Oral Contraceptives: Crozer Keystone Family Medicine Department, Crozer Keystone Health Does Formulation Matter? System, Springfield, Pa (Dr
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Online ExcluSivE Kathryn A. Szabo, MD; Eric A. Schaff, MD Oral contraceptives: Crozer Keystone Family Medicine Department, Crozer Keystone Health Does formulation matter? System, Springfield, Pa (Dr. Szabo); Philadelphia Women’s Center, Pa OCs come in a variety of formulations, but verifiable (Dr. Schaff) differences are hard to find. Here’s help selecting the one [email protected] that’s best for your patient. The authors reported no potential conflict of interest relevant to this article. or a healthy woman interested in contraception, there PrActicE are multiple oral contraceptive (OC) formulations on rEcommendationS F the market from which to choose. But are there any sig- › Consider prescribing mono- nificant differences in their effectiveness or safety profiles that phasic pills as the first choice make one formulation superior? for women starting oral Comparative trials of OCs have attempted to answer these contraceptives (OCs), given questions by evaluating formulations that contain the syn- the lack of advantage in using thetic components: ethinyl estradiol, norethindrone, le- multiphasic formulations and the larger number of studies vonorgestrel, desogestrel, norgestimate, gestodene, and showing the safety and ef- drospirenone. ficacy of monophasic pills. B Unfortunately, many studies that have evaluated OCs have had methodological weaknesses, making their clinical sig- › Avoid prescribing OCs with nificance confusing. Few randomized controlled trials (RCTs) estrogen—even with ultra- low estrogen—for women at have been double blinded or adequately powered to find in- high risk for venous throm- frequent outcomes like pregnancy or adverse events. Trials are boembolism, given that there rarely reproduced by other researchers, and many have been are no studies that show funded by pharmaceutical companies with conflicts of inter- differences in low (25-35 mcg) est. Despite these shortcomings, it is possible to glean valuable ethinyl estradiol vs ultra- data from existing studies. low (10 mcg) formulas. C With that in mind, our purpose here is to consider whether there are significant differences in effectiveness, cycle control (bleeding), side effects, or satisfaction that may help physi- Strength of recommendation (SOR) cians and patients select the appropriate formulation. A Good-quality patient-oriented evidence B Inconsistent or limited-quality patient-oriented evidence comparing OC effectiveness C Consensus, usual practice, opinion, disease-oriented OC effectiveness is determined by the inherent properties to evidence, case series prevent ovulation, conception, and/or implantation when the formulation is used correctly,1,2 and during typical inconsis- tent 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 com- jfponline.com Vol 62, no 10 | october 2013 | the journal of family practice E1 bined OCs, see “A closer look at combined side effects and adverse events yet remain OCs” on page E3.) Theoretically, progestins at a level sufficient to provide menstrual with longer half-lives may be more effective at cycle control with minimal breakthrough preventing ovulation if a pill is not taken the bleeding. Advantages of ultra-low estrogen same time each day, and extended cycle pills (10 mcg) products include reduction of estro- provide more continuous suppression of ovu- genic side effects,9 but disadvantages include lation. But, no studies have found any formu- breakthrough bleeding, which can negatively lation to be more effective than another. affect adherence.10 In a double-blind RCT of z A 2004 cochrane review4 compared 649 women comparing OCs with gestodene progestins in OCs by examining 22 different 75 mcg and either 20 or 30 mcg ethinyl estra- trials with various study protocols. The re- diol (EE), more intermenstrual breakthrough view found a lower rate of discontinuation in bleeding occurred with the 20 mcg group patients taking OCs with second-generation (P<.05). This difference was not enough to progestins compared with first-generation cause an increased discontinuation rate in progestins (relative risk [RR]=0.79; 95% con- the 20-mcg EE group.11 fidence interval [CI], 0.61-0.91), and an even z Progestin-only pills (PoPs) are recom- lower rate of discontinuation with third- mended for women who cannot or should generation OCs. Additionally, cycle control not take estrogen in OCs, and women who was better in second-generation progestin are breastfeeding. The advantages of POPs Extended-cycle OCs compared with first-generation proges- include a simplified and fixed regimen. Dis- OCs have a tin OCs. Rates of effectiveness, cycle con- advantages include irregular bleeding and greater risk of trol, and side effects were similar between menstrual cycle length. A 2010 Cochrane breakthrough drospirenone (DRSP) and desogestrel. The review examined various POP formulations bleeding, which reviewers concluded that second- and third- in 6 different trials and concluded that there can decrease generation progestins are preferred over first- is insufficient research to compare POPs in adherence and generation progestins in combined OCs,4 terms of efficacy, acceptability, and continu- increase although the evidence is not strong. ation rates.12 discontinuation, z What about generics? To be con- z Monophasic vs multiphasic OCs. Bi- thus increasing sidered an FDA-approved bioequivalent phasic and triphasic OCs were introduced in the risk of generic to a brand name formulation, pharmaco- an effort to decrease the amount of hormone pregnancy. kinetic studies must demonstrate that a prod- and the side effects. Their phasic nature also -at uct provides equivalent serum levels. There tempts to mimic the pattern of rising and falling are no studies evaluating differences in effec- estrogen and progesterone levels seen during a tiveness of generic vs brand name OCs. Ge- normal menstrual cycle. Cochrane reviews in neric OCs typically cost about 50% less than 200913 and 201114 compared the cycle control brand name OCs.5 The Society of Obstetri- and side effects of biphasic vs monophasic, cians and Gynaecologists of Canada supports and triphasic vs monophasic formulations of generic formulations “providing increased OCs, respectively. The 2009 review compar- choice and less expensive options.”6 ing biphasic and monophasic OCPs was lim- ited to one study of 533 women using biphasic pills and 481 women using monophasic pills. What are the differences No differences were found in intermenstrual among the options? bleeding, amenorrhea, or discontinuation While OCs, in general, are thought to cause due to intermenstrual bleeding. side effects, when compared with a placebo, The 2011 review comparing triphasic no significant findings have been noted in and monophasic OCs included 21 studies, the frequency of headache, nausea, vomiting, and found no significant difference in dis- breast pain, or weight gain.7,8 This being the continuation due to medical reasons, cycle case, it is unlikely that there are differences disturbance, intermenstrual bleeding, or ad- among formulations. verse events. Both of the Cochrane reviews z ultra-low estrogen. Estrogen in OCs concluded that monophasic pills should be has been reduced to 10 to 35 mcg to minimize the first choice for women starting OCs given E2 the journal of family practice | october 2013 | Vol 62, no 10 orAl Contraceptives the lack of advantage in using multiphasic formulations, and the larger number of stud- A closer look at combined oCs ies showing the safety and efficacy of mono- combined oral contraceptives (OCs) have only one estrogen, ethinyl phasic pills. estradiol (EE), in various doses, formulated with a progestin. proges- The 2009 Cochrane review compared bi- tins can be grouped chronologically. first-generation progestins, com- phasic and triphasic OCPs in terms of cycle monly referred to as “estranes,” include norethindrone, norethindrone control and side effects.13 The first trial exam- acetate, and ethynodiol diacetate. Second-generation progestins, ined in this review included 458 women and called “gonanes,” are more potent and allow the use of lower doses. compared 2 biphasic pills and one triphasic they include norgestrel and levonorgestrel (LNG). pill, all containing levonorgestrel (LNG) and third-generation progestins, also called “gonanes,” have reduced an- EE. It found no important differences among drogenic and metabolic effects and include norgestimate, desogestrel, the 3 formulations, but found that 252 of the and gestodene (not available in the united States). finally, there is a initial 458 women (55%) discontinued the newer miscellaneous category: drospirenone, an antimineralocorticoid study for various reasons. with progestogen and antiandrogenic activity. The second trial included 469 wom- en (169 [36%] of whom withdrew from the study), and compared a biphasic pill contain- ing norethindrone with 2 triphasic pills, one traceptive cycle.16 Nonadherence often oc- containing LNG and the other containing curs during transitions between successive norethindrone. This study showed no dif- packs of OCs.17 It has been reported that ferences between the biphasic and triphasic 47% of women using OCs miss one pill, and pills containing norethindrone, but inferior 22% miss 2 pills per