Health Sciences Authority - Update on Evra® and thromboembolism

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25 Mar 2008: Update on Evra® and thromboembolism

This is an update on the further findings from the recently completed studies reviewing the relative risk of venous thromboembolism (VTE) associated with use of Ortho Evra® compared to combined oral contraceptives (COC) [please refer to HSA ADR News Bulletin (March 2007; Vol.9 No.1) for the earlier review.]

Evra® (Johnson & Johnson) is a transdermal combined contraceptive patch containing 6mg norelgestromin (NGMN) and 600mcg ethinyl estradiol (EE) that has been registered locally since 2003. Ortho Evra® is the formulation of Evra® marketed in U.S, containing 6mg NGMN and 750mcg EE.

Application of findings on Ortho Evra® to Evra®

The post-marketing safety data available are largely based on Ortho Evra®. Although the dosage and manufacturing processes are different for Evra® and Ortho Evra®, the patches are designed to deliver similar systemic amounts of EE and NGMN and have been demonstrated to be bioequivalent. Evra® was approved for marketing based on data obtained with Ortho Evra®. Similarly, the post-marketing data would be considered applicable to Evra®.

VTE associated with use of hormonal contraceptives

COC are known to be associated with an increased risk of VTE. The incidence of VTE in healthy, non-pregnant women who are not taking a COC is about 4 cases per 100,000 women per year of use. The incidence of VTE associated with COC, ranges from 10.3 to 21 cases per 100,000 women per year of use and remains lower than that of pregnancy (60 cases per 100,000 women per year of use).

Since marketing, there has been a higher number of spontaneous case reports of VTE associated with patients on Ortho Evra® and Evra® compared to COC which raised the concern as to whether hormonal transdermal patches could be associated with a higher VTE risk.

Review of epidemiology studies conducted

Since the update in March 2007, an additional unpublished epidemiology study (BCDSP LNG-30 OC study) and an analysis of new data from the previously completed epidemiology study (BCDSP NGM-35 OC¹ study) were conducted to evaluate the relative risk of VTE in Ortho Evra® users compared to other COC users. BCDSP LNG-30 OC study showed odds ratio 2.0 (95% C.I 0.9–4.1) while the analysis of new data from BCDSP NGM-35 OC study showed odds ratio 1.1 (95% C.I 0.6–2.1).

To date, three nested case-control epidemiology studies, using electronic health claims database, have been conducted to compare the relative risk of VTE in Ortho Evra® users against other COC users (using 30–35mcg EE and either levonorgestrel or norgestimate) in women aged 15–44. The studies are i3 Ingenix study², BCDSP NGM-35 OC study and BCDSP LGN-30 OC study. Of the studies, only i3 Ingenix study reached statistical significance at an odds ratio 2.4 (95% CI 1.1–5.5).

Table 1: Summary of epidemiology studies comparing estimates (odds ratios) of VTE risk in users of Ortho Evra® versus COC

Epidemiologic Study	Comparator Product	Odds Ratio (95% CI)
i3 Ingenix	NGM / 35 mcg EE	2.4 (1.1-5.5)ª
BCDSP NGM-35 OC	NGM / 35mcg EE	0.9 (0.5-1.6) 1.1 (0.6-2.1)^b,3
BCDSP LNG-30 OC	LNG / 30mcg EE	2.0 (0.9-4.1)

a – Increase in risk of VTE is statistically significant
b – Separate estimate from 17 months of data on new cases not included in the previous estimate
NGM – Norgestimate
LNG – Levonorgestrel
EE – Ethinyl estradiol

Conclusion

Healthcare professionals should take into consideration the findings above when selecting the appropriate contraceptives for their patients. The local package insert of Evra® has been amended to include the findings of the latest epidemiology studies on Ortho Evra®. HSA will continue to monitor the safety profile of this drug and update healthcare professionals when more information becomes available.

References

Contraception 2006 Mar;73:223-8.
2. Obstet Gynecol 2007 Feb;109(2):339-46.
3. Contraception 2007 Jul;76:4-7.

Last updated on 02 Jul 2010 16:58:05