of 0.88 per 100 woman-years (95% CI 0.44-1.33) and a product-failure rate of 0.7 per 100 woman-years (95% CI 0.31-1.10).10 According the SPC, Evra is less effective as a contraceptive in women weighing 90kg or more.2

Effect on cycle control

Combined data from the two randomised controlled trials5^,8^,9 and one non-randomised trial9 suggest that withdrawal bleeding with the patch started, on average, a day later than with a COC, lasted 5-6 days (a day longer than with a COC), and extended into the next cycle of patch use.11 Breakthrough spotting, but not breakthrough bleeding (sufficient to require more than one tampon or sanitary towel), was more common among patch-users than among COC-users, in the early cycles.5 Amenorrhoea occurred in 0.1% of patch-users and 0.2% of COC-users.5

Compliance

In the fully reported randomised trial, women kept diary-card records of their contraceptive use.5 Where this information was available and adequate for a particular cycle, it was used to assess whether compliance with therapy during that cycle was "perfect" (defined as "21 consecutive days of drug-taking, which could have included the use of replacement patches, followed by a 7-day drug-free interval"). From these data, the investigators calculated that the mean proportion of each participant's cycles that demonstrated perfect compliance was higher with Evra than with the COC (88.2% vs. 77.7%, p<.001). However, there are several weaknesses in the trial, which make the reliability of this result questionable. The trial was not designed to show a difference in compliance between the two contraceptives,11 it was non-blinded, and the compliance data were based on self-reported information. Furthermore, the reported measure of "perfect compliance" is not the same as true long-term compliance because the reported results took no account of how long women actually remained in the trial. This is particularly important because there were more discontinuations in the trial among users of Evra, both overall (30% vs. 24% with the COC) and because of unwanted effects (13% vs. 5%; no p values reported). Since "perfect compliance" as assessed in the trial does not take into account discontinuation rates, it may be that true long-term compliance is no better with Evra than with a COC.

Unwanted effects

The unwanted effects of Evra appear similar to those of COCs, although in trials, typical cyclical symptoms were more common with Evra,5 for example, breast tenderness (seen in 19% vs. 6% of patients, p<.001) and dysmenorrhoea (13% vs. 10%, p=0.04). Most of the breast discomfort occurred in the first two cycles. It is unknown if the risk of venous thromboembolism with Evra is different from that with COCs. In a pooled analysis of data from three studies, around 2% of patches fell off and another 3% detached partially.12 In one randomised trial, application-site reaction (reported by 20% of women) was the commonest cause of withdrawal (2.6%).5

Drug interactions

The SPC for Evra advises that women who take hepatic enzyme-inducing drugs while using Evra should use a barrier method of contraception while on, and for 28 days after stopping, the enzyme-inducing drug. In women on Evra, tetracycline therapy does not seem to reduce serum concentrations of either ethinylestradiol or norelgestromin.3 The SPC for Evra advises that women on antibacterials (apart from tetracycline) should use a barrier method of contraception until 7 days after stopping the antibacterial therapy.

Cost

At around £101 per year, the cost of Evra to the NHS is more than that of any COC. For example, the annual cost of COCs providing 20µg ethinylestradiol daily ranges from around £12 for Loestrin 20 to £37 for Mercilon.

Conclusion

▼Evra is the first combined hormonal contraceptive to be formulated as a patch. In women taking Evra, breast discomfort and vaginal spotting in early cycles and dysmenorrhoea are more common than with a combined oral contraceptive (COC), but otherwise the range of unwanted effects appears to be broadly similar with the two types of contraceptive. Women appear to be twice as likely to discontinue using Evra because of unwanted effects than they are a COC. There is a considerable risk of environmental pollution if the patches are not disposed of properly and both the prescriber and the woman need to bear this in mind when considering use of Evra.

There is no convincing evidence that long-term compliance is better with Evra than with a COC, nor on whether the patch is any more or less effective than a COC in preventing pregnancy. In our view, the claim (on the company's website for women using Evra) that the patch is "just as effective as the contraceptive pill" is misleading. Furthermore, we believe that such promotion of a prescription-only medicine to women prescribed it (including the website's use of the slogan, "Evra The Right Contraceptive Choice") breaches the advertising regulations and should therefore be stopped immediately.

On current evidence, Evra offers no compelling clinical advantages over COCs, and it costs much more.