Evra® (Johnson & Johnson) is a combination transdermal contraceptive patch containing 6mg norelgestromin (NGMN) and 0.6mg ethinylestradiol (EE) and is designed to release these hormones over a 7-day period. It has been registered in Singapore since 2003.
Hormonal contraceptives are known to be associated with an increased risk of venous thromboembolism (VTE), particularly during the first year of use of oral contraceptives (OC). In all cases, the risk of VTE increases with age and in the presence of other risk factors for VTE (e.g. obesity). The incidence of VTE in healthy, non-pregnant women who are not taking an OC is about 5 cases per 100,000 women per year. For those taking combined OC containing second generation progestogens, this incidence is about 15 per 100,000 women per year of use. Some studies have reported a greater risk of VTE in women using preparations containing third generation progestogens; the incidence is about 25 per 100,000 women year of use. The risk of VTE with transdermal patches is yet to be established although it remains very small and less than the risk of VTE associated with pregnancy, which is estimated as 60 per 100,000 pregnant women years.
In the last two years, there has been a higher number of spontaneous case reports of VTE associated with patients on this transdermal hormonal contraceptive compared to combined OC which raised the concern as to whether transdermal patch could be associated with a higher VTE risk.
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Studies
Recent studies have been conducted to attempt to shed some light to the post-marketing observation. Most of the studies were on Ortho Evra®, the product marketed in the United States, comprising 6mg NGMN and a higher content of EE at 0.75mg. Although the dosage and the manufacturing process for Evra® is different from that for Ortho Evra®, the patches were designed to deliver similar systemic amounts of EE and NGMN, and have been demonstrated to be bioequivalent. Hence the post-marketing data and studies on Ortho Evra® are considered to apply equally to Evra®.
a) Pharmacokinetic studies
The pharmacokinetic (PK) profile for the transdermal patches appears to be different from the PK profile for OCs as demonstrated in the studies below:
i) Ortho Evra® versus OCs
A PK study designed to analyse the difference in delivery of EE using Ortho Evra® and a conventional OC (containing norgestimate (NGM) 250mcg and EE 35mcg) over a 7-day period found that Ortho Evra® has higher steady state concentrations and lower peak concentrations compared to OCs. Under steady state conditions, there was an increased exposure of oestrogen (AUC0-168 and Css for EE were 55% and 60% higher, respectively) in women using Ortho Evra® compared to those taking conventional OC. The peak blood levels of oestrogen (Cmax) however were about 25% lower in women using Ortho Evra®. While the oestrogen level with the patch remained constant for one week until the patch was removed, the peak blood levels with a daily birth control pill rapidly declined to levels that were lower than on the Ortho Evra®.
As a result of this finding, the US Food and Drug Administration has amended the US package insert of Ortho Evra® to include this new information and a statement that although this increased oestrogen exposure may carry a theoretical risk of increased VTE, the clinical significance is not known.
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ii) Evra® versus OCs
A PK study comparing Evra® and OC (containing NGM 250mcg and EE 35mcg) showed that Cmax values were found to be two-fold higher for NGMN and EE in subjects administered with the OC compared to Evra®, while overall exposure (AUC and Css) was comparable in subjects treated with Evra®. Inter-subject variability (%CV) for the PK parameters following delivery from Evra® was higher relative to the variability determined from the OC.
The clinical relevance of this finding is yet to be determined; and caution should be exercised when making a direct comparison of these PK parameters.
b) Epidemiology studies
The results of two separate epidemiological studies sponsored by Johnson & Johnson that were designed to evaluate the risk of VTE in Ortho Evra® and OC (containing NGM 250mcg and EE 35mcg) were recently completed. These two studies with a nested case-control design were conducted in the US in women aged 15 to 44 years using electronic health claims data. The study by Cole et al1 found a two-fold increase in the risk of VTE in current users of Ortho Evra® compared to current OC users (OR 2.4, 95% CI 1.1–5.5). However, the study by Jick et al2 did not find an increase in risk of VTE for current users of Ortho Evra® compared to current OC users (OR 0.9, 95% CI 0.5–1.6). The epidemiology studies, comparing the risk of VTE in women using the transdermal hormonal contraceptive patch to the risk in women using conventional OC, are being extended as new electronic health claims data becomes available.
Conclusion
HSA will continue to monitor the safety profile of these drugs and update our healthcare professionals when more information becomes available. Although HSA has not received any reports of serious adverse reactions associated with Evra®, the local package insert of Evra® will be amended to include the findings of the studies on Ortho Evra® and Evra® as both products are bioequivalent.
References
- Obstet Gynecol. 2007 Feb;109(2 pt 1):339-46.
- Contraception. 2006 Mar; 73(3): 223-8.
