Contraceptive treatments: A review of current hormone options and newer agents for women

Key Points

Abstract

Contraceptive treatments for women have increased during the past decade, creating more options for women who may have previously failed other methods or had contraindications to estrogen-containing medications. Contraception methods have expanded and reliance on a daily pill is no longer needed, therefore affording better compliance and overall patient satisfaction. Over-the-counter emergency contraception has become available for women older than 17 years of age and is available by prescription for younger patients. FDA recently approved a new emergency contraceptive that is available by prescription. Because there are more contraceptive options, healthcare providers must be aware of differences in dosing and side effect profiles and be familiar with the contraindications to all available products. Understanding the appropriate use for each option will help providers assist women in selecting the optimal formulation based on individual preferences. This review discusses current contraceptive options including recently approved, newer agents. (Formulary. 2011;46:54–63.)

Combined oral contraceptives (COC) are among the most popular contraceptive methods today.¹ The pill, transdermal patch, and intravaginal ring differ in progestin content and in the amount of ethinyl estradiol (EE) they contain. There are many different types of progestins with varying potencies and androgenic properties.

In addition to differing EE doses and progestin types, COCs also vary in cycle length and phase type. It has not been established whether one particular formulation is more effective than another. Selecting the right type of CHC for the patient may take several cycles to establish, requiring the patient to switch between different types of COCs or alternative CHC methods.

21-DAY COCS

The standard regimen of COCs consists of 21 days of active hormonal therapy followed by 7 days of placebo. COCs are available in monophasic, biphasic, and triphasic regimens. Monophasic pills were developed first and contain the same amount of both hormones throughout the 21 days.² In the 1980s, biphasic and triphasic pills were developed with the dual intent of decreasing side effects experienced with monophasic regimens and mimicking the normal menstrual cycle.^3,4 Biphasic pills have 2 phases of increasing EE and progestin throughout the 3 active treatment weeks, and triphasic pills provide different hormone amounts 3 times during the cycle. Cochrane reviews concluded that there is insufficient evidence to determine superiority of one type of COC for the prevention of pregnancy and improvement in bleeding patterns.^2-4 Available evidence suggests that monophasic regimens should be used first line for COC initiation.^2-4

4-PHASIC REGIMEN

In May 2010, FDA approved the first 4-phasic oral contraceptive.⁵ It is different from other COCs because it contains a bioidentical synthetic estrogen, estradiol valerate, instead of EE. Also, the progestin component is dienogest. Other available COC products contain levonorgestrel, norethindrone, or drospirenone. The 28-day dosage regimen consists of estradiol valerate 3 mg for 2 days then estradiol valerate/dienogest 2 mg/2 mg for 5 days, estradiol valerate/dienogest 2 mg/3 mg for 17 days, estradiol valerate 1 mg for 2 days, followed by 2 days of placebo. Two large, multicenter, open-label phase 3 trials demonstrated its efficacy and safety in preventing pregnancy (Pearl indexes 1.64 and 1.04). The most common adverse effects reported were headache (with migraines), menorrhagia, irregular bleeding, breast pain and tenderness, nausea or vomiting, acne, and increased weight gain.⁵ Currently, its clinical advantage over other COCs has not been established.

24-DAY COCS

Until recently, there were only 2 products formulated as 24-day regimens, both with 24 days of active hormonal therapy followed by 4 days of placebo. The first contains 20 μg of EE and 1-mg norethindrone with 75-mg ferrous fumarate in the inactive pills. The second contains 20 μg of EE and 3 mg of drospirenone as the progestin.

Drospirenone differs from other progestins in that it is derived from spironolactone and has antimineralocorticoid and anti-androgenic properties.⁶ It can cause mild natriuresis, which counteracts the sodium and water retention that occurs with estrogen.⁷ Similar to spironolactone, drospirenone can also cause hyperkalemia and should be used with caution with other medications that increase potassium levels such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, potassium-sparing diuretics, and nonsteroidal anti-inflammatory drugs.⁸ With its anti-androgenic properties, drospirenone can also improve facial hirsutism.⁹ In addition to the indication for contraceptive use, the drospirenone-containing medication is also approved for the treatment of moderate acne in patients aged 14 years and older and for premenstrual dysphoric disorder.⁸

The proposed advantage of 24-day regimens include decreased duration of withdrawal bleeding, decreased intermenstrual bleeding, and less spotting. A study by Nakajima et al compared the incidence of intracyclic bleeding between the 24-day regimen of EE 20 μg/1 mg norethindrone and the 21-day regimen of the same hormones.¹⁰ Results showed that by the sixth cycle, the mean number of intracyclic bleeding days was significantly lower among patients taking the 24-day regimen than for those on the 21-day regimen (0.95 vs 1.63; P =.005).The duration of withdrawal bleeding was significantly less for the 24-day regimen than the 21-day regimen by cycle 2 (3.69 vs 4.57; P<.001). Those taking the 24-day regimen had significantly fewer mean number of bleeding days than those in the 21-day regimen in cycles 2 to 6 (18.6 vs. 23.2; P<.001). Improvements in bleeding patterns may be seen with 24-day regimens; however, a clinical advantage has not been demonstrated over traditional 21-day regimens.

EXTENDED-CYCLE COCS

There are 3 available formulations of extended-cycle COCs.^6,11,12 Two include 84 days of active pills containing 30-μg EE and 150 μg of levonorgestrel, followed by 7 days of inactive pills for a 91-day regimen.⁶ One of these formulations uses a low dose of 10-μg EE in each tablet of the placebo week. A third product consists of 84 days of 20-μg EE and 100 μg of levonorgestrel followed by 7 days of low-dose 10-μg EE.¹¹ Adding low-dose estrogen to the placebo week has been proposed as a way to decrease side effects related to estrogen withdrawal however, there are no comparison trials to support this theory.⁶ Additional studies are needed to determine the advantage of low-dose EE over placebo.

The first 84-day oral contraceptive was approved in 2003 and has been shown to be safe and effective in preventing pregnancy in a randomized, multicenter, open-label study.^12,13 The 1-year study compared the 91-day cycle formulation (30-μg EE and 150 μg of levonorgestrel) to a 28-day conventional regimen of 30-μg EE and 150 μg of levonorgestrel.¹³ Results showed that patients on the extended cycle regimen had fewer total days of scheduled withdrawal bleeding or spotting than those on the 28-day regimen, due to the inherent difference in number of cycles and the number of hormone-free days. However, on a per-cycle basis, the percent of total possible bleeding and/or spotting days was similar in both groups (46.4% vs 42.5%). Discontinuation because of bleeding problems occurred in 7.7% of extended-cycle patients and in 1.8% of those on the conventional regimen.

Extended-cycle products offer a decreased number of cycles compared to conventional oral regimens (4 vs 13). Patients desiring the convenience of fewer scheduled withdrawal bleeding days may benefit from these products; however, there may be an increased incidence of breakthrough bleeding. Women wishing to achieve the same effect as an 84-day extended-cycle regimen can use 4 packs of monophasic products and skip the placebo weeks contained in the first 3 packs.

CONTINUOUS-CYCLE COCS

Continuous, 365-day contraception may be an appealing option for women wishing to avoid bleeding days. In 2009, FDA approved the first continuous-use COC containing 20-μg EE and 90-μg levonorgestrel dispensed in 28-day packages.¹⁴ An open-label, multicenter, phase 3 clinical trial showed that 58.7% of women experienced amenorrhea by cycle 13 and 79% reported absence of bleeding.¹⁵ The incidence of bleeding with or without spotting decreased with each cycle from 93.9% in cycle 1 to 21% in cycle 13. Spotting without bleeding was initially reported but frequency decreased from cycle 6 (26.7%) to cycle 13 (20.2%).

This study demonstrated that continuous EE/levonorgestrel increased the incidence of amenorrhea and decreased the number of bleeding and spotting days over time. A continuous-cycle regimen reduces the frequency of withdrawal bleeding and may also be achieved by skipping the placebo week in conventional monophasic COC formulations.

RECENTLY APPROVED COCS

Two new 24-day COC regimens were approved by FDA in fall 2010.^16,17 One is the first COC to contain the lowest dose of EE of 10 μg (Lo Loestrin Fe).¹⁶ It contains 24 tablets of 10 μg EE/1 mg norethindrone acetate followed by 2 tablets of 10-μg EE and then 2 tablets of ferrous fumarate. In a 1-year multicenter, open-label clinical trial with 1,270 women aged 18 to 35 years, the Pearl index was 2.92 pregnancies per 100 woman-years of use (95% CI, 1.94–4.21). Currently, there is insufficient data comparing efficacy and adverse effects between the 10-μg EE and traditional low-dose regimens containing 20- to 35-μg EE.

The second newer 24-day regimen contains 20-μg EE and 3-mg drospirenone in the active pills and 451-μg levomefolate calcium in both the active and placebo pills (Beyaz).¹⁷ This formula is also approved for acne and premenstrual dysphoria but has the added indication to raise folate levels in order to decrease the risk of neural tube defects in the event that a woman becomes pregnant while taking the medication or shortly after discontinuing it. The dose of levomefolate is equivalent to 400-μg folic acid, the recommended minimum supplemental dose for women of childbearing age.^17,18 In addition to having similar warnings regarding hyperkalemia, the prescribing information also includes possible interactions with drugs that can reduce folate levels such as methotrexate and cholestyramine, as well as antiepileptics such as carbamazepine, phenytoin, phenobarbital, primidone, and valproic acid. This formulation has not been compared to traditional regimens in clinical studies.

In December 2010, FDA approved the second COC containing folate. This new formulation (Safyral) is similar to Yasmin, a 21-day regimen COC containing 30-μg EE and 3-mg drospirenone.^19,20 Safyral contains the same amount of EE and drospirenone as Yasmin but also contains 451-μg levomefolate calcium in the active and placebo pills.¹⁹ In addition to the prevention of pregnancy, this new formulation also has an indication to raise folate levels, reducing the risk of neural tube defects in a pregnancy that may occur while taking it or shortly after discontinuing it. The clinical advantage over traditional regimens has yet to be determined.

TRANSDERMAL CONTRACEPTIVE PATCH

A transdermal contraceptive patch was approved by FDA in 2001 and brought to the market in 2002. The patch is an option for patients who are noncompliant with daily oral contraception or who want an alternative to daily pills. Each patch contains EE 20 μg/day plus norelgestromin 150 μg/day.²¹

A new patch is applied, removed, and replaced at 7-day intervals for 3 weeks then removed for 7 days permitting withdrawal bleeding to occur. The cycle is repeated after the 7 days of withdrawal bleeding. The patch should be avoided in women weighing more than 198 pounds (90 kg) as it may be less effective. Pooled data from 3 studies including 3,319 women using the patch showed that 5 of 15 pregnancies occurred in those weighing more than 198 pounds.²²

FDA issued a warning in November 2005 stating that women using the transdermal patch were exposed to 60% higher levels of EE compared to women using daily oral contraceptives containing 35 μg of EE, thus potentially increasing their risk of venous thromboembolism (VTE).^23,24 This warning required additional labeling informing patients and healthcare providers to weigh the risks and benefits of use.

Another label update was required in January 2008 after another study provided additional data supporting the increased risk of VTE and pulmonary embolism (PE) in women with risk factors who used the patch.^25,26

FDA continues to support the use of the patch in women without underlying conditions that would put them at risk of VTE. Healthcare providers should continue to screen women using the patch for cardiovascular and thrombotic risk factors to ensure that a patient does not develop new medical conditions which would limit its efficacy or use.

CONTRACEPTIVE VAGINAL RING

Another option for patients who are noncompliant or for those not wanting daily dosing is the contraceptive intravaginal ring. Each ring contains 21 days EE and etonogestrel, allowing vaginal placement of the ring for 3 weeks at a time.²⁷ The ring can be left in place for up to 4 weeks with continued contraception protection for women wishing to extend their cycles. The ring releases 15 μg of EE and 120 μg of etonogestrel daily and bypasses first-pass metabolism due to vaginal insertion.

Women using the ring should not have a higher risk of vaginal infections compared to nonusers.²⁸ A study of 59 women was conducted to assess differences in vaginal and endocervical bacteria after using the ring. No difference was found, however, the manufacturer reports vaginitis as a common side effect which occurred in 5% to 14% of women enrolled in clinical trials and accounted for 1% to 2.5% of cases of discontinued use.²⁷ Although the ring has a lower dose of EE, the same contraindications for combined oral contraception apply.

In a recent study comparing an 84-day COC with the intravaginal ring in 75 women, there was no increase in breast tenderness, headache, or leg pain from baseline.²⁹ A decrease in dysmenorrhea and irritability and an increase in weight gain were also reported from baseline.

MISSED DOSE MANAGEMENT

Combination contraceptive pills, the transdermal patch, and the intravaginal ring are highly effective. With perfect use of these methods, the failure rate is 0.3% but with typical use, failure rates are estimated to be 8%.³⁰ It is important to emphasize adherence and to counsel women on proper management of missed oral doses or a displaced patch or ring. The risk of ovulation is greater if doses are missed earlier in the cycle and when products containing low-dose EE are used.

ADVERSE EFFECTS

DRUG INTERACTIONS

Liver enzyme inducers increase estrogen metabolism, thereby decreasing its efficacy.³⁷ Rifampin and anticonvulsants such as phenytoin, carbamazepine, barbiturates, primidone, topiramate, and oxcarbazepine decrease the efficacy of CHCs. An opposite effect is observed with lamotrigine; CHCs significantly decrease the drug's efficacy. Women taking any of these agents long term should use alternative methods of contraception such as the medroxyprogesterone acetate injections, an intrauterine device, or the progestin-only subdermal implant. Most broad-spectrum antibiotics do not affect contraceptive effectiveness. However, each interaction should be evaluated on a case-by-case basis.

Non-nucleoside reverse transcriptase inhibitors and protease inhibitors may decrease CHC efficacy.³⁷ Patients taking these agents should use a contraceptive with a minimal dose of 30 μg of EE, according to the US Medical Eligibility Criteria. Progesterone-only contraceptives may also be an acceptable alternative.

INITIATING COMBINED HORMONAL CONTRACEPTION

There are 3 methods of initiating contraceptive treatment: quick-start, Sunday start, and day-1 start.¹ The quick-start method involves starting the oral dose, patch, or ring on the day of the office visit or when the prescription is received. Sunday start involves initiating treatment on the first Sunday after the start of the menstrual period. Back-up methods of pregnancy prevention, such as barrier protection, should be used for the first 7 days of either of these initiation methods.

First-day start initiation requires beginning contraception on the first day of the menstrual cycle. Back-up protection is not needed for the first-day start. It is important to note the available 4-phasic oral contraceptive should be started on the first day of the menstrual period with back-up protection used during the first 9 days.⁵

PROGESTIN-ONLY AND INTRAUTERINE CONTRACEPTION

Progestin-only pill. Progestin-only pills (POPs), commonly referred to as the "mini pill," are frequently prescribed to postpartum breastfeeding women or in women with a contraindication to estrogen.³⁸ Each pill contains 35 μg of levonorgestrel and is taken every day for 28 days without a placebo week.³⁹ Progestin-only pills are associated with a higher failure rate if the dose is not taken at the same time every day. Progestin has a short half-life, which requires compliance within a 3-hour window each day. If a dose is taken outside the 3-hour window, back-up barrier protection must be used for 48 hours. Patients are commonly unaware of the difference between the POPs and COCs and follow the same instructions for missed doses of COCs.

The most common side effect of POPs is irregular menstrual bleeding. Up to 12.4% of patients reported some type of spotting within the first month of therapy. The incidence of spotting decreases to about 2.6% by 18 months.^38,39 If a patient continually misses doses, they should be counseled to consider other contraceptive alternatives.

Drug interactions with POPs are similar to those seen with COCs, however, there is no documentation of interactions with antibiotics except rifampin.³⁷ Overall, POPs are a good option for women to use in the short term. With new contraception formulations on the market that do not have strict dosing windows, women should be advised to consider long-term contraceptive options.

Progestin injection. The progestin injection, depo-medroxyprogesterone acetate (DMPA), is available as a 150-mg intramuscular (IM) or 104-mg subcutaneous (SC) formulation.⁴⁰ The injection is given every 11 to 13 weeks IM or every 12 to 14 weeks SC. A pregnancy test should be performed prior to administering the next dose if a patient is more than 1 week late for her injection and she reports recent unprotected intercourse. The most common side effects reported are irregular bleeding and amenorrhea.⁴¹ For some women, amenorrhea is desired. However, other women prefer to have a withdrawal bleed to ensure they are not pregnant. Two common concerns associated with use of DMPA include delayed return to fertility and loss of bone mineral density with more than 2 years of use.

It is currently recommended that women who plan to become pregnant in the next 12 months discontinue DMPA and use another contraception option.⁴² Studies have shown up to 6 to 12 months of delayed return to fertility in some women, but DMPA has not been shown to cause long-term infertility.^41,42

In 2004, FDA required that a black box warning be added to the prescribing information notifying healthcare professionals of the risk of decreased bone mineral density after 2 years of DMPA use.^43,44 Evaluation of conducted studies suggests the loss is reversible upon cessation of use.⁴⁵ A statement released in 2006 from the World Health Organization supports no restriction on length of use of DMPA.⁴⁶ If a patient should require or prefer to continue use after 2 years, a bone mineral density scan may be performed if other risk factors are present. The Society for Adolescent Medicine recommends that patients take 1,300 mg of calcium with 400 IU of vitamin D daily while using DMPA.⁴⁷

Intrauterine contraception. There are currently 2 intrauterine contraceptive devices (IUCs) available in the United States. A levonorgestrel IUC (LNG-IUC) is a progestin-only device, which provides contraceptive protection for 5 years.⁴⁸ The other IUC, Copper 380 T IUC (CuT 380 IUC), is nonhormonal and effective for 10 years.⁴⁹ The CuT 380 IUC disrupts tubal transport of ovum and sperm and interferes with sperm function and fertilization. The LNG-IUC thickens cervical mucus, suppresses the endometrium, and in some women, can suppress ovulation.⁵⁰ Neither device is an abortifacent. Both are approved for contraception use, however, CuT 380 IUC is also approved for emergency contraception (EC) within 5 days of unprotected intercourse and the LNG-IUC is approved for treatment of heavy menstrual bleeding.^48-50

Intrauterine contraceptives are an appropriate and safe form of contraception for either nulliparous or parous women.⁵⁰ Optimal candidates for IUC use include those with contraindications to CHCs, compliance issues, or who have no desire for further pregnancies. In general, any woman without contraindications may be offered an IUC as a form of contraception. The IUCs have a significantly lower pregnancy rate compared to COCs or POPs. Typical failure rates associated with COC use is 8% compared to 0.8% and 0.2% for CuT 380 IUC and LNG-IUC, respectively.³⁰

Bleeding patterns differ between the devices and can be a cause of removal if the patient has not been well educated on what to expect. Bleeding can become heavier with the CuT 380 IUC but amenorrhea can occur in 20% of women using the LNG-IUC. Both cause an increase in bleeding/spotting in the first 6 months and both may possibly cause pain.^48-50

Subdermal implant. The only subdermal implant available in the United States contains etonogestrel 68 mg.^51,52 The device is approved for 3 years of contraceptive protection and carries the same warnings and has a similar side-effect profile as other progestin-only methods.^51,52 The main reason for removal of the implant is excessive bleeding and spotting. Up to 11% of patients discontinued the implant because of increased bleeding, with some patients reporting up to 17.7 days of bleeding during a 90-day period. Studies conducted with the subdermal implant excluded women weighing greater than 130% of their ideal body weight and, therefore, the device is not recommended for use in that population. The implant is easily inserted and removed in a trained physician's office.

EMERGENCY CONTRACEPTION

Emergency contraception has been used since the 1970s to prevent unwanted pregnancy after unprotected intercourse.⁵³ The most common oral methods used today are the combined estrogen-progesterone regimen of 2 doses 12 hours apart, each containing 100-μg EE with 0.5-mg levonorgestrel, and the progestin-only regimen with a single or 2-dose protocol for a total of 1.5-mg levonorgestrel. The only option a patient has to receive EC as a combined estrogen-progesterone regimen is to take multiple COC pills. It has been shown that levonorgestrel 1.5 mg as a single dose is as effective as taking 0.75 mg 12 hours apart.⁵⁴ The American College of Obstetricians and Gynecology recommends using the levonorgestrel-only regimen as the preferred method because of its decreased nausea and vomiting profile and increased efficacy.⁵³ The CuT 380 IUC is also FDA approved for EC use within 5 days of unprotected intercourse.

The progestin-only method is available as a single tablet of 1.5-mg levonorgestrel or 2 tablets of 0.75 mg each.⁵³ This formulation is available over the counter for women 17 years of age or older. A prescription is required for women younger than 17 years old.

Emergency contraception should be initiated within 5 days after intercourse because its efficacy decreases with time. The package insert of the levonorgestrel-only method recommends using it up to 72 hours after intercourse, but it has been shown that emergency contraception can be initiated within 5 days of intercourse.⁵⁴

Women should be counseled on side effects such as nausea, vomiting, irregular bleeding, and spotting.⁵³ Women should also be told to expect the menstrual cycle to be early or delayed by a week or more. Additionally, some patients have also experienced abdominal pain, dizziness, headache, and fatigue.

Ulipristal acetate is a progesterone receptor modulator that prevents ovulation after the luteinizing hormone surge. This agent was approved by FDA in August 2010 and is given as a single 30-mg dose within 120 hours after intercourse.⁵⁵ A recent single-blind, randomized, non-inferiority trial showed that ulipristal acetate is an effective alternative to the levonorgestrel-only regimen that can be used within 72 hours after unprotected intercourse (OR=0.68; 95% CI, 0.35-1.31).⁵⁵ In a second group of women in the same trial, ulipristal acetate was effective when used between 72 and 120 hours of unprotected intercourse (OR=0.57; 95% CI, 0.29-1.09). Common reported side effects were headache, nausea, and abdominal pain.

CONCLUSION

Many new contraceptive methods have emerged since the first oral contraceptive pill. Selecting the right method requires understanding the patient's medical and medication history and their needs beyond contraceptive benefits. A thorough understanding of the different options is important for the healthcare provider to counsel patients properly and manage adverse effects. Proper patient education is necessary to ensure efficacy and manage patient expectations for the method prescribed. With new developments of contraception, it is important to stay up to date to provide the optimal choice for women.

Dr Kim is a clinical pharmacist and clinical assistant professor at the University of Illinois at Chicago College of Pharmacy. Dr Wasik is regional director of clinical pharmacy for Coventry Healthcare, Downer's Grove, Ill.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

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