A new contraceptive method should ideally provide improved access or a higher quality and safety option. Although unintended pregnancy rates in the United States are decreasing, significant disparities across race and socioeconomic status remain,1 and these disparities actually doubled from 1994 to 2011 even though the overall unintended pregnancy rate decreased.1-3 Specifically, people of color, those with lower income, and people with lower education levels had higher rates of unintended pregnancies than did White people with higher education and income, suggesting disparate access to contraception services.1 Thus, as new contraceptive methods are introduced, we must assess if they have the potential to address this disparity as well as continue to provide higher quality and safer options.
In this Update, we critically review the phase 3 data on efficacy and safety for 3 new methods that were introduced to the US market over the past year to evaluate their impact on the current contraceptive landscape.
The first method, newly approved by the US Food and Drug Administration (FDA), is a combined oral contraceptive (OC) that contains a novel endogenous estrogen, estetrol, or E4 (Nextstellis). E4 is a natural estrogen produced in the fetal liver that has lower potency and a longer half-life than estradiol. Nextstellis is a monophasic 24/4 OC pill that contains E4 14.2 mg and drospirenone 3 mg in each of the 24 hormone-containing pills. Most combined hormonal contraceptives (CHCs) in the United States today contain synthetically made ethinyl estradiol (EE) due to its high potency and oral bioavailability. Outside of the reproductive system, EE upregulates the production of hepatic proteins and alters procoagulant and anticoagulant factors, which results in an overall increase in venous thromboembolic (VTE) risk among CHC users.2
After widespread use of combined oral contraceptives (COCs) started in the 1960s, data emerged regarding increased VTE risk.3 Subsequent research discovered that the type of estrogen used in CHCs directly correlates with the thrombosis risk due to the hepatic upregulation with both first- and second-pass metabolism. Although this risk was reduced as the EE dose decreased below 50 µg and concurrent VTE risk factors were contraindicated, CHC users still faced a 2-fold increase in VTE risk compared with nonusers.4,5 EE in contraceptive formulations increases VTE risk, likely related to upregulation of procoagulant factors and decreasing anticoagulant proteins.2 By contrast, a phase 2 trial of Nextstellis demonstrated more neutral effects of E4/drospirenone on hemostatic parameters compared with EE/levonorgestrel or EE/drospirenone.6 Furthermore, E4/drospirenone exhibited lower increases in hepatic proteins, such as angiotensinogen, triglycerides, and sex-hormone binding globulin.7 These findings together suggest that this novel CHC pill has a more favorable cardiovascular adverse effect profile compared with currently available CHCs.
The second contraceptive method is a new transdermal patch that contains EE and levonorgestrel (Twirla); this is in contrast to the available EE/norelgestromin contraceptive patch (Xulane). Transdermal contraceptive patches can offer some users easier adherence as compared with a daily OC.8 Until this past year, the only transdermal contraceptive available in the United States was Xulane, which contains a daily dose of EE 35 µg and norelgestromin 150 µg. Norelgestromin is eventually metabolized to levonorgestrel derivatives.9 Twirla is administered in the same manner as Xulane and contains a daily hormone exposure equivalent to a COC containing EE 30 µg and levonorgestrel 120 µg. Similar to EE/norelgestromin, the EE/levonorgestrel patch also is contraindicated in obese patients (body mass index [BMI] ≥30 kg/m2) due to decreased efficacy and increased risk for VTE. Additionally, phase 3 data demonstrated decreasing efficacy of Twirla in overweight users (BMI ≥25–30 kg/m2), perhaps further limiting the population that may benefit from this contraceptive method.10 These issues with efficacy and weight likely are related to the fact that levonorgestrel distribution is weight dependent, with evidence of lower plasma levels in obese individuals.11-13
The third new method is a prescription vaginal contraceptive gel with lactic acid, citric acid, and potassium bitartrate (Phexxi) designed to prevent pregnancy by maintaining an acidic vaginal environment that is inhospitable to sperm. For many decades, vaginal contraceptives, including vaginal spermicidal gels, provided easy access to a nonhormonal and flexible method of moderately effective contraception for many users. Phexxi is a prescription vaginal pH regulator administered as a gel and active for 1 hour after application. All previous vaginal gels sold in the United States are applied similarly, are available over the counter, and include nonoxynol-9, which is a surfactant that damages sperm cell membranes. Recent data from a phase 3 trial demonstrated similar contraceptive effectiveness of Phexxi when compared with available nonoxynol-9 alternatives.14
Continue to: New OC with the novel estrogen E4 demonstrates good safety profile for VTE...