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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 , norethindrone, le- multiphasic formulations and the larger number of studies vonorgestrel, , norgestimate, , and showing the safety and ef- . 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) —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 , 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 - 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 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 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 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 , , vomiting, and found no significant difference in - dis breast , 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

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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 “,” include norethindrone, norethindrone control and side effects.13 The first trial exam- , and ethynodiol diacetate. Second-generation progestins, ined in this review included 458 women and called “,” are more potent and allow the use of lower doses. compared 2 biphasic pills and one triphasic They include and (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 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 cycle.18 Ovulation and cycle control in the biphasic pill containing pregnancy are more likely to occur if pills are norethindrone compared with the triphasic missed in the first week after menses. containing LNG. The review concluded that Extended-cycle OCs prevent hormonal the choice of progestin type (LNG preferred fluctuations and provide continuous sup- over norethindrone) might be more impor- pression of FSH and luteinizing hormone tant than the choice of phasic regimen.13 (LH), decreasing the likelihood of ovula- z Monthly vs extended-cycle OCs. tion and, therefore, pregnancy. Because the When OCs were first introduced, researchers extended-cycle regimen decreases the num- believed that women would prefer a 21-day ber of transitions between packs of OCs, one formulation followed by a 7-day pill-free time might expect a reduction in the risk associ- that mimicked an average woman’s men- ated with nonadherence at the beginning of strual cycle because the withdrawal bleed- a cycle. However, extended-cycle OCs have a ing would be an indicator that she was not greater risk of breakthrough bleeding, which pregnant. Extending the time between men- can decrease adherence and increase discon- ses has since garnered increased interest. tinuation of the method, thereby increasing Extended-cycle preparations are available for the risk of pregnancy. durations ranging from 84 to 365 days.15 A multicenter RCT of 682 women exam- A study of 99 women evaluated the im- ined the efficacy and safety of the extended- pact of omitting the first 3 combined OC cycle OC Seasonale (30 mcg EE/150 mcg LNG) pills (second and third generation) on ovu- compared with a traditional cycle OC Nor- lation during a 28-day cycle. While none of dette-28 (30 mcg EE/150 mcg LNG). Women the women experienced ovulation, follicle- received either 4, 91-day extended cycles stimulating hormone (FSH) reached a maxi- (n=456) or 13, 28-day regular cycle (n=226) mal serum concentration in most women regimens over the course of one year. On av- during the first 7 pill-free days, indicating erage, 38% of women in the extended- cycle complete pituitary recovery. Additionally, group reported unscheduled (breakthrough) the researchers detected increases in serum bleeding, while 18% of women in the con- estradiol, indicating that follicular growth up ventional cycle group reported unscheduled to preovulatory size is common in women bleeding. Breakthrough bleeding decreased missing the first one to 3 pills of their con- with each successive cycle of the extended reg-

jfponline.com Vol 62, No 10 | october 2013 | The Journal of Family Practice E3 TABLE Oral contraceptives: A review of the options

Estrogen Progestin Mono- vs Monthly vs Generic name Brand name dose (mg) dose (mg) multiphasic extended cycle Progestin only Norethindrone Aygestin - 5 Monophasic Monthly acetate Norethindrone Camila, Errin, - 0.35 Monophasic Monthly only Jolivette, Nora-BE, Nor-QD, Ortho Micronor First-generation Ethinyl estradiol Demulen* Days 1-21: 0.05 Days 1-21: Monophasic Monthly progestin and ethynodiol 1 Days 22-28: diacetate inert pills Days 22-28: inert pills Kelnor, Zovia Days 1-21: Days 1-21: Monophasic Monthly 0.035 1 Days 22-28: Days 22-28: inert pills inert pills Ethinyl estradiol Gildess Fe 1/20† Days 1-21: Days 1-21: Monophasic Monthly and Junel 1/20, Junel 0.02 1 norethindrone 1/20 Fe,† Loestrin 21 Days 22-28: Days 22-28: 1/20, Loestrin 1/20 inert pills inert pills Fe,† Microgestin 1/20, Microgestin 1/20 Fe† Gildess 1.5/30 Days 1-21: Days 1-21: Monophasic Monthly Fe,† Junel 1.5/30, 0.03 1.5 Junel 1.5/30 Fe,† Days 22-28: Days 22-28: Loestrin 21 1.5/30, inert pills inert pills Loestrin 1.5/30 Fe,† Microgestin 1.5/30, Microgestin 1.5/30 Fe† Balziva, Femcon Fe,† Days 1-21: Days 1-21: Monophasic Monthly Ovcon 35, 0.035 0.4 Zenchent, Zeosa† Days 22-28: Days 22-28: inert pills inert pills Brevicon, Modicon, Days 1-21: Days 1-21: Monophasic Monthly Nelova, Necon 0.035 0.5 0.5/35,* Nortrel Day 22-28: Day 22-28: 0.5/35 inert pills inert pills Cyclafem 1/35, Days 1-21: Days 1-21: Monophasic Monthly Genora 1/35, Necon 0.035 1 1/35, Norethin 1/35, Day 22-28: Days 22-28: Norinyl, Nortrel inert pills inert pills 1/35, Ortho-Novum 1/35

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TABLE Oral contraceptives: A review of the options (continued)

Estrogen Progestin Mono- vs Monthly vs Generic name Brand name dose (mg) dose (mg) multiphasic extended cycle First-generation Ethinyl estradiol Ovcon 50 Days 1-21: Days 1-21: Monophasic Monthly progestin and 0.05 1 (continued) norethindrone Days 22-28: Days 22-28: (continued) inert pills inert pills Loestrin 24 Fe† Days 1-24: Days 1-24: Monophasic Monthly 0.02 1 Days 25-28: Days 25-28: inert pills inert pills Necon 10/11* Days 1-21: Days 1-10: Biphasic Monthly 0.035 0.5 Days 22-28: Days 11-21: inert pills 1 Aranelle, Leena, Days 1-21: Days 1-7: Triphasic Monthly Tri-Norinyl 0.035 0.5 Days 22-28: Days 8-16: inert pills 1 Days 17-21: 0.5 Days 22-28: inert pills Estrostep Fe,† Tri- Days 1-5: Days 1-21: Triphasic Monthly Legest Fe,† 0.02 1 Tilia Fe† Days 6-12: Days 22-28: 0.03 inert pills Days 13-21: 0.035 Days 22-28: inert pills Cyclafem 7/7/7, Days 1-21: Days 1-7: Triphasic Monthly Necon 7/7/7, Nortrel 0.035 0.5 7/7/7, Ortho-Novum Days 22-28: Days 8-14: 7/7/7 inert pills 0.75 Days 15-21: 1 Second generation Ethinyl estradiol Alesse,* Aviane, Days 1-21: Days 1-21: Monophasic Monthly progestin and Lessina,* Levlite, 0.02 0.1 levonorgestrel Lutera, Sronyx Days 22-28: Days 22-28: inert pills inert pills

continued

jfponline.com Vol 62, No 10 | october 2013 | The Journal of Family Practice E5 TABLE Oral contraceptives: A review of the options (continued)

Estrogen Progestin Mono- vs Monthly vs Generic name Brand name dose (mg) dose (mg) multiphasic extended cycle Second-generation Ethinyl estradiol Altavera, Levlen,* Days 1-21: Days 1-21: Monophasic Monthly progestin and Levora,* 0.03 0.15 (continued) levonorgestrel Microgynon, Days 22-28: Days 22-28: (continued) Nordette,* inert pills inert pills Ovranette, Portia* Enpresse, Days 1-6: Days 1-6: Triphasic Monthly Levonest,* 0.03 0.05 Triphasil,* Days 7-11: Days 7-11: Tri-Levlen,* Trivora 0.04 0.075 Days 12-21: Days 12-21: 0.03 0.125 Days 22-28: Days 22-28: inert pills inert pills Lybrel Days 1-28: Days 1-28: Monophasic 365-day cycle 0.09 0.02 LoSeasonique Days 1-84: Days 1-84: Monophasic 91-day cycle 0.02 0.1 Days 85-91: 0.01 Introvale, Jolessa, Days 1-84: Days 1-84: Monophasic 91-day cycle Quasense, 0.03 0.15 Seasonale Day 85-91: Day 85-91: inert pills inert pills Seasonique Days 1-84: Days 1-84: Monophasic 91-day cycle 0.03 0.15 Days 85-91: 0.01 Ethinyl estradiol Cryselle-28, Days 1-21: Days 1-21: Monophasic Monthly and norgestrel Lo/Ovral-28, 0.03 0.3 Low-Ogestrel* Days 22-28: Days 22-28: inert pills inert pills Ovral-28, Ogestrel Days 1-21: Days 1-21: Monophasic Monthly 0.05 0.5 Days 22-28: Days 22-28: inert pills inert pills Third -generation Ethinyl estradiol Desogen, Days 1-21: Days 1-21: Monophasic Monthly progestin and desogestrel Emoquette, 0.03 0.15 Ortho-Cept, Days 22-28: Days 22-28: Reclipsen, Solia inert pills inert pills Azurette, Kariva, Days 1-21: 0.02 Days 1-21: Biphasic Monthly Mircette 0.15 Day 22-23: inert pills Day 24-28: 0.01

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TABLE Oral contraceptives: A review of the options (continued)

Generic name Brand name Estrogen Progestin Mono- vs Monthly vs dose (mg dose (mg) multiphasic extended cycle Third -generation Ethinyl estradiol Caziant, Cesia, Days 1-21: Days 1-7: Triphasic Monthly progestin and desogestrel Cyclessa, Velivet 0.025 0.1 (continued) (continued) Days 22-28: Days 8-14: inert pills 0.125 Days 15-21: 0.15 Days 22-28: inert pills Ethinyl estradiol MonoNessa, Ortho- Days 1-21: Days 1-21: Monophasic Monthly and Cyclen, Previfem, 0.035 0.25 norgestimate Sprintec Days 22-28: Days 22-28: inert pills inert pills Ortho Tri-Cyclen Lo, Days 1-21: Days 1-7: 0.18 Triphasic Monthly Tri-Lo-Sprintec, 0.025 Days 8-14: TriNessa Lo Day 22-28: 0.215 inert pills Days 15-21: 0.25 Days 22-28: inert pills Ortho Tri-Cyclen, Days 1-21: Days 1-7: Triphasic Monthly TriNessa, 0.035 0.18 Tri-Previfem, Days 22-28: Days 8-14: Tri-Sprintec inert pills 0.215 Days 15-21: 0.25 Days 22-28: inert pills Miscellaneous Ethinyl estradiol Beyaz,‡ Gianvi, Yaz Days 1-24: 0.02 Days 1-24: 3 Monophasic Monthly progestin and Days 25-28: Days 25-28: drospirenone inert pills inert pills Ocella, Safyral,‡ Days 1-21: 0.03 Days 1-21: 3 Monophasic Monthly Yasmin, Zarah Days 22-28: Days 22-28: inert pills inert pills Estradiol valerate Natazia Days 1-2: 3 Days 1-2: 0 Multiphasic Monthly and Days 3-7: 2 Days 3-7:2 Days 8-24: 2 Days 8-24: 3 Days 25-26: 1 Days 25-26: 0 Days 27-28: Days 27-28: inert pills inert pills

*21-day formulation without inert pills also available. +Also contains 75 mg ferrous fumarate in pills Days 22-28 or Days 24-28. ‡Beyaz and Safyral also contain 0.451 mg levomefolate in Days 1-28. Adapted from: Oral contraceptives. Monthly Prescribing Reference. October 9, 2012. Available at: http://www.empr.com/oral-contraceptives/article/123837/#. Accessed September 23, 2013.

jfponline.com Vol 62, No 10 | october 2013 | The Journal of Family Practice E7 imen, from a median of 12 days with the first irritation, tiredness, bloating and menstrual cycle, to a median of 4 days during the fourth pain” with the extended-cycle regimen.24 and final cycle. This study also reported no significant differences in side effects between the extended- and traditional- cycle regimens, OCs effect on weight, BP, including changes in lipids, body weight, and premenstrual symptoms blood pressure, or endometrial hyperplasia.19 Weight gain. A 2008 Cochrane review exam- Another RCT examined the difference in ined 3 placebo-controlled RCTs and conclud- bleeding patterns, side effects, and acceptabil- ed that the available evidence was insufficient ity between a standard 28-day cycle OC and to determine the effect of combined hormon- an extended-regimen 168-day cycle OC in 32 al contraceptives on weight, and that larger women. Both OCs contained 20 mcg EE and doses of estrogen were not shown to cause 100 mcg LNG, and the study was conducted larger weight gain.25 over 6 months. Women in the extended-cycle One RCT examined the effects of OCs on regimen reported significantly fewer days of variations in total body water, fat mass, and bloating (0.7 vs 11.1 days; P=.04), and men- fat-free mass throughout the menstrual cycle strual pain (1.9 vs 13.3 days; P<.01). There was to determine if different doses of estrogen no significant difference in reported headache, (15 vs 30 mcg EE) or different types of proges- breast tenderness, nausea, , or pre- tins (gestodene 60 mcg vs DRSP 3 mg) affect menstrual symptoms. Women in the extended weight gain. This study only included 80 wom- cycle group also reported significantly fewer en randomized to the 2 treatment groups, bleeding days that required sanitary pads (18.4 plus a control group using male condoms. vs 33.8 days; P<.01). However, there was no sta- No differences were found in total body wa- tistically significant difference in the total num- ter or fat mass. There was, however, a signifi- ber of days in which any degree of bleeding cant increase in fat-free mass in women in the occurred (34.9 days in the monthly cycle group, EE/gestodene group compared with the con- 25.9 days in the extended cycle group; P=.33).20 trols, indicating a possible effect of the andro- In a study of 126-day extended-cycle OCs genic properties of gestodene compared with with 30 mcg EE and 3 mg drospirenone, the DRSP (which has antiandrogenic properties) bleeding profile improved over time, and en- in increasing muscle mass.26 dometrial biopsies revealed no hyperplasia.21 In a 6-month study of DRSP compared Another benefit of the extended cycle is per- with LNG, mean body weight fell by 0.8 to sonal preference, ie, controlling the timing of 1.7 kg in women treated with DRSP compared one’s menses,22 for example, in athletes dur- with a 0.7 kg weight gain in the LNG group ing training and competition. (P<.05).27 A multicenter RCT comparing OCs Continuous use of OCs prevents the cy- with EE 30 mcg/DRSP 3 mg vs EE 30 mcg/ clic fluctuations of serum levels of EE and pro- desogestrel 150 mcg concluded that EE/ gestogen and, hence, the cyclic variations of DRSP has a more favorable effect on body related serum-based metabolic parameters. weight than EE/desogestrel. This finding may Extended-cycle OCs can make it easier to ti- have resulted from the antimineralocorticoid trate other medications affected by hormonal and mild diuretic effects of DRSP.28 fluctuations. Another study of extended-cycle z Hypertension. In a review of progestin- DRSP OCs compared with monthly OCs over only OCs in normotensive women, the authors 6 months showed no difference in lipid, car- could find no evidence to show a statistically bohydrate, and coagulation markers.23 significant increase in blood pressure.29 Six RCTs were included in a Cochrane re- In a study of 120 women randomized to view of monthly vs extended-cycle combined drospirenone/EE or LNG/EE, the drospire- pills. It found no significant differences in -ef none group had a mean decrease in systolic ficacy, adherence, discontinuation rates, and blood pressure from 107 to 103 mm Hg, and patient satisfaction. Significant differences a significantly lower mean blood pressure noted included improvement of menstrual- compared with the LNG group.30 Another associated symptoms of “, genital study of 80 women over 6 months random-

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ized into 3 groups, each having 3 mg DRSP Women using a 20 mcg EE/100-mcg LNG with either 30, 20, or 15 mcg EE, found that OC experienced reductions in HDL and small systolic blood pressure decreased by 1 to 4 increases in LDL and triglycerides compared mm Hg compared with an elevation in blood with a 30 mcg EE/150-mcg LNG OC.39 A study pressure of 4 mm Hg in the LNG/EE group.27 of gestodene 75 mcg with either 20 or 30 mcg In women with well-controlled blood EE for 13 cycles found a greater increase in pressure who are younger than 35 years old, triglyceride levels in the formulation with a nonsmokers, and otherwise healthy, the higher dose of estrogen (P = .029).40 American College of Obstetricians and Gyne- Barkfeldt and colleagues41 conducted cologists (ACOG) recommends a trial of OCs a double-blind RCT that evaluated the ef- with blood pressure monitoring.31 fects of lipid on 98 women who z . One Cochrane review looked at received 2 different types of progestin-only studies that compared combined OCs with pills, desogestrel 75 mcg/d vs LNG 30 mcg/d. placebo, and found that OCs improved the There were minimal changes in the lipid pro- condition. However, there was insufficient file except for decreasing trends in levels of evidence regarding the difference in effective- HDL, its subfractions, and apolipoprotein-I ness of various formulations of OCs in treat- and -II. No differences were observed be- ing acne.32 There was no difference between tween the 2 formulations, including LDL and first-and second-generation progestins,33 apolipoprotein-B, despite the higher proges- between second- and third-generations,34 or tin dose found in desogestrel.41 While OCs are third-generation progestins vs DRSP.35 Third-generation progestins with “lesser thought to cause z Premenstrual symptoms. A 2005 open- androgenicity” may allow more “expression” side effects, label RCT compared the effects of DRSP/ of the effects of estrogen on lipids. A prospec- when compared 20 mcg EE with the second-generation pro- tive study of 66 women over 9 months com- with a placebo, gestin LNG/30 mcg EE on premenstrual paring either desogestrel (50/100/150 mcg) there have been symptoms after 6 menstrual cycles. In the and EE (35/30/30 mcg) with LNG (50/100/ no significant premenstrual phase, the DRSP/EE group 150 mcg) and EE (30/40/30 mcg) showed that findings showed less negative mood and weight gain.36 the desogestrel formulation increased HDL, regarding the A 2012 Cochrane review examined the whereas LNG decreased HDL.42 Another study frequency of effects of OCs containing DRSP on premen- compared monophasic desogestrel/EE with headache, strual dysphoric disorder (PMDD) vs placebo triphasic LNG/EE in 37 healthy young women. nausea, and other OC formulations. The review in- While both preparations led to an increase in vomiting, breast cluded 5 trials and found that DRSP is associ- total cholesterol, the desogestrel formulation pain, or weight ated with significantly greater improvements led to a reduction in the LDL.43 A 1995 study gain. than placebo in symptoms of PMDD, but was of DRSP compared with LNG for 6 months inconclusive on whether DRSP formulations showed that HDL increased in the DRSP group have greater effects on PMDD than other (P<.05) but triglyceride levels showed a greater OC formulations.37 increase in the DRSP group (P<.05).27 z Dysmenorrhea. A 2009 Cochrane re- The use of OCs in the absence of risk fac- view compared 10 studies examining the role tors does not appear to promote coronary ar- of different formulations of combined OCs tery disease (CAD), and there is no reason to in management of and con- withhold OCs from dyslipidemic women. In cluded there is no difference in improvement women with LDL of more than 160 mg/dL or among different OC preparations.38 multiple cardiac risk factors, ACOG recom- mends a nonhormonal method of contracep- tion, such as an (IUD).31 OCs and coronary heart disease Estrogen has several favorable effects on circu- lating lipoproteins, including increasing high- OCs and glucose metabolism, density lipoprotein (HDL), and increasing thromboembolism low-density lipoprotein (LDL) receptor activ- Glucose metabolism. Oelkers and col- ity, thereby enhancing removal of LDL. leagues27 studied glucose levels in 80 healthy

jfponline.com Vol 62, No 10 | october 2013 | The Journal of Family Practice E9 women assigned to 4 equal groups who re- loss of BMD in young postadolescent women ceived 3 mg DRSP combined with 30-, 20-, taking OCs. It concluded that pills with 20 and 15-mcg doses of EE or LNG/30-mcg EE. and 30 mcg of estrogen were associated with Each woman underwent oral glucose toler- the same reduction in BMD.54 ance testing pretreatment and at the end of However, a 2009 Cochrane review con- the 6-month OC cycle. On treatment, fasting cluded that combined OCs do not affect bone glucose was unchanged for all groups, but health, ie, fracture rate, BMD, or biochemical the area under the curve for the glucose toler- markers of bone change. Thirteen RCTs were ance increased for all formulations. Although reviewed and researchers concluded that the not statistically significant among groups, the relationship between OC use and fracture DRSP/30-mcg EE group had a 19% worsening risk cannot be determined from the limited of glucose tolerance.27 This research suggests data currently available.55 that women with diabetes who are other- z Cancer. Research does not support the wise healthy, nonsmokers, and younger than notion that OCs contribute to cancer. In fact, 35 years of age can safely use OCs. reduced endometrial and ovarian cancers z Thromboembolism. Estrogen has have been shown among users of OCs con- been known to increase the risk of venous taining 50 mcg EE.56-58 Low-dose formula- thromboembolism (VTE) by increasing tions (≤35 mcg EE) have been less studied but prothrombin and decreasing antithrombin also confer a substantial risk reduction.59 ACOG III.44 In OC users, the incidence of VTE is in- Data are conflicting regarding a slight recommends creased by a factor of 3 to 5.45 While several increase in risk for breast cancer in current a nonestrogen studies have compared high-dose estrogen or recent users of OCs from older, higher-es- hormonal (50 mcg) with low-dose (≤35 mcg) OCs,46,47 trogen doses; that risk returns to normal over alternative, there is no information about any differenc- time.60 The World Health Organization recog- such as es in low (25-35 mcg) EE vs ultra-low doses nizes this slight risk, but has concluded that progestin- (10 mcg). the benefits of OCs outweigh the risks. 61 only pills or an Third-generation desogestrel-contain- IUD, for obese ing OCs have a slightly increased risk of women. VTE compared with second-generation Evidence-based guidelines pills4 unexplained by bias and confound- are lacking ing factors.49,50 It has been estimated that There is a paucity of RCTs with sufficient du- 25 additional cases of VTE occur every year ration and sample size that compare different among 100,000 women using third-genera- OC formulations to provide evidence-based tion OCs compared with 10 additional cases guidance for physicians. While some phar- per 100,000 women using second-generation maceutical companies market their products OCs.51 A meta-analysis that included 9 case for particular benefits, these findings too control and 3 cohort studies estimated an often come from noncomparative trials, ie, odds ratio for third- vs second-generation their product vs placebo. OCs of 1.7 (95% CI, 1.4-2.0).52 A 2010 meta- analysis refutes these findings, showing So here’s what we know… no difference in OCs containing the third- No OC formulation is more effective at pre- generation progestin gestodene vs other for- venting pregnancy than any others. Cycle mulations.53 Because obesity (BMI >30 kg/m2) control, ie, less intermenstrual bleeding, is is an independent risk factor for VTE, ACOG improved with 30 to 35 mcg EE formulations recommends a non-estrogen-containing hor- compared with ultra-low dose (20 mcg) EE. monal method such as progestin-only pills or There are no advantages to choosing a mul- an IUD for obese women.31 tiphasic formulation over a monophasic OC. z Bone mineral density (BMD). A 2000 While extended-cycle formulations have study compared 2 OCs with the same dose of more breakthrough bleeding than monthly progestin (gestodene 75 mcg) and 2 doses of cycles, overall they have fewer days of men- EE (20 vs 30 mcg) to determine if there was strual bleeding, which tend to decrease even a correlation between dose of estrogen and further in successive cycles. Extended-cycle

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formulations have decreased days of bloating HDL, and the significance of LDL reduction and menstrual cramping. by desogestrel, require further investigation. There is no evidence that different doses There is no evidence that OCs affect bone of estrogen or progestin affect weight gain or health indices such as fracture rate, BMD, or total body water. DRSP leads to a more favor- biochemical markers of bone change. OC able lean body mass profile than LNG and formulations with higher doses of estrogen desogestrel, which may be related to its anti- have been shown to reduce ovarian and en- mineralocorticoid effect. While both second- dometrial cancer, presumably due to fewer and third-generation progestin formulations ovulatory cycles. However, similar reduc- have been shown to improve acne, there is no tions should therefore be observed with low- evidence to indicate a preference. er EE dose formulations, as well. There is also little evidence to recom- Clearly, the literature indicates that there mend a particular OC to avoid adverse events is little evidence to recommend one OC for- such as CAD or VTE; in fact, the evidence is mulation over another. All currently marketed often contradictory. Epidemiologic studies OCs have low-dose EE. However, when coun- confirm that venous thromboembolic disease seling patients, keep in mind that extended is similar for 20 and 30 mcg EE. There may be cycle formulations decrease some side effects an increase in VTE with desogestrel, but re- and generic formulations reduce costs. JFP cent evidence finds no significant increase. The clinical significance that DRSP increases Correspondence While Eric A. Schaff, MD, Philadelphia Women’s Center, 777 Apple- triglyceride levels while it decreases LDL and tree Street, #7, Philadelphia, PA 19106; [email protected] extended-cycle formulations have more breakthrough References bleeding than 1. Chandra A, Martinez GM, Mosher WD, et al. Fertility, family 14. Van Vliet HA, Grimes DA, Lopez LM, et al. Triphasic versus planning, and reproductive health of U.S. women: data from the monophasic oral contraceptives for contraception. Cochrane Da- monthly cycles, 2002 National Survey of Family Growth. Vital Health Stat. 2005; tabase Syst Rev. 2006;(3):CD003533. overall they 25:1-160. 15. Anderson FD, Gibbons W, Portman D. Safety and efficacy of an 2. Keam SJ, Wagstaff AJ. Ethinyl estradiol/drospirenone: a review of extended-regimen oral contraceptive utilizing continuous low- have fewer days its use as an oral contraceptive. Treat Endocrinol. 2003;2:49-70. dose ethinyl estradiol. Contraception. 2006;73:229-234. of menstrual 3. Krattenmacher R. Drospirenone: pharmacology and pharmaco- 16. Elomaa K, Rolland R, Brosens I, et al. Omitting the first oral con- kinetics of a unique progestogen. Contraception. 2000;62:29-38. traceptive pills of the cycle does not automatically lead to ovula- bleeding. 4. Maitra N, Kulier R, Bloemenkamp K, et al. in com- tion. Am J Obstet Gynecol. 1998;179:41-46. bined oral contraceptives for contraception. Cochrane Database 17. Adams Hillard PJ. Oral contraception noncompliance: The extent Syst Rev. 2004;(3): CD004861. of the problem. Adv Contracept. 1992;8(suppl 1):S13-S20. 5. Oral Contraceptives at Drugstore.com. Available at: http:// 18. Rosenberg M, Waugh MS. Causes and consequences of oral con- www.drugstore.com/pharmacy/drugindex/rxsearch. traceptive noncompliance. Am J Obstet Gynecol. 1999;180(suppl 2): asp?search=oral+contraceptive. Accessed January 24, 2011. S276-S279. 6. Society of Obstetricians and Gynaecologists of Canada State- 19. Anderson, FD, Hait, H. A multicenter, randomized study of an ment on Generic Contraceptions. J Obstet Gynecol Canada. extended cycle oral contraceptive. Contraception. 2003;68:89-96. 2008;30:271-272. 20. Kwiecien M, Edelman A, Nichols MD, et al. Bleeding patterns and 7. Coney P, Washenik K, Langley RG, et al. Weight change and patient acceptability of standard or continuous dosing regimens adverse event incidence with a low-dose oral contraceptive: of a low-dose oral contraceptive: a randomized trial. Contracep- two randomized, placebo-controlled trials. Contraception. tion. 2003;67:9-13. 2001;63:297-302. 21. Foidard JM, Sulak PJ, Schellschmidt I, et al; the Yasmin Extended 8. O’Connell K, Davis AR, Kerns J. Oral contraceptives: side effects Regimen Study Group. The use of an oral contraceptive contain- and depression in adolescent girls. Contraception. 2007;75: ing and drospirenone in an extended regimen 299-304. over 126 days. Contraception. 2006;73:34-40. 9. Redmond GP, Olson WH, Lippman JS, et al. Norgestimate and 22. Shakespeare J, Neve E, Hodder E. Is a lifestyle ethinyl estradiol in the treatment of acne vulgaris: a randomized, drug? Results of database analysis. BMJ. 2000;320:291. placebo-controlled trial. Obstet Gynecol. 1997;89:615-622. 23. Machado RB, de Melo NR, Maia Jr. H, et al. Effect of a continuous 10. Rosenberg MJ, Waugh MS, Long S. Unintended pregnancies and regimen of contraceptive combination of ethinylestradiol and use, misuse and discontinuation of oral contraceptives. J Reprod drospirenone on lipid, carbohydrate and coagulation profiles. Med. 1995;40:355-360. Contraception. 2010;81:102-106. 11. Endrikat J, Muller U, Dusterberg B. A twelve-month compara- 24. Edelman A, Gallo MF, Nichols, MD, et al. Continuous versus tive clinical investigation of two low-dose oral contraceptives cyclic use of combined oral contraceptives for contraception: containing 20 micrograms ethinylestradiol/75 micrograms systematic Cochrane review of randomized controlled trials. Hu- gestodene and 30 micrograms ethinylestradiol/75 micrograms man Reprod. 2006;21:573-578. gestodene, with respect to efficacy, cycle control, and tolerance. 25. Gallo MF, Lopez LM, Grimes DA, et al. Combination contracep- Contraception. 1997;55:131-137. tives: effects on weight.Cochrane Database Syst Rev. 2008, Issue 4. 12. Grimes DA, Lopez LM, O’Brien PA, et al. Progestin-only pills for 26. Machado RB, Tachotti F, Cavenague G, et al. Effects of two differ- contraception. Cochrane Database Syst Rev. 2010(1):CD007541. ent oral contraceptives on total body water: a randomized study. 13. Van Vliet HA, Grimes DA, Helmerhorst FM, et al. Biphasic versus Contraception. 2006;73:344-347. monophasic oral contraceptives for contraception. Cochrane Da- 27. Oelkers W, Foidart JM, Dombrovicz N, et al. Effects of a new oral tabase Syst Rev. 2006:(3):CD002032. contraceptive containing an anti-mineralocorticoid progestogen,

jfponline.com Vol 62, No 10 | october 2013 | The Journal of Family Practice E11 drospirenone, on the renin- system, body weight, contraceptives containing ethinylestradiol and either desogestrel blood pressure, glucose tolerance, and lipid metabolism. J Clin of levonorgestrel on serum lipids and lipoproteins with particular Endo Metabol. 1995;80:1816-1821. regards to LDL size. Contraception. 2001;64:11-16. 28. Foidart JM, Wuttke W, Bouw GM, et al. A comparative investi- 44. Ouyang P, Michos ED, Karas RH. Hormone replacement therapy gation of contraceptive reliability, cycle control, and tolerance and the cardiovascular system: lessons learned and unanswered of two monophasic oral contraceptives containing either dro- questions. J Am Coll Cardiol. 2006;47:1741-1753. spirenone or desogestrel. Eur J Contracept Reprod Health Care. 45. Martinelli I. Risk factors in venous thromboembolism. Thromb 2000;5:124-134. Haemost. 2001;86:395-403. 29. Hussain, SF. 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Third generation oral con- tives in the treatment of acne vulgaris. Am J Obstet Gynecol. traceptives and risk of : meta-analysis. BMJ. 2003;188:1158-1160. 2001;323:131-134. 35. Huber J, Foidart JM, Wuttke W, et al. Efficacy and tolerability of a 53. Heinemann LA, Dinger JC, Assmann A, et al. Use of oral contra- monophasic oral contraceptive containing ethinylestradiol and ceptives containing gestodene and risk of venous thromboem- drospirenone. Eur J Contracept Reprod Health Care. 2000;5:25-34. bolism: outlook 10 years after the third-generation “pill scare”. 36. Sangthawan, M, Taneepanichskul, S. A comparative study of Contraception. 2010;81:401-407. monophasic oral contraceptives containing either drospirenone 54. Paoletti AM, Orru M, Floris S, et al. Evidence that treatment with 3 mg or levonorgestrel 150 mcg on premenstrual symptoms. Con- monophasic oral contraceptive formulations containing ethinyl- traception. 2005;71:1-77. estradiol plus gestodene reduces bone reabsorption in young 37. Lopez LM, Kaptein AA, Helmerhorst FM. Oral contraceptives women. Contraception. 2000;61:259-263. containing drospirenone for premenstrual syndrome. Cochrane 55. Lopez LM, Grimes DA, Schulz KF, et al. Steroidal contraceptives: Database Syst Rev. 2009,(2):CD006586. effect on bone fractures in women. Cochrane Database Syst Rev. 38. Wong CL, Farquhar C, Roberts H, et al. for 2009;(2):CD006033. primary dysmenorrhoea. Cochrane Database Syst Rev. 2009, Issue 4. 56. Schlesselman JJ. Oral contraceptives and neoplasia of the uterine 39. Endrikat J, Klipping C, Cronin M, et al. An open label, compara- corpus. Contraception. 1991;43:557-580. tive study of the effects of a dose-reduced oral contraceptive 57. Hankinson SE, Colditz GA, Hunter DJ, et al. A quantitative assess- containing 20 mcg ethinyl estradiol and 100 mcg levonorgestrel ment of oral contraceptive use and risk of ovarian cancer. Obstet on hemostatic, lipids, and carbohydrate metabolism variables. Gynecol. 1992;80:708-714. Contraception. 2002;65:215-221. 58. LaVecchia C, Franceschi S, Decarli A. Oral contraceptive use 40. Brill K, Then A, Beisiegel U, et al. Investigation of the influence and the risk of epithelial ovarian cancer. Br J Cancer. 1984;50: of two low-dose monophasic oral contraceptives containing 31-34. 20 micrograms ethinylestradiol/75 micrograms gestodene and 59. Royar J, Becher H, Chang-Claude J. Low-dose oral contraceptives: 30 micrograms ethinylestradiol/75 micrograms gestodene, on protective effect on ovarian cancer risk. Int J Cancer. 2001;95: lipid metabolism in an open randomized trial. Contraception. 370-374. 1996;54:291-297. 60. Collaborative Group on Hormonal Factors in Breast Cancer. 41. Barkfeldt J, Virkkunen A, Dieben T. 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