By Rebecca H. Allen, MD, MPH, Editor
This study was a re-analysis of drospirenone 4 mg Phase III efficacy trials comparing 590 non-obese and 325 obese patients who showed equivalent pregnancy rates with Pearl Indices of 3.0 (95% confidence interval [CI], 1.3 to 5.8) and 2.9 (95% CI, 0.8 to 7.3), respectively.
Creinin MD, Angulo A, Colli E, Archer DF. The efficacy, safety, and tolerability of an estrogen-free oral contraceptive drospirenone 4 mg (24/4-day regimen) in obese users. Contraception 2023;128:110136.
The interaction between obesity and oral contraceptive efficacy has been a controversial issue. The authors undertook this study to examine the effectiveness of the progestin-only oral contraceptive drospirenone in obese users.
This is a study that re-analyzed data from three Phase III efficacy trials of the drospirenone 4 mg (24/4-day regimen) pill that took place both in Europe and the United States. Overall, the inclusion criteria were sexually active, non-breastfeeding patients aged 15 to 45 years with non-severe blood pressure measurements (< 159/99 mmHg in the United States and < 140/< 90 mmHg in Europe). Obese participants could be included if they had no personal or family history of venous thromboembolism (VTE) that occurred at younger than 55 years of age, diabetes with vascular involvement, or valvular heart disease with thrombogenic complications. In Europe, but not in the United States, obese users were required to be nonsmokers. Participants received the study drug and were followed between nine and 13 cycles, depending on the study site. Study visits were conducted at regular intervals. Data collected included bleeding patterns, adverse events, laboratory safety evaluations, and VTE screening via clinical questions. A pharmacokinetic substudy was performed in the United States that entailed collecting drospirenone drug levels at day 24 of the first and sixth cycles. The secondary analysis evaluated efficacy by Pearl Index, safety, tolerability, and pharmacokinetic parameters stratified by body mass index (BMI) (< 30 kg/m2 vs. ≥ 30 kg/m2). Efficacy data were reported for U.S. participants only.
The three trials enrolled a total of 1,571 European and 1,006 U.S. participants who were included in the analysis. For the efficacy analysis, which used data from U.S. participants ≤ 35 years of age only, there were eight pregnancies among 590 non-obese users and four pregnancies in the 325 obese users. The Pearl Indices of 3.0 (95% confidence interval [CI], 1.3 to 5.8) and 2.9 (95% CI, 0.8 to 7.3) were not statistically significantly different. There were no VTE events reported in the studies nor any significant differences between the two groups in weight changes or blood pressure. Treatment-emergent adverse events that led to discontinuation were reported in 244 (11.3%) non-obese and 39 (9.2%) obese participants. The median weight of the sample population for the pK analysis was 73 kg, and the median plasma drospirenone exposure was 661.3 ng∙h/mL. Systemic exposure was related to weight, with exposure dropping by 23.6% for weights of 118 kg or the 95th percentile by weight.
COMMENTARY
Drospirenone 4 mg (24/4-day regimen) is a progestin-only contraceptive pill that was approved for use in the United States on June 6, 2019. Unique to many contraceptive trials for approval, women with a BMI ≥ 30 kg/m2 were permitted to enroll in the drospirenone studies. Interestingly, the European trials ended up enrolling 71 (4.5%) participants with obesity compared with more than one-third of U.S. trial participants being obese (n = 354, 35.2%). As the prevalence of obesity increases globally and in the United States, it is important to have data regarding the efficacy and safety of contraceptive medications in this population.
The authors of this study found that the efficacy of drospirenone 4 mg in preventing pregnancy was no different between non-obese and obese users ≤ 35 years of age, despite approximately 20% lower systemic drug exposure. There were no substantive differences between the two groups in safety or tolerability. It is important to note that women with significant hypertension, smoking, and diabetes, depending on the study site, were excluded from participating; therefore, these data may not be generalizable to all obese users of drospirenone.
In general, obesity affects oral contraceptive steroid absorption and metabolism. Obese users may take longer to reach a therapeutic level after starting oral contraceptives or after a hormone-free interval.1 Nevertheless, data are inconsistent on the actual effects of obesity on oral contraceptive effectiveness in the real world. The Centers for Disease Control and Prevention’s United States Medical Eligibility Criteria for Contraceptive Use (USMEC) state that progestin-only pills have no safety or efficacy concerns for obese women (category 1).2 Combined oral contraceptive pills are rated category 2 (benefits generally outweigh risks) mainly because of concerns regarding the increased risk of VTE in obese users. However, the risk of VTE in obese women using combined pills is less than the VTE risk they would experience during pregnancy or the postpartum period. The USMEC also mentions that effectiveness of some combined oral contraceptive formulations may be decreased with increasing BMI, although the data are “minimal and conflicting.”2
There are emerging data that 24/4 oral contraceptive pill regimens may be more effective than 21/7 regimens overall and especially in obese women.3,4 Therefore, 24/4 regimens may be preferred in this population, since there are fewer hormone-free interval days. Although drospirenone 4 mg still is brand-name (Slynd) and it is difficult to obtain insurance coverage for patients, there are 24/4 generic combined oral contraceptive pills that could be considered. Overall, obese women are candidates for all contraceptive methods and should be counseled regarding all their choices.
REFERENCES
- Simmons KB, Edelman AB. Hormonal contraception and obesity. Fertil Steril 2016;106:1282-1288.
- Curtis KM, Tepper NK, Jatlaoui TC, et al. US Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep 2016;65:1-103.
- American College of Obstetricians and Gynecologists. Use of hormonal contraception in women with coexisting medical conditions. Practice Bulletin Number 206. Published February 2019. https://www.acog.org/clinical/clinical-guidance/practice-bulletin/articles/2019/02/use-of-hormonal-contraception-in-women-with-coexisting-medical-conditions
- Dinger J, Do Minh T, Buttman N, Bardenheuer K. Effectiveness of oral contraceptive pills in a large U.S. cohort comparing progestogen and regimen. Obstet Gynecol 2011;117:33-40.
