Treatment of unfavorable bleeding patterns in contraceptive implant users: a randomized clinical trial of curcumin.

BACKGROUND: Some users of the etonogestrel contraceptive implant experience bothersome bleeding, which can reduce contraceptive satisfaction and continuation. Few strategies exist to manage this bleeding. The exact mechanism of progestin-induced bleeding is unknown, but it is likely multifactorial (eg, impaired angiogenesis, "leaky" fragile vasculature, and inflammation). Curcumin, the active ingredient in turmeric, has anti-inflammatory, antiproliferative, and antiangiogenic properties, which may make it a useful agent for implant-associated bothersome bleeding. OBJECTIVE: This study aimed to evaluate whether curcumin decreases frequent or prolonged bleeding or spotting in contraceptive implant users. STUDY DESIGN: The study was a randomized, double-blind, placebo-controlled trial. Here, etonogestrel implant users with frequent or prolonged bleeding or spotting were enrolled and randomized to either 600-mg Theracurmin HP (Immunovites, Las Vegas, NV) or placebo daily for 30 days. The term "frequent" was defined as ≥2 independent bleeding or spotting episodes, and the term "prolonged" was defined as ≥7 consecutive days of bleeding or spotting in a 30-day interval. Implant use was confirmed by clinical examination and negative gonorrhea and chlamydia and pregnancy tests. Enrolled participants initiated study treatment after 3 consecutive days of bleeding or spotting; if no bleeding or spotting occurred within 30 days of enrollment, the participants were withdrawn from the study. Study treatments were encapsulated to maintain a similar appearance. Participants used text messages to record daily bleeding patterns and study drug compliance. Bleeding was defined as a day that required the use of protection with a pad, tampon, or liner, and spotting was defined as a day with minimal blood loss that did not require the use of any protection. Our primary outcome was the total number of days without bleeding or spotting during the 30 days of study drug or placebo exposure. The secondary outcomes included total number of bleeding-free days, bleeding episodes, and satisfaction. A sample size of 22 per group provided 80% power at an alpha level of .05 to demonstrate a 6-day difference between groups. RESULTS: From February 2021 to November 2022, 58 individuals enrolled in the study with 54 participants (93%) completing 30 days of treatment (26 in the curcumin group and 28 in the placebo group). Of note, 1 individual in the curcumin arm did not experience a qualifying bleeding event and, thus, never initiated treatment and, per protocol, was withdrawn from the study. Participant characteristics did not differ between groups, including length of implant use at study enrollment (placebo, 521±305 days; curcumin, 419±264 days). The study groups did not differ concerning any bleeding-related outcome (mean days without bleeding or spotting: curcumin, 16.7±6.9; placebo, 17.5±4.8; P=.62; mean bleeding-free days: curcumin, 23.4±4.9; placebo, 22.4±4.5; P=.44; bleeding episodes: curcumin, 2.0±0.8; placebo, 2.1±0.8; P=.63). In addition, satisfaction with the implant as contraception and acceptability of bleeding over the study period did not differ by study group (P=.54 and P=.30, respectively). CONCLUSION: Daily use of curcumin did not improve bleeding patterns in users of the etonogestrel contraceptive implant experiencing frequent or prolonged bleeding patterns.

The Risk of Breakthrough Bleeding Justifies the Use of Combined Hormonal Contraception Over Progesterone-Only Pills While Breastfeeding.

Breakthrough bleeding is a side effect of progesterone-only pills (POPs) in 40% of women, and is reduced to 10% with combined hormonal contraceptives (CHCs). In addition, breakthrough bleeding is reduced if POP is supplemented with norethisterone. As breakthrough bleeding is responsible for a quarter of women stopping the pill, it is vital to realize that CHC is an alternative to POP-even during lactation. CHCs are considered safe during lactation, do not reduce milk production, nor impede infant development. Nevertheless, CHCs are often not prescribed for lactating mothers due to this misconception that they reduce milk production. Among Orthodox Jews, breakthrough bleeding frequently results in stopping POP, as Jewish religious law prohibits any physical contact of the mother with her partner during active bleeding, and for 7 days after bleeding. When such bleeding occurs, not choosing a CHC alternative, results in couples risking discontinuation of POP, and in conceiving within a year of the previous birth, with its increased risk of preterm labor and birth defects. To measure how physicians respond to the presumed dilemma of balancing the risk of breakthrough bleeding versus the concern of reduction of milk production, we conducted a preliminary online survey. Physicians were asked if they would prescribe CHC instead of POP to breastfeeding mothers, 3 months postpartum with breakthrough bleeding. Half of the physicians responded they would prescribe CHC, whereas close to half of the physicians responded that they would not. The main reasons given by the respondents for avoiding CHC was a concern regarding possible milk reduction. These results confirm a significant degree of a lack of updated pharmacological information regarding the options of oral contraceptive use for lactating mothers, particularly for those where breakthrough bleeding has major behavioral and religious consequences. Thus, we contend that the risk of breakthrough bleeding justifies the more routine use of CHC in lieu of POP in lactating mothers.

Pooled analysis of two phase 3 trials evaluating the effects of a novel combined oral contraceptive containing estetrol/drospirenone on bleeding patterns in healthy women.

OBJECTIVE: To evaluate the bleeding patterns of a new combined oral contraceptive containing estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg in a 24/4-day regimen. STUDY DESIGN: We pooled bleeding data from two parallel, open-label, 13-cycle phase 3 trials that enrolled participants 16 to 50 years old with body mass index (BMI) ≤35 kg/m2. Participants reported vaginal bleeding/spotting in daily diaries. For this bleeding analysis, we included participants with at least one evaluable cycle. We calculated mean frequencies of scheduled and unscheduled bleeding/spotting episodes and median duration of bleeding/spotting episodes, and assessed associations between treatment compliance, BMI and recent hormonal contraceptive use on bleeding/spotting outcomes. RESULTS: We included 3409 participants with 33,815 cycles. Scheduled bleeding/spotting occurred in 87.2% to 90.4% of participants/cycle, with a median duration of 4 to 5 days. Unscheduled bleeding/spotting decreased from 27.1% in Cycle 1 to 20.6% in Cycle 2 to ≤17.5% from Cycle 5 onwards. Most (66.5%) unscheduled bleeding/spotting episodes were spotting-only. Between 5.8% and 7.8% of users/cycle experienced absence of any scheduled or unscheduled bleeding/spotting. Missing one or more active pills resulted in a higher occurrence of unscheduled bleeding/spotting (adjusted odds ratio [aOR] 2.13 [95% confidence interval 1.68-2.70]) and absence of scheduled bleeding/spotting (aOR 2.36 [1.82-3.07]). Participants with a BMI ≥30 kg/m2 reported more absence of scheduled bleeding/spotting (aOR 1.68 [1.37-2.05]). Switchers and starters reported similar frequencies of unscheduled bleeding/spotting (aOR 0.94 [0.83-1.07]) and absence of scheduled bleeding/spotting (aOR 1.00 [0.85-1.19]). Three percent of participants discontinued for a bleeding-related adverse event. CONCLUSION: E4/DRSP use results in a predictable bleeding pattern with limited unscheduled bleeding/spotting. Noncompliance and BMI affect bleeding patterns. IMPLICATIONS STATEMENT: Most estetrol/drospirenone users experience a predictable and regular bleeding pattern. Providers can educate patients about the expected bleeding patterns and should advise users that they may infrequently experience no scheduled bleeding/spotting. This information may improve user acceptability and continuation of this new oral contraceptive.

Breakthrough bleeding episodes in pediatric severe hemophilia a patients with and without inhibitors receiving emicizumab prophylaxis: a single-center retrospective review.

Emicizumab has been widely used for prophylaxis in patients with hemophilia A (HA) of all ages, with or without factor VIII inhibitors. Data on emicizumab efficacy are certainly significant; however, protection against bleeding is not absolute, and the breakthrough bleeding risk can be approximately equivalent to that of patients with mild HA. This single-center retrospective review aimed to present the rate and management of breakthrough bleeding events in pediatric HA patients with and without inhibitors who are on emicizumab prophylaxis. Fifty-one pediatric patients on emicizumab prophylaxis that were followed up at Birmingham Children's Hospital between March 1, 2018, and May 15, 2021, were included in the current study. Our results showed that 56.8% (29/51) experienced no bleeding events, and 80.3% (41/51) had no major treated bleeds during the follow-up period. A total of 29.4% (15/51) had minor bleeds that resolved spontaneously or with antifibrinolytics. Overall, 19.6% (10/51) of the patients received additional FVIII to prevent or treat breakthrough bleeding. One patient had a major bleeding event in the form of hematuria. However, it resolved without treatment. Both major and minor bleeding episodes occurred in 7.8% (4/51) of patients. None of the patients with inhibitors (5/51) developed breakthrough bleeding. Only a few, mostly minor, breakthrough bleeding episodes were reported in our cohort. The balance between bleeding control and the risk of inhibitor development after episodic factor administration should be considered. Therefore, careful decisions should be made in managing bleeding events.Supplemental data for this article is available online at.

Effects of progestin-only contraceptives on the endometrium.

INTRODUCTION: The contraceptive activity of synthetic progestins is mediated through three basic mechanisms: (a) An anti-gonadotrophic action leading to the inhibition of ovulation; (b) Changes in cervical mucus characteristics that inhibit sperm penetration and (c) desynchronization of the endometrial picture necessary for implantation. AREAS COVERED: Mechanisms involved in the progestin-induced endometrium desynchronization are individually reviewed for each of the routes of administration and, whenever possible, by individual members of the various families of synthetic progestin derivatives. EXPERT OPINION: For contraceptive purposes, progestins are today administered through several routes: orally, as injections, subdermally and via the vagina or the uterine cavity. Given this variety of modalities, their effects may differ, depending on the route of administration, concentration reached at the level of the endometrium and the duration of use. These are characterized by inactivation of the endometrium. Progestin-only contraception provides a safe and effective control of fertility regulation, although, they are associated with the problem of endometrial break through bleeding that may lead to discontinuation. Unfortunately, in spite of a major research effort over two decades, there is not, as yet, an established long-term intervention available to manage bleeding irregularities, making mandatory a deeper understanding of the mechanisms involved is required.

Treatment of Unfavorable Bleeding Patterns in Contraceptive Implant Users: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether a short course of tamoxifen decreases bothersome bleeding in etonogestrel contraceptive implant users. METHODS: In a 90-day, double-blind randomized control trial, we enrolled etonogestrel implant users with frequent or prolonged bleeding or spotting. A sample size of 40 per group (N=80) was planned to compare 10 mg tamoxifen or placebo twice daily for 7 days after 3 consecutive days of bleeding or spotting no more than once per 30 days (maximum three treatments). Participants then entered a 90-day open-label study where all received tamoxifen if needed every 30 days (maximum three treatments). Participants used text messages to record daily bleeding patterns. Our primary outcome was the total number of consecutive amenorrhea days after the first treatment. Secondary outcomes included time to bleeding or spotting cessation and restart after first treatment, overall bleeding patterns, and satisfaction. RESULTS: From January 2017 to November 2018, 112 women enrolled in the study; 88 (79%) completed 90 days, and 79 (71%) completed 180 days. Participant characteristics did not differ between groups; mean age 24, majority identified as white not Hispanic with at least some college education. After the first treatment, the tamoxifen group reported an average of 9.8 (95% CI 4.6-15.0) more consecutive days of amenorrhea and more total days of no bleeding (amenorrhea or spotting) in the first 90 days (median 73.5 [range 24-89] vs 68 [range 11-81], P=.001). The placebo group showed a similar treatment benefit after first active use of tamoxifen in the open-label phase. At the end of the randomized study (first 90 days), women who received tamoxifen reported higher satisfaction (median 62 mm [range 16-100]) than those treated with placebo (46 mm [range 0-100]; P=.023). CONCLUSION: A short course of tamoxifen reduces problematic bleeding and improves satisfaction in users of etonogestrel implants. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02903121.

Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis.

Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation.Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting.Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations.Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

Comparison of low dose versus ultra-low dose hormone therapy in menopausal symptoms and quality of life in perimenopause women.

The study was to compare the efficacy, safety, and tolerability of low dose versus ultra-low dose hormone therapy (HT) in the management of perimenopause symptoms and quality of life. Retrospective analysis of perimenopause patients prescribed for 25 weeks HT in the outpatient clinic of menopause. A total of 132 perimenopause women were included in two treatment regimens: one with low dose HT (LD-HT) and one with ultra-low dose HT (ULD-HT). Changes in serum levels of follicle-stimulating hormone, estradiol as well as transvaginal ultrasound (TVUS), the 36-item Short Form Health Survey (SF-36), the Kupperman Index (KI), and adverse effects were assessed at baseline, 4, 13, and 25 weeks. By the end of 25 weeks of treatment, each score of SF-36 domains for both LD-HT and ULD-HT groups were increased, the KI decreased, and the endometrial thickness increased in both groups and there was no statistical difference between two groups. Both groups have negligible differences in incidence of adverse effects. Low dose and ultra-low dose HT both can serve in improving symptoms of perimenopause, thereby offering a better quality of life with decreased incidence of side effects. Ultra-low dose treatment may have a better advantage on safety and tolerance.

Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill.

INTRODUCTION: Approximately 100 million women currently use combined oral contraceptives. Combined oral contraceptives use is associated with increased risk of venous thromboembolic events and cardiovascular disease. Progestin-only pills do not increase the risk of venous thromboembolic events, stroke and myocardial infarction but are associated with a poor cycle control. A novel estrogen-free pill containing only drospirenone (DRSP) was developed to improve bleeding pattern, tolerability and acceptance without increasing venous thromboembolic events risks in contraception. MATERIAL AND METHODS: Two prospective, multicenter Phase III studies in healthy women aged 18-45 years were performed to demonstrate the efficacy and safety of a drospirenone-only pill in a regimen of 24 days of 4 mg of drospirenone tablets followed by 4 days of placebo. A total of 1571 women (14 329 exposure cycles) were analyzed: 713 patients in the 13-cycle study 1 with 7638 exposure cycles and 858 patients in the 9-cycle study 2 with 6691 exposure cycles. The primary endpoint was the overall Pearl index, calculated for each study separately, and for both pooled. As main secondary efficacy endpoint, the "method failure Pearl index" including all pregnancies during "perfect medication cycles" was evaluated. EudraCT registration numbers: 2010-021787-15 & 2011-002396-42. RESULTS: Calculations on pooled studies 1 and 2 with 1571 patients gave an overall Pearl index (based on 14 329 cycles) of 0.7258 (95% CI 0.3133 to 1.4301). No single case of deep vein thrombosis or pulmonary embolism and only one case of hyperkalemia were reported. Additional information such as laboratory parameters, body mass index, bodyweight, heart rate and blood pressure showed no statistically significant changes due to the treatment. CONCLUSIONS: This is the first report of a new drospirenone-only oral contraceptive providing clinical efficacy similar to combined oral contraceptives, with a good safety profile, and favorable cycle control.

Bleeding patterns with the 19.5 mg LNG-IUS, with special focus on the first year of use: implications for counselling.

Objective: The aim of the study was to provide an additional, detailed description of early bleeding patterns with the 19.5 mg levonorgestrel-releasing intrauterine system (LNG-IUS). Methods: We conducted a pooled analysis of the bleeding diaries of participants in a previously reported phase II randomised controlled study (n = 741) and a phase III study (n = 2904), with 2-year extension phase (n = 707), of the 19.5 mg LNG-IUS. Main outcome measures were the median number of bleeding and/or spotting days per 30-day reference period for 12 months and the influence of the previous contraceptive method and levonorgestrel dose on bleeding patterns. Results: The pooled analysis comprised 1697 women. There was a progressive decline in the number of bleeding and/or spotting days from month 1: the proportion of women with ≤4 bleeding and/or spotting days per month increased from 6.2% in month 1 to 15.8% in month 2, 26.0% in month 3, 39.3% in month 6 and 54.1% in month 12. The median number of bleeding and/or spotting days in month 1 was lowest in women who had previously been using an LNG-IUS. Conclusion: Analysis of bleeding diaries using 30-day reference periods provides detailed insight into bleeding changes in the first months following placement of the 19.5 mg LNG-IUS. This insight may prove useful when counselling women about contraceptive choice and method continuation.

[Efficacy and safety of low-dose levonorgestrel-releasing intrauterine system in Chinese women: a multicenter, single-arm, open labeled interventional trial].

Objective: To evaluate the efficacy, bleeding profile and safety of low-dose levonorgestrel-releasing intrauterine system (LNG-IUS 8) in Chinese healthy women of childbearing age. Methods: A multi-center, open-label, single-arm clinical trial conducted at 16 centres in China enrolled 773 healthy women of childbearing age (mean age 31.6 years old, range 18 to 40 years old) , who demanded contraception, from April 2006 to June 2013. All women placed LNG-IUS 8 for 3 years and then been followed up at 3, 6, 9, 12, 18, 24, 30, 36 months. The efficacy variables including pregnancy rate and expulsion rate were analyzed using life table, while observing adverse events (AE) to evaluate the safety. The bleeding profile happened during the study was assessed using 90-day reference intervals (World Health Organization criteria) . Results: Eight pregnancies occurred among 773 women, resulting in a overall Pearl index of 0.42 per 100 women years. The 3-year cumulative pregnancy rate was 0.37 per 100 women years and the 3-year cumulative expulsion rate was 1.99 per 100 women years. The number of women with bleeding/spotting reduced and the bleeding/spotting days declined over time. Totally 219 AE were reported related to LNG-IUS 8 placements. The most common AE were vaginal bleeding (8.2%, 63/773) and the ovarian cyst (6.2%, 52/773) . LNG-IUS 8 had an improving effect on dysmenorrhea that the percentage of women with dysmenorrhea as well as the days of dysmenorrhea decreased over time. The percentage of women satisfied or very satisfied with LNG-IUS 8 was 87.2% (622/713) . Conclusion: LNG-IUS 8 is highly effective and safe for Chinese healthy women of childbearing age.

Twelve month follow-up of a contraceptive implant outreach service in rural Papua New Guinea.

BACKGROUND: Poor access to contraception contributes to persistently high maternal mortality rates in Papua New Guinea (PNG). Since 2012 contraceptive implants have been provided to women in rural areas of PNG through outreach services but follow-up data in these communities on continuation and acceptability is lacking. OBJECTIVE: To gain insight into women's experience with contraceptive implants by assessing the acceptability, satisfaction, 12 month continuation rates and efficacy of contraceptive implants among women in rural PNG. MATERIAL AND METHODS: We undertook a cross-sectional survey of women in two rural provinces who had received a contraceptive implant at least 12 months prior using a structured questionnaire. We sought information on device continuation rates, satisfaction scores, side effects and failure rates. RESULTS: Of the 860 women surveyed, 97% (n = 836) still had the device in situ after 12 months and 92% (n = 793) were very happy with it. Seventy-six percent of women (n = 654) reported no side effects. Irregular bleeding was the most commonly reported side effect (n = 178, 20.6%) but only 7% (n = 13) said the bleeding was bothersome. Documented failure rates were 0.8% although pregnancy at the time of insertion could not be excluded in any of these cases. CONCLUSION: Twelve month implant follow-up data in this study showed high continuation rates and high levels of satisfaction among a rural population in PNG. Implants have the potential to lower maternal morbidity and mortality and simultaneously address the unmet need for contraception in these communities.

Tamoxifen for the treatment of breakthrough bleeding with the etonogestrel implant: a randomized controlled trial.

OBJECTIVE: The etonogestrel (ENG) subdermal implant can cause frequent breakthrough bleeding in some users. The objective of this study was to evaluate whether a short course of tamoxifen reduces bleeding/spotting days compared to placebo in ENG implant users. STUDY DESIGN: In this double-blind trial, we randomized ENG implant users with frequent or prolonged bleeding or spotting to tamoxifen 10 mg or placebo twice daily for 7 days, to be started after 3 consecutive days of bleeding/spotting. Treatment was repeated as needed up to three times in 180 days. Subjects completed a daily text message bleeding diary. A sample size of 56 provided 80% power to detect a difference of 6 days of bleeding/spotting per 30 days by two-sample t test. Ovulation was monitored by urinary metabolites of progesterone. RESULTS: From March 2014 to February 2015, 56 women enrolled. Fifty-one completed at least 30 days of follow up, and 34 completed 180 days. Compared to women randomized to placebo, women randomized to tamoxifen reported 5 fewer days of bleeding/spotting over 30 days (95% confidence interval [CI] -9.9 to -0.05, p=.05), and 15.2 more continuous bleeding-free days (95% CI 2.8-27.5 days, p=.02) after first use of study drug. Conclusions could not be drawn after 30 days due to higher-than-expected dropout. No ovulation was detected. CONCLUSION: First use of tamoxifen by ENG implant users reduces bleeding/spotting days and provides a longer cessation of bleeding/spotting than placebo, without compromising ovulation suppression. Further study is needed to determine whether this effect is maintained with repeat use. IMPLICATIONS: Women with frequent ENG implant-related breakthrough bleeding may experience a reduction in bleeding/spotting days and an increase in continuous bleeding-free days in the month following first use of tamoxifen. This short course of tamoxifen was well tolerated with bleeding cessation noted within a median of 5 days.

A single-arm phase III study exploring the efficacy and safety of LNG-IUS 8, a low-dose levonorgestrel intrauterine contraceptive system (total content 13.5 mg), in an Asia-Pacific population.

OBJECTIVE: The objective was to evaluate the efficacy and safety of a low-dose levonorgestrel intrauterine system with total content 13.5 mg (average approximately 8 µg/24 h over the first year; LNG-IUS 8; Jaydess®) in an Asia-Pacific population. STUDY DESIGN: An open-label, single-arm phase III study conducted at 25 centers in China, Australia and Korea assessed LNG-IUS 8 use over 3 years in nulliparous and parous women (N=1114) aged 18-40 years with regular menstrual cycles (21-35 days). Primary outcome was pregnancy rate, expressed as the Pearl Index. Secondary outcomes included 3-year cumulative failure rate, treatment-emergent adverse events (TEAEs), discontinuation rate, bleeding profile and placement pain. RESULTS: The full analysis set comprised 925 women (mean age 31.6 years, 6.4% nulliparous). Overall unadjusted Pearl Index was 0.35 (95% confidence interval 0.15-0.70); the 3-year cumulative failure rate was 0.9% (95% confidence interval 0.4-1.9). TEAEs and study drug-related TEAEs were reported in 70.1% and 31.2% of women, respectively. Overall, 27.9% of women discontinued the study, 16.9% due to adverse events. Frequent or prolonged bleeding (World Health Organization criteria) decreased from the first to the twelfth 90-day reference intervals (from 5.0% to 0.7% and from 44.1% to 3.0%, respectively), and the percentage of women with amenorrhea increased over time (from 0.4% to 10.8%). Pain on placement was reported as "none" or "mild" in 91.9% of women. CONCLUSIONS: LNG-IUS 8 was an effective and well-tolerated contraceptive method, providing another option for women in the Asia-Pacific region. IMPLICATIONS: In this phase III study, LNG-IUS 8 was shown to be highly effective and well tolerated in an Asia-Pacific population and was not associated with any new or unexpected safety events. LNG-IUS 8 provides another contraceptive option for women in the Asia-Pacific region.

Pooled analysis of two randomized, open-label studies comparing the effects of nomegestrol acetate/17ß-estradiol and drospirenone/ethinyl estradiol on bleeding patterns in healthy women.

OBJECTIVES: To obtain more precise and detailed information regarding the bleeding patterns of nomegestrol acetate (NOMAC)/17ß-estradiol (E2) and drospirenone/ethinyl estradiol (DRSP/EE) and to identify whether baseline demographic characteristics were associated with unscheduled bleeding, absent scheduled bleeding, or amenorrhea. STUDY DESIGN: This analysis pooled results from two pivotal open-label, randomized trials that compared bleeding patterns of NOMAC/E2 and DRSP/EE. In the two studies 4317 women aged 18-50 years from 24 countries across the Americas, Europe, and Asia underwent treatment. RESULTS: 2835 women taking NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen and 938 women taking DRSP/EE (3 mg/30 µg) in a 21/7-day regimen had at least 1 evaluable cycle for vaginal bleeding analyses. The frequency of absent scheduled bleeding was higher (p<.0001) for women using NOMAC/E2 than DRSP/EE across all 11 cycles (cycles 2-12), ranging between 17.6% and 31.6% and between 3.4% and 5.8%, respectively. For women who had absent scheduled bleeding in cycles 2, 3, or 4 the incidence of absent scheduled bleeding in subsequent cycles was high and ranged between approximately 50%-60% for NOMAC/E2 and approximately 40%-50% for DRSP/EE. Amenorrhea increased over time with both regimens, being higher with NOMAC/E2. Both absent scheduled bleeding and amenorrhea with NOMAC/E2 were more common in older women, overweight women, switchers, and smokers; unscheduled bleeding was more common in starters, but had no association with age, body mass index, and smoking. CONCLUSIONS: NOMAC/E2 is associated with a higher prevalence of absent scheduled bleeding compared with DRSP/EE. Absent scheduled bleeding and amenorrhea were associated with age, body weight, switching and smoking. Unscheduled bleeding was more common in starters. IMPLICATIONS: Information about the factors associated with bleeding patterns may help clinicians provide guidance to women considering use of the NOMAC/E2 oral contraceptive.

Iatrogenic metrorrhagia after the use of itraconazole for onychomycosis.

We present first case report on itraconazole, a drug very commonly used for onychomycosis, used along with simvastatin that caused metrorrhagia. The suggested probable mechanism is the inhibition of steroidogenesis, especially estrogens that resulted in low-estrogen breakthrough bleeding. This article emphasizes the importance of drug interaction check prior the initiation of onychomycosis treatment.

Co-administration of St. John's wort and hormonal contraceptives: a systematic review.

OBJECTIVES: St. John's wort (SJW) is a known strong inducer of the cytochrome P450 (CYP) 3 A4 enzyme, and both the ethinyl estradiol and progestin components of hormonal contraceptives are substrates of CYP3A4. This systematic review examined whether the co-administration of SJW and hormonal contraceptives leads to significant safety or efficacy concerns. STUDY DESIGN: Systematic review. METHODS: PubMed and Cochrane Library databases were searched for articles of any comparative study design (clinical or pharmacokinetic) that examined potential interactions between SJW and hormonal contraceptives in women of reproductive age. RESULTS: Of the 48 identified articles, four studies met inclusion criteria and compared use of combined oral contraceptives (COCs) alone to the use of COCs co-administered with SJW. Two studies demonstrated no change in markers of ovulation, but one study demonstrated increased follicular growth and probable ovulation when COCs were co-administered with SJW. Three studies demonstrated an increased risk of breakthrough bleeding with COCs and SJW. Three studies showed changes in at least one pharmacokinetic parameter that suggested a significantly decreased exposure to hormone concentrations when COCs were co-administered with SJW. The only study that did not demonstrate any significant pharmacokinetic differences examined a SJW product containing a low amount of hypericin. CONCLUSION: Limited evidence showing increased risk of ovulation and breakthrough bleeding raises concern for decreased contraceptive efficacy when COCs are co-administered with SJW. The pharmacokinetic evidence is mixed but suggests that SJW administration may be associated with weak to moderate induction of the metabolism of COCs.

Combined oral contraceptive treatment for bleeding complaints with the etonogestrel contraceptive implant: a randomised controlled trial.

OBJECTIVE: Estimate symptom improvement rate of women with bleeding complaints using the etonogestrel contraceptive implant when started on continuous combined oral contraceptives (COC). METHODS: We conducted a double-blinded randomised controlled trial of women reporting troublesome bleeding related to their etonogestrel contraceptive implant and desiring intervention. Participants received continuous COCs or placebo for four weeks to evaluate self-reported bleeding improvement at four weeks. Participants could continue study treatment or prescribed COCs for another eight weeks if desired. We planned to enroll 130 participants between two sites (80% power to detect a 20% effect size at a 0.05 significance level, with 10% loss to follow up). RESULTS: We closed the study after enrolling 26 participants due to recruitment futility. All women on COCs and 75% of placebo users reported bleeding improvement at four weeks (p = 0.09), with 92% and 42%, respectively, reporting significant improvement (p = 0.03). The median number of days until bleeding stopped for at least four days in COC and placebo users was 1 day (range 1-9) and 4.5 days (range 1-28), respectively (p = 0.63). Eight (75%) COC and five (42%) placebo users opted to continue study treatment (p = 0.41). Despite bleeding improvement, women who desired implant removal at enrollment were more likely to re-request removal than those who initially considered other interventions (3 of 5 [60%] vs 1 of 17 [6%], p = 0.03). CONCLUSION: Although women who have troublesome bleeding while using the contraceptive implant may experience improvement with no treatment over 4 weeks, women using COCs are more likely to report significant improvement. Clinicaltrials.gov registration number: NCT01963403.