What is the difference between Alesse (levonorgestrel and ethinyl estradiol) 21 and Alesse (levonorgestrel and ethinyl estradiol) 28?

Alesse 21 vs Alesse 28: Practical Differences

The only difference between Alesse 21 and Alesse 28 is the number of pills in the pack—Alesse 21 contains 21 active hormone pills only, while Alesse 28 contains the same 21 active hormone pills plus 7 placebo (inactive) pills. Both formulations contain identical active ingredients (100 mcg levonorgestrel and 20 mcg ethinyl estradiol) and provide equivalent contraceptive efficacy, safety, and clinical outcomes 1.

Active Hormone Content

• Both formulations deliver the same monophasic regimen of 100 mcg levonorgestrel with 20 mcg ethinyl estradiol for 21 consecutive days 1
• This low-dose combination has demonstrated a Pearl Index of 0.88 in large clinical trials, indicating highly effective contraception 1
• The 20 mcg ethinyl estradiol dose is among the lowest available, though it requires strict adherence as studies show more follicular activity when these lower-dose pills are missed compared to 30 mcg formulations 2

The 7-Day Difference

• Alesse 21: Contains only 21 active hormone pills; patients must remember to restart a new pack after a 7-day pill-free interval
• Alesse 28: Contains 21 active hormone pills plus 7 placebo pills; patients take one pill daily without interruption, automatically maintaining the correct timing 2

Clinical Implications for Adherence

• The 28-day pack design helps maintain the daily pill-taking habit and reduces the risk of extending the hormone-free interval beyond 7 days 3
• Extending the hormone-free interval increases the risk of follicular development and potential ovulation, particularly with 20 mcg ethinyl estradiol formulations 3, 2
• If the hormone-free interval is extended to 24-48 hours late (days 8-9), backup contraception is required for 7 consecutive days of active pill use 3
• If extended ≥48 hours (day 9 or later), emergency contraception should be considered if unprotected intercourse occurred in the previous 5 days 3

Efficacy and Safety Profile

• Both formulations demonstrate identical contraceptive effectiveness with proper use, with breakthrough bleeding occurring in 12.9% of cycles and spotting in 10.1% of cycles 1
• The levonorgestrel component (a second-generation progestin) provides a safer coagulation profile compared to third and fourth-generation progestins 3, 2
• The venous thromboembolism risk increases from 1 per 10,000 to 3-4 per 10,000 woman-years during use, which remains significantly lower than pregnancy risk (10-20 per 10,000 woman-years) 2

Practical Recommendation

Choose Alesse 28 for most patients, particularly those new to oral contraceptives, those with a history of missed pills, or anyone who may benefit from the continuous daily routine. The placebo pills serve as a reminder system that reduces the risk of timing errors when restarting the next pack 2. The only scenario where Alesse 21 might be preferred is for highly motivated patients who specifically request fewer pills or have concerns about taking inactive tablets.

Common Pitfalls to Avoid

• Do not assume patients understand they must restart Alesse 21 exactly on day 8—explicitly counsel on this timing 3
• Remember that 20 mcg formulations require stricter adherence than 30-35 mcg formulations; seven consecutive days of pill-taking is necessary to reliably prevent ovulation 2
• Counsel patients that if they miss 2 or more pills during the first week and had unprotected intercourse in the previous 5 days, emergency contraception should be considered 3