Efficacy and safety of drospirenone as a progestin‐only pill in Japanese women: A phase III study

Abstract

Aim

To evaluate the efficacy and safety of 4 mg of drospirenone (DRSP), a progestin‐only pill (POP), for contraception in Japanese women.

Methods

This was a multicenter, open‐label, single‐arm study. The dosing period of DRSP was 13 cycles, each lasting for 28 days. In one cycle, 4 mg of DRSP was administered orally once daily for the first 24 days, followed by a placebo for 4 days.

Results

Data from 276 subjects were analyzed, with a total of 3319 DRSP exposure cycles. Pregnancy occurred in one subject. The overall Pearl Index [95% CI] was 0.39 [0.01, 2.18], and the cumulative pregnancy rate [95% CI] was 0.40% [0.06, 2.81]. Of the 276 subjects, 273 (98.9%) experienced treatment‐emergent adverse events (TEAEs) and 264 (95.7%) experienced adverse drug reactions. All TEAEs were mild or moderate, with no severe events. The most common TEAE was intermenstrual bleeding (irregular uterine bleeding) (89.5%). Although 31.9% of the subjects had risk factors for venous thromboembolism (VTE), no VTE‐related TEAEs were observed. The incidence of unscheduled bleeding [95% CI] across all cycles was 91.6% [87.7, 94.3].

Conclusions

DRSP, the first POP in Japan, is effective and safe as a contraceptive in Japanese women. It provides a new contraceptive option for Japanese women, including those at risk of VTE for whom combined oral contraceptives are contraindicated.

INTRODUCTION

Contraception is necessary to prevent unplanned pregnancies, and reliable contraceptive methods initiated by women are particularly desirable. The number of unplanned pregnancies in Japan is estimated to be around 610 000 per year. ¹ In addition, the number of induced abortions in Japan in 2022 was 122 725, of which 34 161 (28%) were in women aged 35 or older. ² In a survey by the Japan Family Planning Association, the most common feeling among women who underwent induced abortions was “feeling sorry for the fetus,” followed by “a necessary choice in life” and “feeling guilty.” ³

Currently, the reliable contraceptive methods available in Japan include oral contraceptives (OCs), levonorgestrel–intrauterine system, copper intrauterine device, and sterilization surgery, of which OCs are most widely used. OCs include a combination of estrogen and progestin (combined oral contraceptives: COCs) and progestin‐only pills (POPs). In many Western countries, both COCs and POPs are approved, but in Japan, only COCs are currently approved. The global prevalence rate of OC use in 2019 was 8%. ⁴ Among the 7 major countries, the prevalence rates of OCs are 13.7% in the United States, 28.5% in Canada, 26.1% in the United Kingdom, 19.1% in Italy, 33.1% in France, 31.7% in Germany, and 2.9% in Japan. ⁴ According to the latest survey, the prevalence rate of OCs in Japan rose to 16% in 2023, but it is still low compared to Europe and North America. ³

Estrogens in COCs dose‐dependently affect the blood coagulation–fibrinolytic system and platelet function, ⁵ increasing the risk of venous thromboembolism (VTE) and cardiovascular events. ⁶ Therefore, in Japan, COCs are contraindicated in women at risk of thromboembolism, those with cardiovascular disease, and smokers aged >35 years who smoke more than 15 cigarettes per day. In addition, the Japan Society of Obstetrics and Gynecology guidelines recommend the administration of COCs with caution to women aged >40 years due to an increased risk of cardiovascular events. ⁷ POPs are not associated with any increase in VTE risk, and WHO guidelines recommend POPs more highly than COCs for smokers, women with obesity, hypertension, valvular disease, or deep vein thrombosis, women with a history of pulmonary embolism, and breastfeeding women. ⁸ In Europe, POP‐containing desogestrel has been used since 2003 and has been shown to be as effective as COCs; however, the acceptable time window for missed doses is approximately 12 h, making them less convenient for use. ⁹ Drospirenone (DRSP), a spironolactone derivative, is a fourth‐generation progestin with progestational, anti‐androgenic, and anti‐mineralocorticoid properties. ¹⁰ DRSP has been approved as a POP for contraception in both the United States ¹¹ and Europe ¹² at a dose of 4 mg for 24 days with a 4‐day hormone‐free period (24/4 dosing). The mechanism of action of DRSP in contraception is thought to involve progesterone‐based effects of inhibiting follicular development, suppressing ovulation, and increasing the viscosity of cervical mucus. ¹³ In recent years, Grandi et al. have proposed the inhibition ratio (IR), an index of the contraceptive effect of POPs, which is the ratio of the amount of progestin contained in the POP to the minimum amount of progestin that inhibits ovarian function. ¹⁴ The IR of POP‐containing DRSP was 200%, which is relatively higher than that of POP‐containing desogestrel (125%), and theoretically a high contraceptive effect can be expected. ¹⁴ In clinical trials conducted in the United States and Europe, DRSP demonstrated contraceptive efficacy comparable to that of COCs and POP‐containing desogestrel. ¹⁵ , ¹⁶ , ¹⁷ Additionally, no VTE‐related adverse events have been observed in clinical trials conducted in Europe and the United States in populations, including subjects at risk of VTE. ¹⁸ Furthermore, the acceptable time window for missed doses of DRSP is 24 h, which is longer than that for desogestrel. ¹⁹

A phase I/II clinical trial in Japan demonstrated that the pharmacokinetic and pharmacodynamic profiles of DRSP in Japanese women were similar to those in Caucasian women, with no notable problems. ²⁰ Based on the results of the phase I/II clinical trial, a phase III trial was conducted to verify the efficacy and safety of DRSP in Japanese women.

MATERIALS AND METHODS

Design

This phase III, multicenter, open‐label, single‐arm study evaluated the efficacy and safety of DRSP for contraception in Japanese women. The study was conducted across 15 sites in Japan from January 2022 to October 2023. This study consisted of a screening period, a treatment period consisting of 13 cycles of 28 days each, and a 6‐week follow‐up period. Among all subjects, those who agreed to continue receiving DRSP continued to receive DRSP for up to 24 cycles after completing the 13‐cycle treatment period.

This study was registered in the jRCT database (jRCT2031210556) on January 18, 2022, and subject enrollment began on January 31, 2022.

Study population

The subjects were Japanese women who wished to use contraception. The key inclusion criteria were (1) premenopausal women aged ≥20 years who were capable of childbearing, (2) those who wished to use OCs continuously for 13 cycles, and (3) women with normal menstrual periods and cycles. There were no restrictions on smoking history, body mass index (BMI), postpartum period, or breastfeeding history. The key exclusion criteria were (1) those with ovulation disorder, infertility, abnormal genital bleeding, active VTE, severe liver disease, severe renal failure, or malignant tumors, (2) pregnant women, (3) those with systolic blood pressure (SBP) ≥160 mmHg or diastolic blood pressure (DBP) ≥100 mmHg, (4) those with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >3 times the upper limit of normal, and (5) those with positive cervical cytology.

Intervention and treatment protocol

In this study, 4 mg DRSP tablets (active tablet) were administered orally once daily at approximately the same time each day for the first 24 days, followed by a placebo tablet for the next 4 days (24/4 dosing). The treatment period consisted of thirteen 28‐day treatment cycles. The first dose was administered on the first day of the menstrual cycle. If subjects missed taking a dose of one or two active tablets, they were to take the missed active tablet as soon as they remembered. During the study period, the subjects took pregnancy tests using a urinary human chorionic gonadotropin test kit. Pregnancy tests were performed at the start of each cycle and on the day after the last medication in cycle 13. The use of gonadotropin‐releasing hormone derivatives, female hormones, HIV protease inhibitors, non‐nucleoside reverse transcriptase inhibitors, hepatitis C virus treatment drugs, CYP3A4 derivatives, and CYP3A4 inhibitors was prohibited.

Efficacy outcome measures

The primary endpoint was the overall Pearl Index (PI) for the total number of cycles of DRSP exposure. Cycles in which at least one dosing was confirmed were considered exposed cycles, and the overall PI was calculated using the following formula: overall PI = number of pregnancies × 1300/number of exposed cycles. ²¹ Pregnancies with an estimated date of conception within the exposure cycles were used to calculate the overall PI. The evaluation criterion was an upper limit of the two‐sided 95% confidence interval (CI) of the overall PI being less than four. The secondary endpoints were (1) PI in evaluable cycles, (2) PI in perfect cycles, (3) overall pregnancy rate (%) = number of pregnancies/number of subjects × 100, (4) cumulative pregnancy rate, (5) cumulative continuation rate, and (6) cumulative discontinuation rate. An evaluable cycle was defined as an exposure cycle involving sexual activity without the use of an additional contraceptive method (but including cycles in which pregnancy was confirmed). A perfect cycle was defined as a cycle that excluded the following cycles from the evaluable cycle: (1) a period between cycles exceeding 6 days, (2) four or more missed doses or two consecutive missed doses during a cycle, and (3) protocol deviations that affect outcomes.

Endocrinology

Serum estradiol (E2), progesterone, luteinizing hormone (LH), and follicle‐stimulating hormone (FSH) levels were measured at baseline, on days 28 ± 4 of cycles 3, 6, and 13, and 3 and 6 weeks after 13 treatment cycles were completed.

Safety and tolerability outcome measures

Treatment emergent adverse events (TEAEs) were collected. The severity of TEAEs was classified as follows: mild—events that required no treatment and did not interfere with the continuation of the study or daily life; moderate—events that required treatment but did not preclude continued participation in the study, or those that interfered with daily life; severe—events that precluded continued participation in the study or significantly disrupted daily life. Among TEAEs, events leading to discontinuation of study drug, hyperkalemia, VTE, myocardial infarction, thrombosis, cerebrovascular disorders, and liver disorders were defined as significant TEAEs. The incidence of TEAEs was calculated by stratification according to the VTE risk factors, smoking history, age, and BMI. VTE risk factors were defined as any of the following: metabolic or vascular disease, a history of thrombophlebitis, pulmonary embolism, cerebrovascular disease, coronary artery disease, smoking at an age of >35 years, age of >40 years, or BMI >25.0 kg/m².

The number of bleeding days, incidence rates of scheduled and unscheduled bleeding, and non‐bleeding rate were compiled for each cycle. Scheduled bleeding was defined as bleeding that began between 24 and 29 days after the initiation of active tablets and ended within 8 days, and unscheduled bleeding was defined as any other bleeding. The incidence of bleeding lasting for >14 days was tabulated. Menstrual recovery at the end of DRSP administration and the cumulative menstrual recovery rate were calculated. Clinical examination, blood coagulation tests (prothrombin time: PT; PT‐international normalized ratio: PT‐INR; activated partial thromboplastin time: APTT and d‐Dimer), urinalysis, and electrocardiography were performed.

Statistical analysis

Guidelines for the clinical evaluation of OCs state that the number of cycles required to evaluate efficacy is 12 or more (including 24 or more cycles), and the total number of cycles is at least 2400. ²² , ²³ Based on this, assuming 13 cycles per person, the number of people required was 185. Taking into account potential dropouts, the sample size for this study was set at 260 cases.

Among the enrolled subjects, cases excluding those who did not take any of the study drug and those who were pregnant at the start of the first cycle were defined as the full analysis set (FAS) and were used for efficacy analysis. All subjects who received the study drug at least once were included in the safety analysis set (SAS). The package insert for OCs in Japan states that the 1‐year pregnancy rate with typical use is 9.0%. Considering that this was a clinical trial, we assumed a 1‐year pregnancy rate threshold of 4%, which is less than half of 9.0%, and set the upper limit of the two‐sided 95% CI for the overall PI to be less than four as a criterion for efficacy. Point estimates and two‐sided 95% CIs in the Poisson approximation were calculated for the overall PI and the PI for evaluable cycles and perfect cycles. Cumulative pregnancy rates, cumulative continuation rates, and cumulative discontinuation rates were estimated using the Kaplan–Meier method. Statistical analyses were performed using SAS ver. 9.4 (SAS Institute Inc., Cary, NC, USA).

RESULTS

Subject characteristics

A total of 286 subjects were enrolled, of whom 276 received the study drug (Figure 1). Of the 276 subjects, 35 dropped out and 241 completed 13 cycles of the study. Among them, 52 subjects continued to receive the study drug for 24 cycles. Of the 189 subjects who underwent follow‐up, 4 dropped out and 185 completed. Reasons for dropping out during the 13‐cycle treatment period included withdrawal of consent (n = 25), adverse events (n = 5), pregnancy (n = 1), lost to follow‐up (n = 1), and others (n = 3), and in the follow‐up period, pregnancy (n = 1) and others (n = 3). Two hundred and seventy‐six subjects were included in the FAS and SAS. The mean age of the subjects was 31.2 years (age >35: 32.2%), and the mean BMI was 21.48 kg/m² (BMI > 25 kg/m²: 13.0%) (Table 1). The proportion of subjects with high blood pressure (SBP ≥130 mmHg or DBP ≥85 mmHg) and one or more risk factors for VTE was 6.9% and 31.9%, respectively.

FIGURE 1.

Subjects disposition. Of the 286 subjects enrolled, 276 received the study drug, and 241 completed 13 cycles of treatment.

TABLE 1.

Subject characteristics.

n	276
Age (years), mean ± SD	31.2 ± 6.7
Aged >35 years, n (%)	89 (32.2%)
BMI (kg/m2), mean ± SD	21.48 ± 3.32
BMI > 25 kg/m2, n (%)	36 (13.0%)
SBP (mmHg), mean ± SD	109.8 ± 11.0
DBP (mmHg), mean ± SD	67.4 ± 8.9
SBP ≥ 130 mmHg or DBP ≥ 85 mmHg, n (%)	19 (6.9%)
Smoking, n (%)
Smoker	40 (14.5%)
Ex‐smoker	29 (10.5%)
More than 15 cigarettes per day	15 (37.5%)
VTE risk factors, n (%)
Subject with complication or history for VTE risk factor a	34 (12.3%)
Smokers >aged 35 or non‐smokers aged >40	35 (12.7%)
BMI > 25.0 kg/m2	36 (13.0%)
Number of VTE risk factors a
None	188 (68.1%)
1	74 (26.8%)
2	11 (4.0%)
3	3 (1.1%)
≥1	88 (31.9%)
Usual contraceptive method
Oral contraceptives	176 (63.8%)
IUD	0
IUS	1 (0.4%)
Condom	153 (55.4%)
Rhythm method	3 (1.1%)
History of pregnancy, n (%)	115 (41.7%)
Menstrual cycle (days), mean ± SD	29.4 ± 2.3
Medical history and comorbidity, n (%)	235 (85.1%)
Concomitant medications, n (%)	246 (89.1%)

Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; IUD, intrauterine device; IUS, intrauterine system; SBP, systolic blood pressure; SD, standard deviation; VTE, venous thromboembolism.

^a Complications of metabolic disease and vascular disease or history of thrombophlebitis, pulmonary embolism, cerebrovascular disease, and coronary artery disease.

Medication adherence

Medication adherence rate throughout the cycles was 99.9 ± 0.5%. The number of subjects who did not take medication for 2 consecutive days, 3 consecutive days, or 4 or more consecutive days was 4 (1.4%), 4 (1.4%), and 7 (2.5%), respectively. Over 13 cycles, the estimated cumulative continuation rate [95% CI] and estimated cumulative discontinuation rate [95% CI] were 87.3% [82.8, 90.7] and 12.7% [9.3, 17.2], respectively.

Efficacy outcome

Pregnancy was observed in two subjects. The estimated date of conception was determined to be during the treatment period in one subject and during follow‐up period in the other. One pregnancy that occurred during the treatment period was determined to be due to a missed dose of 8 active tablets. One case in which the estimated date of conception occurred during follow‐up period (ex‐exposed cycles) was excluded from the calculation of the PI. The total number of exposure cycles was 3319, with one case of pregnancy, and the overall pregnancy rate of 0.36% (Table 2). The primary endpoint, the overall PI [95% CI] was 0.39 [0.01, 2.18], with an upper 95% CI limit of less than four, validating the prespecified efficacy for contraception. The total number of evaluable cycles was 3001 with one case of pregnancy, a pregnancy rate of 0.36%, and a PI [95% CI] in evaluable cycles of 0.43 [0.01, 2.41]. The total number of perfect cycles was 2989, with no case of pregnancy, a pregnancy rate of 0.00%, and a PI [95% CI] in perfect cycles of 0.00 [−, 1.60]. The cumulative pregnancy rate [95% CI] up to 13 cycles was 0.40% [0.06, 2.81].

TABLE 2.

Contraceptive efficacy.

n	276
Exposure cycle
Number of pregnancy	1
Pregnancy ratio, %	0.36
Total number of cycles	3319
Overall Pearl Index [95% CI]	0.39 [0.01, 2.18]
Evaluable cycles
Number of pregnancy	1
Pregnancy ratio, %	0.36
Total number of cycles	3001
Overall Pearl Index [95% CI]	0.43 [0.01, 2.41]
Perfect cycles
Number of pregnancy	0
Pregnancy ratio, %	0.00
Total number of cycles	2989
Overall Pearl Index [95% CI]	0.00 [−, 1.60]

Note: An exposure cycle was defined as a cycle in which at least one dose of DRSP was confirmed. An evaluable cycle was defined as an exposure cycle involving sexual activity without the use of an additional contraceptive method (but including cycles in which pregnancy was confirmed). A perfect cycle was defined as a cycle excluding (1) a period between cycles (time between the last dose of DRSP and the first dose of the next cycle) exceeding 6 days, (2) four or more missed doses or two consecutive missed doses during a cycle, and (3) protocol deviations that affect outcomes.

Abbreviation: CI, confidence interval.

Endocrinology

The mean blood progesterone levels were 8.52 ng/mL at baseline, ranging from 0.63 to 0.92 ng/mL during cycles 3–13 and 5.30 and 3.99 ng/mL at 3 and 6 weeks after completion of treatment, respectively (Supplementary Table 1). The mean blood E2 levels were 135.6 pg/mL at baseline, ranging from 46.4 to 55.9 pg/mL in cycles 3–13 and 114.2 and 119.3 pg/mL at 3 and 6 weeks after completion of treatment, respectively. No noteworthy changes in blood LH or FSH levels were observed.

Safety outcome measures

Of the 276 subjects, 273 (98.9%) experienced TEAEs and 264 (95.7%) experienced adverse drug reactions (ADRs) (Table 3). Regarding severity, 116 subjects (42.0%) were mild, 157 subjects (56.9%) were moderate, and no severe case was observed. Significant TEAEs were observed in six subjects (2.2%), of which one case (0.4%) was a serious TEAE. Significant TEAEs leading to discontinuation of study drug included depression, suicide attempt, angioedema, erythema multiforme, and intermenstrual bleeding (irregular uterine bleeding). TEAEs corresponding to the events of concern in COCs included AST and ALT increased. No hyperkalemia was observed. Serious TEAEs were observed in four subjects (1.4%), of which one (0.4%) with invasive ductal breast carcinoma was judged to be an ADR (patient: 28 years old, no family history of breast cancer within third‐degree relatives, history of taking DRSP and ethinyl estradiol combination drugs). A serious TEAE leading to the discontinuation of study drug was observed in one subject (0.4%). No TEAEs leading to death were observed. The incidence of TEAEs was 87.0% in cycles 2–4 and 75.3% in cycles 11–13, and the incidence of TEAEs did not increase with cycles. TEAEs with an incidence of 10% or more included intermenstrual bleeding (89.5%), nasopharyngitis (31.9%), COVID‐19 (29.0%), headache (23.2%), abdominal pain (16.3%), diarrhea (14.9%), pyrexia (14.5%), abdominal pain lower (14.1%), heavy menstrual bleeding (11.6%), and nausea (10.1%). Intermenstrual bleeding was observed in 247 cases, with 243 cases (88.0%) being mild and 4 cases (1.4%) being moderate. The incidence rates of TEAEs in various strata are shown in Supplementary Tables 2–5. There were no clear differences in the incidence of TEAEs between the various strata: VTE risk factors (no 96.8% vs. yes 98.9%) (Supplementary Table 2), smoking history (no 97.5% vs. yes 97.5%) (Supplementary Table 3), age (≤35 96.3% vs. >35100.0%) (Supplementary Table 4), and BMI (≤25 kg/m² 97.1% vs. >25 kg/m² 100.0%) (Supplementary Table 5).

TABLE 3.

TEAEs.

N = 276	Number of events	n (% [95% CI])
Total number of TEAEs	3226	273 (98.9% [96.9, 99.6])
TEAEs by relationship with DRSP
Not related to DRSP	938	9 (3.3%)
Related to DRSP	2288	264 (95.7% [92.6, 97.5])
TEAEs by severity
Mild	2785	116 (42.0%)
Moderate	441	157 (56.9%)
Severe	0	0
Significant TEAEs	7	6 (2.2%)
TEAEs leading to discontinuation	5	5 (1.8%)
Serious TEAEs	4	4 (1.4%)
Serious TEAEs by relationship with DRSP
Not related to DRSP	3	3 (1.1%)
Related to DRSP	1	1 (0.4%)
Serious significant TEAEs	1	1 (0.4%)
Serious TEAEs leading to discontinuation	1	1 (0.4%)
TEAEs leading to death	0	0
TEAEs by cycle
Cycle 1		184 (66.7%)
Cycle 2–4		235 (87.0%)
Cycle 5–7		215 (81.7%)
Cycle 8–10		195 (76.5%)
Cycle 11–13		186 (75.3%)
Follow‐up		88 (46.6%)
TEAEs ≥10%
Intermenstrual bleeding		247 (89.5%)
Mild		243 (88.0%)
Moderate		4 (1.4%)
Severe		0
Nasopharyngitis		88 (31.9%)
Mild		40 (14.5%)
Moderate		48 (17.4%)
Severe		0
COVID‐19		80 (29.0%)
Mild		27 (9.8%)
Moderate		53 (19.2%)
Severe		0
Headache		64 (23.2%)
Mild		41 (14.9%)
Moderate		23 (8.3%)
Severe		0
Abdominal pain		45 (16.3%)
Mild		35 (12.7%)
Moderate		10 (3.6%)
Severe		0
Diarrhea		41 (14.9%)
Mild		40 (14.5%)
Moderate		1 (0.4%)
Severe		0
Pyrexia		40 (14.5%)
Mild		28 (10.1%)
Moderate		12 (4.3%)
Severe		0
Abdominal pain lower		39 (14.1%)
Mild		35 (12.7%)
Moderate		4 (1.4%)
Severe		0
Heavy menstrual bleeding		32 (11.6%)
Mild		32 (11.6%)
Moderate		0
Severe		0
Nausea		28 (10.1%)
Mild		26 (9.4%)
Moderate		2 (0.7%)
Severe		0

Abbreviations: DRSP, drospirenone; TEAEs, treatment emerged adverse events.

The incidence of scheduled bleeding decreased from 36.1% in cycle 1 to 24.9% in cycle 13 (Table 4). The mean number of days for scheduled bleeding per cycle ranged from 2.3 to 3.5 days and did not vary by cycle. The incidence [95% CI] of unscheduled bleeding across all cycles was 91.6% [87.7, 94.3]. The incidence of unscheduled bleeding was 45.3% in cycle 1 and 37.8% in cycle 13 (Table 4). The mean number of days for unscheduled bleeding per cycle ranged from 7.2 to 8.8 days and did not vary by cycle. The incidence [95% CI] of unscheduled bleeding lasting for >14 days was 29.2% [24.1, 34.8], and it decreased from 8.8% in cycle 1 to 4.1% in cycle 13. The combined incidence [95% CI] of scheduled and unscheduled bleeding across all cycles was 96.4% [93.4, 98.0]. The incidence of either scheduled or unscheduled bleeding was 69.3% in cycle 1 and 52.7% in cycle 13. The non‐bleeding rate was 7.9% in cycles 2–4 and 32.8% in cycles 11–13.

TABLE 4.

Scheduled and unscheduled bleeding.

Cycle	Scheduled bleeding		Unscheduled bleeding		Prolonged unscheduled bleeding more than 14 consecutive days	Either scheduled or unscheduled bleeding	Absence of bleeding
	Number of days, mean ± SD	Occurrence, n (%)	Number of days, mean ± SD	Occurrence, n (%)	Occurrence, n (%)	Occurrence, n (%)	Non‐bleeding rates, n (%)
Cycle 1	2.3 ± 1.2	99/274 (36.1%)	8.8 ± 5.6	124/274 (45.3%)	24/274 (8.8%)	190/274 (69.3%)	84/274 (30.7%)
Cycle 2	3.1 ± 2.0	135/270 (50.0%)	8.8 ± 5.5	164/270 (60.7%)	27/270 (10.0%)	226/270 (83.7%)	44/270 (16.3%)
Cycle 3	3.5 ± 1.9	107/268 (39.9%)	8.0 ± 5.0	154/268 (57.5%)	16/268 (6.0%)	203/268 (75.7%)	65/268 (24.3%)
Cycle 4	3.1 ± 1.8	111/266 (41.7%)	7.5 ± 5.3	142/266 (53.4%)	13/266 (4.9%)	201/266 (75.6%)	65/266 (24.4%)
Cycle 5	3.4 ± 1.9	94/263 (35.7%)	7.4 ± 5.9	130/263 (49.4%)	17/263 (6.5%)	186/263 (70.7%)	77/263 (29.3%)
Cycle 6	2.9 ± 1.7	103/258 (39.9%)	7.3 ± 5.2	116/258 (45.0%)	14/258 (5.4%)	172/258 (66.7%)	86/258 (33.3%)
Cycle 7	3.0 ± 1.9	91/255 (35.7%)	7.7 ± 5.7	112/255 (43.9%)	15/255 (5.9%)	171/255 (67.1%)	84/255 (32.9%)
Cycle 8	3.2 ± 2.0	90/255 (35.3%)	8.4 ± 5.4	94/255 (36.4%)	8/255 (3.1%)	156/255 (61.2%)	99/255 (38.8%)
Cycle 9	3.0 ± 1.7	93/254 (36.6%)	7.6 ± 6.0	103/254 (40.6%)	13/254 (5.1%)	157/254 (61.8%)	97/254 (38.2%)
Cycle 10	3.1 ± 1.9	83/249 (33.3%)	8.5 ± 6.0	88/249 (35.3%)	13/249 (5.2%)	138/249 (55.4%)	111/249 (44.6%)
Cycle 11	3.2 ± 1.7	68/247 (27.5%)	7.2 ± 4.8	90/247 (36.4%)	6/247 (2.4%)	129/247 (52.2%)	118/247 (47.8%)
Cycle 12	3.2 ± 2.0	61/242 (25.2%)	7.3 ± 5.1	84/242 (34.7%)	8/242 (3.3%)	125/242 (51.7%)	117/242 (48.3%)
Cycle 13	3.5 ± 2.0	60/241 (24.9%)	7.7 ± 5.2	91/241 (37.8%)	10/241 (4.1%)	127/241 (52.7%)	114/241 (47.3%)
Cycle 2–4	6.2 ± 4.3	183/266 (68.8%)	18.4 ± 13.1	202/266 (75.9%)	43/266 (16.2%)	245/266 (92.1%)	21/266 (7.9%)
Cycle 5–7	6.3 ± 4.3	141/255 (55.3%)	15.1 ± 13.0	174/255 (68.2%)	36/255 (14.1%)	217/255 (85.1%)	38/255 (14.9%)
Cycle 8–10	6.1 ± 4.1	132/249 (53.0%)	15.6 ± 14.2	143/249 (57.4%)	26/249 (10.4%)	187/249 (75.1%)	62/249 (24.9%)
Cycle 11–13	5.9 ± 3.9	105/241 (43.6%)	14.7 ± 13.1	131/241 (54.4%)	18/241 (7.5%)	162/241 (67.2%)	79/241 (32.8%)

Blood coagulation tests showed no notable changes in PT, PT‐INR, APTT, or d‐Dimer (Supplementary Table 6). Changes in blood pressure from baseline are shown in Supplementary Table 7. No change in blood pressure was observed in the subgroup with SBP <130 mmHg and DBP <85 mmHg, but in the subgroup with SBP ≥130 or DBP >85 mmHg, a median decrease of −7.0 mmHg in SBP and −7.5 mmHg in DBP was noted. The cumulative menstrual recovery rates [95% CI] were 23.6% [18.3, 29.9] within 28 days after the last dose, 96.6% [93.1, 98.3] within 56 days, and 100.0% [98.1, 100.0] for overall (Figure 2). No other notable abnormalities were found.

FIGURE 2.

Return of menstrual bleeding. The cumulative menstrual recovery rate was 100.0%.

DISCUSSION

This study demonstrated the efficacy of 24/4 dosing of DRSP‐POP in Japanese women. The overall PI of this study was not different from that of a European phase III study ¹⁵ and a US phase III study of DRSP. ¹⁶ In addition, it was comparable to that of a European phase III trial ²⁴ and a Chinese randomized controlled trial ²⁵ of COCs containing DRSP (DRSP/ethinylestradiol).

Missing a dose of contraceptive pill increases the risk of pregnancy. ²⁶ However, forgetting to take OCs occurs frequently, and a study in Spain found that approximately 60% of women were poor adherents. ²⁶ The United States guidelines state that for most POPs, the dose must be taken within 27 h of the previous dose. ²⁷ This indicates that classical POPs have a 3‐h time window for missed doses. In contrast, the time window for missing a dose is 12 h for desogestrel and 24 h for DRSP. ²⁸ In our study, no pregnancy occurred in the four subjects who did not take DRSP for 2 consecutive days. Although the time window for missed doses of DRSP requires further study, the relatively longer time window for missed doses than that for existing POPs is considered a clinical advantage of DRSP.

Because POPs generally do not increase the risk of thromboembolism, ²⁹ this study included subjects at risk of thrombosis; however, VTE or VTE‐related TEAE was not observed in any case. Our study showed there were no notable changes in blood coagulation tests. In addition, no difference in the incidence of TEAEs was observed among various subgroups stratified by VTE risk factors, smoking history, age, and BMI. Regarding blood pressure, no change was observed in the subgroups with SBP <130 mmHg and DBP <85 mmHg, but a slight decrease was observed in the subgroups with SBP ≥130 or DBP >85 mmHg (median ΔSBP −7.0 mmHg, median ΔDBP −7.5 mmHg). These blood pressure changes have also been reported in European and American studies of DRSP, and those changes in SBP and DBP were comparable to our study. ¹⁵ , ¹⁸ The American Society for Reproductive Medicine guidelines for COCs and VTE state that hypertension is a risk factor for VTE. ³⁰ Therefore, the blood pressure‐lowering effect observed in this study is considered to be beneficial from the perspective of reducing the risk of VTE. This favorable effect in the high blood pressure subgroup may be due to the anti‐mineralocorticoid effects of DRSP. ³¹ These results indicate that DRSP‐POP does not increase the risk of thrombosis, even in Japanese women, and are considered to be clinically significant findings.

The most common TEAE was intermenstrual bleeding (89.49%). Unscheduled bleeding was present in 45.26% of subjects in cycle 1 and 37.76% in cycle 13. These results are similar to those of DRSP's phase III studies in Europe (cycle 1: 49.1%; cycle 13: 22.8%). ¹⁵ POPs are generally known to cause breakthrough bleeding due to weakening of the endometrial microvessels, ³² which can sometimes lead to discontinuation of their use. ³³ , ³⁴ However, in this study, only one subject discontinued DRSP because of bleeding. In overseas clinical trials of DRSP, the rate of discontinuation due to bleeding was 0% in the US phase III trial and 4.2% in the European phase III trial, ³⁴ and the results are comparable to those of this study. The reason why DRSP has a relatively low discontinuation rate due to bleeding may be due to the fact that 24/4 dosing of DRSP results in scheduled bleeding during the 4‐day drug‐free period, although this is not 100%. A comparison of 24/4 dosing of DRSP with 28‐day dosing of desogestrel also showed that the former resulted in a significantly lower incidence of unscheduled bleeding. ³⁵ In addition, the frequency of both scheduled and unscheduled bleeding was relatively lower in cycle 13 compared with cycle 1. Reductions in the frequency and intensity of scheduled and unscheduled bleeding with continued DRSP administration have been reported, ³⁶ , ³⁷ and the reduction in bleeding during continued administration may also be a reason for the low rate of discontinuation due to bleeding. Considering these factors, DRSP may have a lower risk of bleeding than that with existing POPs, and this study demonstrated this property in Japanese women as well. On the other hand, scheduled bleeding does not always occur. Therefore, if there is no scheduled bleeding for two consecutive cycles, it is necessary to check for pregnancy.

After the final dose of DRSP, menstruation resumed in all subjects, and in 96.6% of cases, menstruation resumed within 56 days. The median elimination half‐life of DRSP is ~24 h, ²⁰ and the results of this study indicate that ovarian function is restored early after the discontinuation of DRSP.

This study has several limitations. POPs are not approved in Japan, and COCs cannot be used as comparators because this study included women at risk for VTE. For these reasons, this study was conducted as a single‐arm study without a control group. This study evaluated up to 13 cycles, and longer‐term efficacy and safety assessments need further evaluation. The results of this study were obtained under a high medication adherence rate of 99.9%. In real‐world clinical practice, efficacy may be affected by changes in adherence. Although DRSP allows a 24‐h time window for a missed dose, appropriate guidance on managing missed doses is required.

The DRSP 24/4 dosing regimen demonstrated good contraceptive efficacy, safety, and tolerability in Japanese women. DRSP provides contraceptive efficacy similar to that of COCs and can be administered to women with thromboembolism risk factors, cardiovascular disease, and smokers over 35 years of age, in whom COCs are contraindicated. DRSP, a POP, provides a new, women‐centered, reliable option for contraception to women who wish to seek contraception.

AUTHOR CONTRIBUTIONS

Kunio Kitamura: Conceptualization; investigation; methodology; writing – original draft; writing – review and editing. Enrico Colli: Investigation; methodology; writing – original draft; writing – review and editing. Ryoko Kikuyama: Investigation; methodology; writing – original draft; writing – review and editing. Yumiko Kurihara: Investigation; writing – original draft; writing – review and editing. Rieko Azuma: Investigation; methodology; writing – original draft; writing – review and editing. Tomoya Kagawa: Investigation; methodology; writing – original draft; writing – review and editing.

CONFLICT OF INTEREST STATEMENT

Kunio Kitamura received lecture fees from ASKA Pharmaceutical Co., Ltd. and Fuji Pharma Co., Ltd. Enrico Colli is an employee of Exeltis. Ryoko Kikuyama, Yumiko Kurihara, Rieko Azuma, and Tomoya Kagawa are employees of ASKA Pharmaceutical Co., Ltd.

ETHICS STATEMENT

This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines of the Ministry of Health, Labour and Welfare in Japan. The physician provided a thorough explanation of the study to the participants and obtained written consent to participate in the study of their own free will. The protocol for this study was approved by the Ethics Committee of HURECS (Review Board of Human Rights and Ethics for Clinical Studies Institutional Review Board).

Supporting information

Supplementary Table 1. Endocrinology.

Supplementary Table 2. TEAEs by VTE risk factor.

Supplementary Table 3. TEAEs by smoking habit.

Supplementary Table 4. TEAEs by age.

Supplementary Table 5. TEAEs by BMI.

Supplementary Table 6. Coagulation test.

Supplementary Table 7. Changes in blood pressure.

Kitamura K, Colli E, Kikuyama R, Kurihara Y, Azuma R, Kagawa T. Efficacy and safety of drospirenone as a progestin‐only pill in Japanese women: A phase III study. J Obstet Gynaecol Res. 2025;51(6):e16340. 10.1111/jog.16340

DATA AVAILABILITY STATEMENT

Due to the nature of this research, participants of this study did not agree for their individual data to be shared publicly, so supporting data is not available.