Applied Evidence

Oral contraceptives: Does formulation matter?

Author and Disclosure Information

OCs come in a variety of formulations but verifiable differences between products are difficult to find.




• Consider prescribing monophasic pills as the first choice for women starting oral contraceptives (OCs) given the lack of advantage in using multiphasic formulations, and the larger number of studies showing the safety and efficacy of monophasic pills.

• Avoid prescribing OCs with estrogen—even with ultra-low estrogen—to women at high risk for venous thromboembolism, given that there are no studies that show differences in low (25-35 mcg) ethinyl estradiol vs ultra-low doses (10 mcg) formulas.

Strength of recommendation (SOR)

• Good-quality patient-oriented evidence
• Inconsistent or limited-quality patient-oriented evidence
• Consensus, usual practice, opinion, disease-oriented evidence, case series

For a healthy woman interested in contraception, there are multiple oral contraceptive (OC) formulations on the market from which to choose. But are there any significant differences in their effectiveness or safety profiles that make one formulation superior?

Comparative trials of OCs have attempted to answer these questions by evaluating formulations that contain the synthetic components: ethinyl estradiol, norethindrone, levonorgestrel, desogestrel, norgestimate, gestodene, and drospirenone.

Unfortunately, many studies that have evaluated OCs have had methodological weaknesses, making their clinical significance confusing. Few randomized controlled trials (RCTs) have been double blinded or powered to find infrequent outcomes like pregnancy or adverse events. Trials are rarely reproduced by other researchers and many have been funded by pharmaceutical companies with conflicts of interest. Despite these shortcomings, it is possible to glean valuable data from existing studies.

With that in mind, our purpose here is to review whether there are significant differences in effectiveness, cycle control (bleeding), side effects, or satisfaction that may help physicians and patients select the appropriate formulation.

Comparing OC Effectiveness

OC effectiveness is determined by the inherent properties to prevent ovulation, conception, and/or implantation when the formulation is used correctly.1,2 and during typical inconsistent use in the population (ie, adherence).3 Effectiveness is also measured by whether the method is discontinued and there is a gap in contraception allowing pregnancy to occur.

There is no evidence that any combined or progesterone-only hormonal formulation is inherently better at preventing ovulation, conception, or implantation. (For more on combined OCs, see “A closer look at combined OCs,” on page E3.) Theoretically, progestins with longer half-lives may be more effective at preventing ovulation if a pill is not taken the same time each day, and extended cycle pills provide more continuous suppression of ovulation. But, no studies have found any formulation to be more effective.

A 2004 Cochrane review4 compared progestins in OCs by examining 22 different trials with various study protocols. The review found a lower rate of discontinuation in patients taking OCs with second generation progestins compared with first generation progestins (relative risk [RR]=0.79; 95% Extended-cycle OCs have a greater risk of breakthrough bleeding, which can decrease adherence and increase discontinuation, thus increasing the risk of pregnancy. confidence interval [CI] 0.61-0.91), and an even lower rate of discontinuation with third generation OCs. Additionally, cycle control was better in second generation progestin OCs compared with first generation progestin OCs. Rates of effectiveness, cycle control and side effects were similar between drospirenone and desogestrel. The review concluded that second and third generation progestins are preferred over first generation progestins in combined OCs,4 although the evidence is not strong.

What about generics? To be considered an FDA-approved bioequivalent generic to a brand name formulation, pharmacokinetic studies must demonstrate that a product provides equivalent serum levels. There are no studies evaluating differences in effectiveness of generic vs brand name OCs. Generic medications typically cost about 50% less than brand name OCs.5 The Society of Obstetricians and Gynaecologists of Canada supports generic formulations “providing increased choice and less expensive options.”6

What are the differences among the options?

While OCs, in general, have a reputation of causing side effects, when compared with a placebo, no significant findings have been noted in the frequency of headache, nausea, vomiting, breast pain, or weight gain.7,8 That being the case, it is unlikely there are differences among formulations.

Ultra-low estrogen. Estrogen in OCs has been reduced to 10 to 35 mcg to minimize side effects and adverse events, yet remain at a level sufficient to provide menstrual cycle control with minimal breakthrough bleeding. Advantages of ultra-low estrogen 10 mcg products include reduction of estrogen, side effects9 but the disadvantage includes breakthrough bleeding, which can negatively affect adherence.10 In a double-blind RCT of 649 women comparing OCs with gestodene 75 mcg and either 20 mcg or 30 mcg ethinyl estradiol (EE), more intermenstrual breakthrough bleeding occurred with the 20 mcg group (P<0.05). This difference was not enough to cause an increased discontinuation rate in the 20-mcg EE group.11


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