Injectable Contraception
Laneta Dorflinger, PhD
Sharon L. Achilles, MD, PhD
Injectable contraceptives are widely available, moderately effective, medium-acting (1 to 3 months) reversible methods that can be used discretely and do not require daily action by the user. More than 50 million women worldwide use injectable methods for contraception, which is an estimated 7% of all contraceptive use among married or in-union women.1,2 In the United States, injectable contraceptive use constitutes approximately 4.5% of overall contraceptive use, with use being highest among younger women, women of black race, and never-married women.3
A single injection delivers a depot of active drug, resulting in a serum drug concentration that peaks and then gradually declines to provide a nondaily hormonal contraceptive option that lasts up to several months, with duration dependent on specific formulation. Although users who adhere to the recommended injection schedule enjoy highly effective protection, noncompliance often leads to typical-use effectiveness for this method that is similar to other short-acting reversible hormonal methods. Depot-medroxyprogesterone acetate (DMPA) delivered by intramuscular (IM) or subcutaneous (SC) injection every 3 months is the most widely used injectable contraceptive worldwide and is currently the only FDA-approved injectable contraceptive used clinically in the United States. Other injectable contraceptives available globally include a formulation of the progestin norethindrone enanthate (NET-EN) as well as combined injectable formulations that contain a progestin (typically medroxyprogesterone acetate [MPA] or NET-EN) combined with an estrogen (typically estradiol cypionate or estradiol valerate) (Table 8.1).
DMPA became available in the 1960s with initial indications as treatment for threatened and habitual abortion, as well as gonadal suppression for treatment of endometriosis.4 Investigators soon recognized that DMPA had potential as a potent contraceptive and initiated studies to explore the impact of various doses on effectiveness, side effects, and duration. Ultimately, a dose of 150 mg delivered intramuscularly in the deltoid or gluteus was marketed for 3 months of contraceptive protection. The method became widely available and used worldwide, but remained off-label in the United States for many years due to concerns about breast cancer risk based on data from Beagle dogs, which metabolize MPA differently than do humans.5,6 Following publication of large trials by the World Health Organization
demonstrating no impact of DMPA on human breast cancer, the U.S. FDA granted approval in 1992 for DMPA as a contraceptive. An SC formulation (104 mg/0.65 mL) of MPA was approved by the FDA in 2004 that offered a lower dose option with added potential for self-administration.7,8 Studies on self-injection of DMPA SC have shown substantial improvement in continuation when compared with clinic-based provision, and women cite important benefits of saving time and money when not having monthly clinic visits.9,10 The SC formulation is provided in prefilled syringes, while the IM formulation is provided in vials or prefilled syringes. Following injection, micronized drug is slowly released from the IM or SC depot. As currently labeled, both products are to be administered every 12 to 14 weeks.
demonstrating no impact of DMPA on human breast cancer, the U.S. FDA granted approval in 1992 for DMPA as a contraceptive. An SC formulation (104 mg/0.65 mL) of MPA was approved by the FDA in 2004 that offered a lower dose option with added potential for self-administration.7,8 Studies on self-injection of DMPA SC have shown substantial improvement in continuation when compared with clinic-based provision, and women cite important benefits of saving time and money when not having monthly clinic visits.9,10 The SC formulation is provided in prefilled syringes, while the IM formulation is provided in vials or prefilled syringes. Following injection, micronized drug is slowly released from the IM or SC depot. As currently labeled, both products are to be administered every 12 to 14 weeks.
Table 8.1 Injectable Contraceptive Methods | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Extensive research, largely led by the World Health Organization’s Special Programme on Human Reproduction, was carried out throughout the 1980s and 1990s to evaluate lower doses of DMPA and non-DMPA-based alternative progestin-only injectables aimed at minimizing side effects and developing shorter-acting injectable options containing estrogen to improve bleeding profiles.5,11 Arising largely from the work led by the World Health Organization, NET-EN as well as estrogen/progestin combination injectables became widely available as alternative injectables. NET-EN is a long-chain ester of norethindrone formulated as an oily solution containing 200 mg/mL for IM administration bimonthly. Several clinical trials defined the clinical characteristics and duration of action of NET-EN and compared effectiveness to that of DMPA IM.5,12,13,14 In a large comparative trial of DMPA 150 mg every 3 months and NET-EN 200 mg every 2 months, the 24-month pregnancy rate was the same for both regimens (0.4 per 100 women).14 Although the duration of bleeding and spotting was similar, women using DMPA were 21% more likely to develop amenorrhea compared to women using NET-EN.15 Return to ovulation may be somewhat more rapid following NET-EN use compared to DMPA IM use.16 Mean time to return of fertility is variable with both of these injectables and, on average, is shorter in NET-EN users compared to DMPA users.11,17 Today, NET-EN is registered in a number of countries although global use appears to be modest when compared with DMPA. The highest prevalence of use is in South Africa where 12% of modern contraceptive users, constituting nearly one third of all injectable contraceptive users, are using NET-EN.18
Bleeding irregularities are an important reason that women discontinue progestin-only injectable contraceptives, hence the desire to develop alternatives such as combined injectable methods aimed to improve bleeding patterns.5,19 Studies spanned more than a decade and ultimately advanced the broader availability of the combination of MPA 25 mg plus estradiol cypionate 5 mg (DMPA 25 mg plus E2C 5 mg) and the combination of NET-EN 50 mg plus estradiol valerate 5 mg (NET-EN 50 mg plus E2V 10 mg), the two most widely available combination products today.5,19 Other combination injectables are available, particularly in Latin America, and are listed in Table 8.1, but use is low compared with the DMPA/E2C and NET-EN/E2V products. When combination products (DMPA 25 mg plus
E2C 5 mg or NET-EN 50 mg plus E2V 10 mg) were compared with relevant progestin-only formulations (DMPA or NET-EN, respectively), the combination injectables showed more regular bleeding patterns, less amenorrhea, and less discontinuation for reasons related to bleeding changes. Nevertheless, discontinuation for reasons other than changes in bleeding patterns, including the burden of monthly clinic visits, as well as discontinuation overall were greater for the combination monthly products.20 In the United States, DMPA 25 mg plus E2C 5 mg was marketed between 2000 and 2002 as Lunelle®; however, this product was ultimately withdrawn from the market due to limited market demand and production issues.
E2C 5 mg or NET-EN 50 mg plus E2V 10 mg) were compared with relevant progestin-only formulations (DMPA or NET-EN, respectively), the combination injectables showed more regular bleeding patterns, less amenorrhea, and less discontinuation for reasons related to bleeding changes. Nevertheless, discontinuation for reasons other than changes in bleeding patterns, including the burden of monthly clinic visits, as well as discontinuation overall were greater for the combination monthly products.20 In the United States, DMPA 25 mg plus E2C 5 mg was marketed between 2000 and 2002 as Lunelle®; however, this product was ultimately withdrawn from the market due to limited market demand and production issues.
Pharmacokinetics
Injectable contraceptives deliver a relatively large bolus of active drug compared to either short-acting contraceptives (pills, patch, and ring) or long-acting reversible contraceptives (intrauterine devices [IUDs] and subdermal implants) to maintain a serum drug concentration adequate for contraceptive efficacy for several weeks or months. The pharmacokinetic profiles for injectable contraceptives reflect these differences. Figure 8.1 illustrates pharmacokinetic curve approximations extrapolated to 1 year using publicly available data for the first injection cycle of IM and SC
formulations of DMPA. The data are compared with a “sustained-release” etonogestrel implant that maintains serum progestin concentrations just above the theoretical threshold concentration for ovulation inhibition for 3 years or longer.21
formulations of DMPA. The data are compared with a “sustained-release” etonogestrel implant that maintains serum progestin concentrations just above the theoretical threshold concentration for ovulation inhibition for 3 years or longer.21
 Figure 8.1 Mean serum concentration-time profile of DMPA IM, DMPA SC, and etonogestrel implant over 12 months. DMPA curves reflect actual data for the first 90-day injection interval and modeled data for injection intervals 2 to 4. Circles represent trough values at 6 and 12 months reported during long-term use of DMPA IM (dashed line) and DMPA SC (dotted line).21 The implant (solid line) has the lowest peak. The dashed line at 0.2 ng/mL indicates the estimated threshold needed for a contraceptive effect. (Data sources: etonogestrel implant, physician prescribing information.22; DMPA IM, FDA label and review of a generic formulation.23,24; DMPA SC, blended from PK studies at three injection sites [abdomen, thigh, and upper arm].25,26,27) |
Following DMPA IM or SC injection, serum MPA levels increase for 1 to 3 weeks to peak levels (Cmax). Minimum levels of MPA necessary to ensure contraceptive effectiveness (approximately 0.2 ng/mL) are achieved within the first 24 hours following either IM or SC injection of DMPA.6,24,28 Peak levels decline to mean trough concentrations of approximately 0.4 to 1 ng/mL by 90 days.6,8,24,25,27,29 While no currently published studies directly compare the pharmacokinetics of DMPA administered IM versus SC, SC administration may have lower average Cmax and serum MPA concentrations compared to IM administration in the first 30 days after injection. MPA accumulates with continued IM or SC administration such that trough serum concentrations increase over several injection intervals until a steady state is reached (Figure 8.1). At 12 months, 90-day trough concentrations (C91) for both IM and SC products are similar, about 0.8 ng/mL, which is twice the average trough value reported for the SC product during the first cycle of administration (about 0.4 ng/mL).25 Specifically with regard to the SC product, this small amount of accumulation may explain the reported longer time to ovulation following multiple injections (10 months) compared to single injection (7 months).25,30
As with other hormonal contraceptives, studies of women using DMPA have reported wide interindividual and interstudy variability in pharmacokinetic profiles.30,31,32,33 Interindividual variability in drug concentrations may be related to drug metabolism differences and may contribute to different individual experiences with bleeding and other side effects although no studies have yet carefully explored this. Two ongoing studies are aimed at partially addressing this question by carefully evaluating pharmacokinetic parameters using varying and repeated SC doses in individual women (Clinicaltrials.gov NCT02456584 and NCT02732418). Published Cmax values following DMPA IM administration range from 2.2 to 24 ng/mL,34,35,36,37,38,39,40,41,42,43,44,45,46 and those following DMPA SC administration range from 0.95 to 1.56 ng/mL.8,24,25,26,29 Some data suggest there may be ethnic differences in drug absorption and clearance for IM injectable contraceptives between Asian and Latin American women.47 Interestingly, no pharmacokinetic differences have been observed in Asian and U.S. women using DMPA SC.25,26 Explanations for the wide range of reported Cmax levels following DMPA IM administration include different sampling times (some studies have less frequent sampling such that a true average Cmax cannot be calculated), pharmacokinetic properties related to varying sites of IM injection, injection techniques (including massage or rubbing the injection site), intrinsic participant factors (including BMI, ethnic and metabolic differences), small sample sizes in some studies, and different MPA assays. Further complicating our understanding of the relationship of MPA pharmacokinetics and side effects is that assays for progestins, including MPA, have evolved over time from radioimmunoassay (RIA) to gas chromatography-mass spectrometry (GC-MS) to high-performance liquid
chromatography or ultra-high-performance liquid chromatography with tandem mass spectrometry (HPLC- or UPLC-MS/MS).25,48,49 RIA may overestimate serum levels due to cross-reactivity of antibodies with metabolites or other circulating hormones.50,51,52 Results using GC, LC-, or HPLC-/UPLC-based approaches as opposed to RIA show less interstudy variation and have consistently reported lower average Cmax levels for DMPA IM, ranging from 2 to 4.5 ng/mL.7,22,25,34,35 All three pharmacokinetic studies of DMPA SC24,25,26 measured serum drug concentrations with liquid chromatography, so the differences in the literature are not as varied as those seen with DMPA IM.
chromatography or ultra-high-performance liquid chromatography with tandem mass spectrometry (HPLC- or UPLC-MS/MS).25,48,49 RIA may overestimate serum levels due to cross-reactivity of antibodies with metabolites or other circulating hormones.50,51,52 Results using GC, LC-, or HPLC-/UPLC-based approaches as opposed to RIA show less interstudy variation and have consistently reported lower average Cmax levels for DMPA IM, ranging from 2 to 4.5 ng/mL.7,22,25,34,35 All three pharmacokinetic studies of DMPA SC24,25,26 measured serum drug concentrations with liquid chromatography, so the differences in the literature are not as varied as those seen with DMPA IM.
Mechanism of Action/Pharmacodynamics
The primary mechanism of action for injectable contraceptives (IM and SC formulations) is suppression of ovulation.16,25,53,54,55,56 Following DMPA administration, the circulating level of the MPA effectively blocks the luteinizing hormone (LH) surge, preventing ovulation even though follicle-stimulating hormone (FSH) is not necessarily suppressed.57 FSH levels similar to the midfollicular stage of cycling women can occur across the 3-month injection cycle in DMPA users such that follicular growth is maintained sufficiently to stimulate endogenous estrogen secretion comparable to the early follicular phase of a normal menstrual cycle with use of either IM or SC DMPA.6,25,58 FSH can also be suppressed in some users of DMPA IM.59,60 The reasons for these differences are not well understood, but may be related to the age of women studied,61,62 the timing and frequency of sampling, and pharmacogenetic variations in cytochrome P-450 enzymes, which metabolize contraceptive steroids and have been shown to influence pharmacokinetics and responses.63 In addition to ovulation suppression, thickening of cervical mucus and changes in the endometrium also occur following administration of DMPA,6,64 yet the potential contribution of these effects, if any, to the mechanism of action is unclear given the dominant role of ovulation suppression.
Return to ovulation and fertility is commonly delayed after stopping injectable contraceptives (Figure 8.2). Unlike drugs in short-acting contraceptives (pills, patch, and ring) and LARC methods (IUDs and implants), all of which are quickly metabolized following cessation of use, injectables are formulated as drug depots, intentionally designed to be long-lasting following dosing. The benefit of drug depots is less frequent dosing, which is convenient for the user. The drawbacks include unpredictable delay in return to fertility and inability to stop the drug quickly in the event of allergy or anaphylaxis. Significant allergy to contraceptive steroid hormones is rare as are instances of significant reaction to inactive ingredients in injectable contraceptives (parabens, polyethylene glycols, and polysorbates).65,66
Approximately half of women who discontinue DMPA can expect normal menses to return by 6 months after the last injection, but approximately 25% will not resume a normal menstrual pattern for at least 1 year.25,67 Among 15 women who received multiple doses of DMPA SC, the median time to
ovulation was 10 months after the last injection; earliest return to ovulation was 6 months after the last injection; and 12 women (80%) ovulated within 1 year of the last injection.30 Subcutaneous administration of DMPA may be associated with a slightly greater delay in return to ovulation compared to the IM route. In a comparative study, median time to return of ovulation after a single IM injection of DMPA IM and a single injection of DMPA SC was 183 and 212 days, respectively, although this was not statistically different.25 In this study, the 12-month rates of return to ovulation for DMPA IM users and DMPA SC users were 95% and 97%, respectively.25 Return to fertility following DMPA use is also delayed when compared to other methods, and the delay may be slightly greater with DMPA SC than DMPA IM.4,30
Approximately two thirds of women conceived within 12 months, over 80% conceived within 15 months, and over 90% conceived within 18 months from the last injection of DMPA IM.4 Among 28 women using DMPA SC who stopped treatment to become pregnant, only 1 became pregnant within a year of the last injection, and a second became pregnant 443 days after the last injection (7 women were lost to follow-up).30 Clinician counseling for initiation of DMPA must include details regarding this potential for delay in return to fertility. Women who strongly wish to become pregnant within a year should not initiate or continue use of DMPA.
ovulation was 10 months after the last injection; earliest return to ovulation was 6 months after the last injection; and 12 women (80%) ovulated within 1 year of the last injection.30 Subcutaneous administration of DMPA may be associated with a slightly greater delay in return to ovulation compared to the IM route. In a comparative study, median time to return of ovulation after a single IM injection of DMPA IM and a single injection of DMPA SC was 183 and 212 days, respectively, although this was not statistically different.25 In this study, the 12-month rates of return to ovulation for DMPA IM users and DMPA SC users were 95% and 97%, respectively.25 Return to fertility following DMPA use is also delayed when compared to other methods, and the delay may be slightly greater with DMPA SC than DMPA IM.4,30
Approximately two thirds of women conceived within 12 months, over 80% conceived within 15 months, and over 90% conceived within 18 months from the last injection of DMPA IM.4 Among 28 women using DMPA SC who stopped treatment to become pregnant, only 1 became pregnant within a year of the last injection, and a second became pregnant 443 days after the last injection (7 women were lost to follow-up).30 Clinician counseling for initiation of DMPA must include details regarding this potential for delay in return to fertility. Women who strongly wish to become pregnant within a year should not initiate or continue use of DMPA.
 Figure 8.2 Return to fertility after stopping DMPA. Cumulative conception rate (%) among women seeking pregnancy following discontinuation of a nonhormonal method or following last injection of DMPA IM. (Adapted from Schwallie PC, Assenzo JR, The effect of depomedroxyprogesterone acetate on pituitary and ovarian function, and the return of fertility following its discontinuation: a review, Contraception 10:181-202, 1974.) |
Efficacy
Approximately 6 out of 100 women will become pregnant in the first year of DMPA use with typical use. Injectable contraceptives have perfect-use contraceptive efficacy similar to that observed with typical use of LARC methods, greater than 99%.68 However, similar to short-acting contraceptive methods, the end-user-dependent need for timely and consistent dosing results in typical-use contraceptive effectiveness that diverges from perfectuse efficacy (see Table 1.2).
In a large multicenter international clinical trial conducted by the WHO, no pregnancies occurred during 5,429 woman-months of experience among women receiving IM DMPA 150 mg every 3 months.69 Similarly, no pregnancies occurred in two large multinational clinical trials of DMPA SC, with over 16,000 women-months of use, which specifically included large numbers of overweight and obese women.70 The collective data suggest that contraceptive efficacy for DMPA is not significantly impacted by weight71 or by use of medications that stimulate hepatic enzymes,34,72,73,74 which may be related to both high potency and relatively high serum concentrations of MPA following administration. Like other progestin-only methods, DMPA protects against ectopic pregnancy; a systematic review identified only four ectopic pregnancies in the published literature over almost 50 years.75
The first contraceptive injection can be given at any time if it is reasonably certain that the woman is not pregnant.76 To optimize effective contraception, the first injection should ideally be administered within the first 7 days of the menstrual cycle (before a dominant follicle emerges), or a backup method is recommended for 7 days.76,77 The quick-start, same-day start can be used with injectable contraceptives, and quick-starting contraception has been shown to result in better contraceptive initiation rates and similar contraceptive continuation compared with traditional contraceptive initiation protocols that direct clinicians to restrict initiation to the first 7 days of the menstrual cycle.78,79,80,81,82 In situations when the health care provider cannot be reasonably certain that the woman is not pregnant, the benefits of initiating injectable contraception likely exceed any risk and therefore quick-start initiation is reasonable.76 As is true for most pharmacologic drugs, the limited available data on risks associated with exposure to DMPA in pregnancy are retrospective and significantly confounded
limiting their interpretability.83 However, no indication of significant fetal harm or patterns of serious congenital anomaly exist to support termination of an otherwise desired pregnancy in the setting of DMPA exposure.
limiting their interpretability.83 However, no indication of significant fetal harm or patterns of serious congenital anomaly exist to support termination of an otherwise desired pregnancy in the setting of DMPA exposure.
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