This is the summary of a systematic review assessing the comparative safety and efficacy of Seasonale (ethinyl estradiol 30 μg, levonorgestrel 150 μg, extended 91-day cycle), in the prevention of pregnancy in sexually active women of reproductive age.
This oral contraceptive (OC) combines an estrogen, ethinyl estradiol (EE) 30 μg, and a progestin, levonorgestrel (LNG)150 μg, commonly contained in other OCs in Canada. Duration of active treatment for this product is 84 days, followed by 7 days of placebo. It is the only product available in Canada that is specifically formulated for extended-cycle use. The aim of this formulation, in addition to pregnancy prevention, is a reduction in menstrual bleeding.
The goal of therapy is prevention of pregnancy. Hormonal contraceptives may be used for many years, depending on desire for pregnancy prevention, ongoing sexual relationships, and contraceptive choice. Quality of life and prevention of serious morbidity are important secondary goals.
Two other OC’s with the same dose of EE and LNG (Min-Ovral or Portia) are marketed in Canada, differing only in administration schedule (21 days active, 7 days placebo). A range of other low dose OC’s (EE ≤ 35 μg) are also available, mainly differing in dose level and progestin.
In randomized controlled trials (RCTs) in women of reproductive age, does extended cycle EE 30 µg, LNG 150 µg (84-day active + 7-day placebo) provide a therapeutic advantage, in terms of mortality and morbidity, quality of life and pregnancy prevention, as compared with the same formulation provided in a standard cycle regimen (21-day active, 7-day placebo), or other combined estrogen-progestin oral contraceptives marketed in Canada?
Double-blind and open-label randomized controlled trials are included (the latter because menstrual cycle patterns make blinding impractical), comparing women of reproductive age on extended-cycle contraception (LNG 150 μg, EE 30 μg; 84 days active therapy, 7 days placebo) with standard-cycle (21 days active, 7 days placebo) low-dose OC’s containing the same formulation of LNG and EE or other low-dose estrogen-progestin OC’s available in Canada. An OC is defined as low-dose if it contains ≤35μg EE.
Search strategy and findings
The search included the following electronic databases: Medline (1966-Dec 2008), Embase (1988-Dec 2008), and the Cochrane database. Key search words included “levonorgestrel and ethinyl estradiol”, “contraceptive agents” and “Seasonale”. A search was also carried out for citations or included trials and publications by the lead author. The US FDA and EMEA websites were also searched.
One open label trial met study inclusion criteria (Anderson 2003). This one-year trial compared extended cycle LNG 150μg-EE 30 μg (84 days active, 7 days placebo) with a standard-cycle OC containing LNG 150μg-EE 30 μg (21 days active, 7 days placebo), N=682. There were two additional treatment arms not reported on in the published article: extended cycle LNG 100μg-EE 20 μg (84 days active, 7 days placebo) and standard-cycle OC containing LNG 100μg-EE 20 μg (21 days active, 7 days placebo). As the latter is marketed in Canada (Alesse, Aviane), it is also included as a comparator in this review, although more limited information is available on outcomes. Additional information was obtained from the FDA review of this trial, a Cochrane systematic review (Edelman et al, 2005), and two uncontrolled observational studies: a 2-year extension trial involving a subset of the RCT participants (Anderson 2006), and a 1-year uncontrolled observational study (Kovacs 1994).
Based on a one-year open-label RCT (Anderson 2003), there was no difference in pregnancy rate between LNG-EE extended-cycle and standard-cycle OCs: 4/456 (0.9%) vs. 3/226 (1.3%) (same dose, standard cycle) and vs. 6/231 (2.6%), (lower-dose, standard-cycle); [ITT population on-treatment]. Electronic diaries with daily alarms were used, likely increasing adherence and effectiveness compared with usual use. There were no deaths. Serious adverse events did not differ significantly: 11 (2.4%) on extended-cycle, 3 (1.3%) on the same dose standard-cycle OC and 4 (1.7%) on the lower-dose standard-cycle OC. Quality of life was not reported. Withdrawals due to adverse events in total did not differ on extended-cycle OC compared with the same dose standard cycle OC, but occurred more often than with the lower dose OC: 68 (14.9%), extended-cycle, vs. 17 (7.4%), low-dose standard cycle: ARI=7.5%, NNH=13. There were more withdrawals due to unacceptable bleeding on extended cycle OC: 35 (7.7%) vs. 4 (1.8%), same dose standard cycle OC, ARI=5.9%, NNH=17, and vs. lower dose standard cycle OC, 2 (0.9%), ARI=6.8% NNH=15. More women on extended-cycle OC withdrew early: 185 (40.6%) vs 65 (28.8%) on standard same-dose therapy, ARI=11.8%, NNH=8, and vs. 74 (32%) on standard lower-dose therapy, ARI=8.6%, NNH=12.
Detailed comparisons of menstrual bleeding were only available for the extended versus standard cycle formulation at the same dose (LNG 150μg – EE 30 μg ). There was no difference between the two study arms in total days of menstrual bleeding and spotting: mean number of days in 1 year = 48.2 (± 44.0) on extended-cycle vs 50.8 (± 27.0). Although women on extended-cycle OC had fewer planned menstrual bleeds, they had more breakthrough bleeding and spotting. There was no difference in rates of dysmenorrhea, breast tenderness or nausea. Women on extended-cycle OC experienced fewer headaches: 20.6% vs. 28.3%, ARR=7.7%, NNT=13 and less depressed mood: 2.2% vs. 5.8%, ARR=3.6%, NNT=28, but more menorrhagia: 11.6% vs. 2.6%, ARI=9%, NNH=11.
The annual dose of LNG and EE on extended-cycle OC is 23% higher than with standard-cycle OC’s with the same daily dose. No information is available on rates of rare serious adverse events associated with OC use, such as venous thromboembolism, stroke or myocardial infarction. The longest follow-up period of consecutive use is 2 years, and limited information is available from this uncontrolled observational study (43% early withdrawals). Endometrial biopsies at baseline and end of study on a small subset of extended-cycle OC users in Anderson (2003) failed to find any endometrial pathology, but this was a small subgroup, at one time point, with no control group.
- Seasonale, extended-cycle OC provides no therapeutic advantage in terms of pregnancy prevention. One 1-year open-label randomized controlled trial comparing LNG 150 µg EE 30 µg, (84-day cycle + 7-day cycle placebo) with LNG 150 µg EE 30 µg, (21-day cycle + 7-day cycle placebo) and with LNG 100 µg EE 20 µg, (21-day cycle + 7-day cycle placebo) failed to find an advantage in terms of mortality, morbidity or pregnancy prevention.
- No information is available on quality of life, but there is no evidence to suggest improved tolerability. There were more total withdrawals, and withdrawals due to unacceptable bleeding with extended-cycle LNG-EE, as compared with standard-cycle LNG-EE. There were more withdrawals due to adverse events in total as compared with lower-dose standard-cycle LNG-EE.
- There was no difference in the rate of combined bleeding and spotting over the 1-year period (same dose, extended cycle); planned menstruations occurred less frequently on the extended-cycle formulation, but inter-menstrual bleeding and spotting occurred more frequently.
- The annual dose of LNG and EE is 23% higher than with standard-cycle OC’s with the same daily dose.
- No information is available on rates of rare serious adverse events associated with OC use, such as venous thromboembolism, stroke or myocardial infarction.
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