Ethinylestradiol 30microgram / Desogestrel 150microgram tablets

BackgroundVenous thromboembolism (VTE) poses a significant global health challenge, notably exacerbated by the use of combined oral contraceptives (COCs). Evidence mainly focuses on the type of progestogen used in COCs to establish the increased risk of VTE with less data assessed on the type of estrogen used. This meta-analysis aims to assess the risk of VTE associated with COCs containing synthetic estrogens like ethinylestradiol (EE) versus natural estrogens like estradiol (E2).MethodsA systematic review and meta-analysis was conducted following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Literature searches were performed in December 2023 in MEDLINE and EMBASE to identify clinical studies comparing the VTE risk between COCs containing synthetic versus natural estrogens. Studies were selected through rigorous screening, and data extraction followed standardized protocols, with statistical analyses employing a random effects model.ResultsThe search yielded five relevant studies, involving over 560,000 women/time, demonstrating a significant 33% reduction in VTE risk among users of natural estrogen-based COCs compared to synthetic estrogen-based COCs (OR 0.67, 95% CI 0.51-0.87). Stratification analyses using adjusted hazard ratios (HR) of the main observationnal studies showed a 49% reduced VTE risk of E2-based pills compared to EE in association with levonorgestrel.Discussion and conclusionDespite the longstanding use of EE-based COCs, emerging evidence supports a lower thrombotic risk associated with natural estrogens. This meta-analysis substantiates the lower VTE risk associated with natural estrogen-based COCs compared to synthetic alternatives, advocating for a re-evaluation of contraceptive guidelines to prioritize patient safety and reduce thrombotic risks.

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Breakthrough bleeding (BTB) is a common side effect of hormonal contraception and is thought to impact adherence to combined oral contraceptives (COCs) but respective dose-response relationships are not yet fully understood. Therefore, the objective of this model-based meta-analysis (MBMA) was to establish dose-response for COCs containing different progestin/EE combinations using BTB as the pharmacodynamic endpoint. Data from 25 studies containing BTB information of 4 progestins (desogestrel, drospirenone, gestodene, and levonorgestrel) in combination with ethinyl estradiol (EE) at various dose levels was used for this analysis. The results of our MBMA show that BTB is significantly increased upon initiation of COC use but subsides over time. The time needed for BTB to return to baseline depends on the EE dose and differs marginally between progestins during the initial months of use at the same EE dose. BTB typically returns to baseline within 3 months at the highest (30 μg) dose, whereas it can take significantly longer to reestablish a regular bleeding pattern at lower EE doses (15 and 20 μg), irrespective of the progestin used. The dose-response relationships established for BTB across different progestin/EE combinations can now be used to support the selection of optimal COC dosing/treatment regimens and serve as the scientific basis for evaluating the impact of clinically relevant factors, including drug-drug interactions and demographics, on BTB.

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BackgroundCombined oral contraceptives (COCs) increase venous thromboembolism (VTE) risk, depending on estrogen type, dose, and progestin. While epidemiological studies provide insight into these risks, they require years to complete. The normalized activated protein C sensitivity ratio (nAPCsr), a standardized assay of acquired activated protein C resistance, has emerged as a potential biomarker of COC-induced VTE risk.ObjectivesTo develop a population-based in silico model predicting VTE risk associated with various COC formulations based on their mean nAPCsr values.MethodsWe analyzed 200 plasma samples from non-COC users and 257 from users of 9 different COCs. We constructed an exponential model to correlate the mean nAPCsr of 5 COCs with their available population-based VTE relative risk, as extracted from a published meta-analysis. We assessed model performance using R 2, Spearman's rank correlation coefficient, and the root mean square error, and performed a sensitivity analysis by excluding COC nonusers. We then estimated population-based VTE risks for the 4 COCs not used in model construction.ResultsThe model demonstrated high predictive accuracy (R2 = .96; root mean square error = 0.21; Spearman correlation coefficient = 1) and remained robust despite group size imbalance. Predicted VTE risks for ethinylestradiol 30 μg with dienogest 2 mg, ethinylestradiol 20 μg with drospirenone 3 mg, estradiol 1.5 mg with nomegestrol acetate 2.5 mg, and estetrol 15 mg with drospirenone 3 mg were 4.36, 3.43, 1.50, and 1.45, respectively, consistent with or complementary to existing epidemiological evidence.ConclusionOur model, based on mean nAPCsr, provides a reliable, biomarker-based approach for predicting population-based COC-related VTE risk. This strategy could help shorten the time between product launch and population-based risk assessment.

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AimThis systematic review aimed to assess the efficacy and safety of Drospirenone and Ethinylestradiol Tablets (II) in the treatment of dysmenorrhea.MethodsElectronic databases, namely PubMed, Embase, Cochrane Controlled Register of Trials (CENTRAL), Scopus, Science, CBM, CNKI, Wanfang, and VIP, were searched before September 2022. Randomized controlled trials (RCTs), non-randomized controlled trials, cohort studies, case-control studies, and single-arm studies were included. Furthermore, the Cochrane Risk of Bias Tool for Systematic Reviews version 1 was used for the risk of bias assessment on RCTs. The Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool was used for risk of bias assessment on non-randomized studies. The risk ratio (RR) was calculated for dichotomous data. Mean difference (MD) or standardized MD (SMD) were used as the effect size for continuous data.ResultsA total of 11 studies involving 2,251 participants with dysmenorrhea were included. When Drospirenone and Ethinylestradiol Tablets (II) conventional 24/4-day regimen was compared with placebo, the total efficiency rate (defined as pain symptom disappearing or being relieved) in Drospirenone and Ethinylestradiol Tablets (II) 24/4-day regimen group was higher than in placebo group (RR = 5.55, 95%CI: 2.48-12.39, P P > 0.05).ConclusionDrospirenone and Ethinylestradiol Tablets (II) could improve symptoms of dysmenorrhea and decrease other related pain symptoms. More high-quality evidence is needed to confirm the advantages.Systematic review registration[https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021271605], identifier [CRD42021271605].

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BackgroundCurrent guidelines for polycystic ovary syndrome (PCOS) recommend combined oral hormonal contraceptives as first-line pharmacological treatment to reduce androgen excess and to treat clinical hyperandrogenic skin manifestations, such as hirsutism. However, these are used off-label. We aimed to demonstrate the efficacy of a prolonged-release oral formulation in a 24/4-day regimen for up to nine 28-day consecutive cycles compared with placebo for the clinical management of hirsutism in women with PCOS.MethodsThis was a multinational, multicentre, double-blind, placebo-controlled trial done across 46 sites in Czech Republic, Hungary, Lithuania, Poland, Serbia, Slovakia, Spain and Ukraine. Eligible participants were 2-year-post-menarche women (14-40 years old) with a body mass index (BMI) of 18 to 2 who were diagnosed with clinical hyperandrogenism (adapted modified Ferriman-Gallwey [mFG] score ≥7) plus oligomenorrhea of ≤6 menses per year and/or polycystic ovary morphology. Enrolled participants were randomised (4:1) to prolonged-release once-daily oral dienogest 2 mg (DNG) + ethinylestradiol 0.02 mg (EE) in a 24/4-day regimen (DNG + EE group) or placebo for up to nine 28-day cycles. Co-primary endpoints were: (1) the change from baseline in the adapted mFG score at the end of Cycle 9 or at the early discontinuation visit (EDV), and (2) proportion of responders, defined as participants with an adapted mFG score reduction of 50% from baseline to the end of Cycle 9/EDV. An adapted mFG score was used to assess for specific regions of body hair. No facial hair was assessed. We used a mixed-model repeated measure (MMRM) analysis that was repeated for BMI subgroups ≤30 or >30 kg/m2 but without BMI stratification. Adverse events and safety were monitored throughout. This study is registered with EudraCT, 2021-002178-17.FindingsBetween Nov 2, 2021, and Dec 5, 2023, of 500 patients screened, 305 participants were enrolled and randomised to study groups and 202 participants completed the trial to the end of Cycle 9. The safety set comprised 291 participants (DNG + EE, n = 234; placebo, n = 57) and 256 participants were included in the full analysis set (FAS; DNG + EE, n = 209; placebo, n = 47). 76 (DNG + EE) and 27 (placebo) participants discontinued the trial early, including 18 and four who discontinued due to adverse events; 168 and 34 participants, respectively, completed the trial. Least squares (LS) mean changes from baseline to end of Cycle 9/EDV in adapted mFG score were -3.8 and -1.5 for the DNG + EE and placebo groups, respectively (difference -2.24 ± 0.49 (98.75% CI: -∞, -1.14; p 30 kg/m2 BMI subgroups, the LS mean changes from baseline in adapted mFG score were -3.8 and -3.7 for DNG + EE-treated participants, and -1.9 and -0.6 for placebo, respectively; LS mean treatment group differences were -1.9 (98.75% CI -∞, -0.7; p = 0.0004) and -3.14 (98.75% CI -∞, -0.9; p = 0.0011), respectively (MMRM, FAS). No new safety signals for DNG + EE were observed. The proportion of treatment-emergent adverse events (TEAEs) was similar between study groups. The most frequent TEAEs were headache (n = 49, 17%), intermenstrual bleeding (n = 41, 14%), and nasopharyngitis (n = 33, 11%). Serious TEAEs were reported for six participants (2%): five participants (2%) in the DNG + EE group (abdominal pain [n = 2], pain in extremity [n = 1], hypoesthesia [n = 1] and pulmonary embolism [n = 1]) and one participant (2%) in the placebo group (vestibular neuronitis).InterpretationOur findings show that oral prolonged-release DNG 2 mg plus EE 0.2 mg in a 24/4-day regimen for up to 9 cycles is an effective treatment for hirsutism in women with PCOS, with an acceptable safety profile. Further research is required to assess DNG + EE in treating hirsutism among different cultural and ethnic populations as well its impact on mood disorders (depression and anxiety) in women with hirsutism-associated PCOS.FundingChemo Research S.L.

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Many factors must be considered and discussed with women when initiating a contraceptive method and the risk of venous thromboembolism (VTE) is one of them. In this review, we discuss the numerous strategies that have been implemented to reduce the thrombotic risk associated with combined oral contraceptives (COCs) from their arrival on the market until today. Evidences suggesting that COCs were associated with an increased risk of VTE appeared rapidly after their marketing. Identified as the main contributor of this risk, the dosage of the estrogen, i.e., ethinylestradiol (EE), was significantly reduced. New progestins were also synthetized (e.g., desogestrel or gestodene) but their weak androgenic activity did not permit to counterbalance the effect of EE as did the initial progestins such as levonorgestrel. Numerous studies assessed the impact of estroprogestative combinations on hemostasis and demonstrated that women under COC suffered from resistance towards activated protein C (APC). Subsequently, the European Medicines Agency updated its guidelines on clinical investigation of steroid contraceptives in which they recommended to assess this biological marker. In 2009, estradiol-containing COCs were marketed and the use of this natural form of estrogen was found to exert a weaker effect on the synthesis of hepatic proteins compared to EE. In this year 2021, a novel COC based on a native estrogen, i.e., estetrol, will be introduced on the market. Associated with drospirenone, this preparation demonstrated minor effects on coagulation proteins as compared with other drospirenone-containing COCs. At the present time, the standard of care when starting a contraception, consists of identifying the presence of hereditary thrombophilia solely on the basis of familial history of VTE. This strategy has however been reported as poorly predictive of hereditary thrombophilia. One rationale and affordable perspective which has already been considered in the past could be the implementation of a baseline screening of the prothrombotic state to provide health care professionals with objective data to support the prescription of the more appropriate contraceptive method. While this strategy was judged too expensive due to limited laboratory solutions, the endogenous thrombin potential-based APC resistance assay could now represent an interesting alternative.

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