Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.

BACKGROUND AND OBJECTIVE: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated. METHODS: Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives). RESULTS: After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax. CONCLUSIONS: Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.

Assessment of liver function tests of women taking hormonal contraceptives at University of Gondar comprehensive specialized hospital and Family Guidance Association of Gondar (FGAE), 2022; a comparative cross-sectional study.

INTRODUCTION: Hormonal contraceptives are artificial preparations that contain artificial progestins and Ethinylestradiol; these preparations are utilized by women of reproductive age to prevent pregnancy. Roughly a billion women in the world use some form of contraceptive worldwide. Despite the utility of these preparations, they are linked with several adverse effects, including disturbances of liver functionality and integrity. However, previous studies conducted to assess the association between hormonal contraceptive utilization and liver function tests reported conflicting results, and the effects remained a matter of concern. METHODS: The study enrolled a total of 264 participants, who were allocated into two groups. One group of hormonal contraceptive users who use the medication for a minimum of six months: Depot medroxyprogesterone acetate (DMPA), combined oral contraceptives (COC), Norplant, and Implant users and another age-matched non-user control group in a ratio of 1:1. A semi-structured questionnaire was used to collect socio-demographic, behavioral, and clinical data. Five ml serum blood sample was collected for liver function test analysis on a Beckman Coulter Clinical Chemistry analyzer (DXC 700 AU). Independent t-test was used to compare liver function tests of hormonal contraceptive users and non-user controls, whereas ANOVA followed by a Bonferroni post hoc test was used for intra- (between classes of contraceptives) and inter-group (between each class of contraceptives and controls) comparisons and to identify factors associated. RESULTS: Hormonal contraceptive users were observed to have a statistically significant higher mean value of liver enzymes assessed compared to non-user control groups: aspartate aminotransferase (AST) (47.07±14.79 versus 25.92±7.37; p <0.001), alanine aminotransferase (ALT) (35.83±13.76 versus 16.56 ± 5.03; p <0.001), alkaline phosphatase (ALP) (63.34±14.74 versus 45.41±14.34, p <0.001) and for γ-glutamyl transferase (GGT) (47.37±24.32 versus 19.45 ± 6.86 p <0.001). Similarly, the mean value of total and direct bilirubin (mg/dL) among HC users showed a statistically significant elevation (0.68 ± 0.22 against 0.32 ± 0.13, p <0.001) for total bilirubin and (0.14 ± 0.06 against 0.06 ± 0.03, p <0.001) for direct bilirubin respectively. However, no statistically significant result was observed in the mean values of total protein and albumin. For total protein (6.7 ± 0.89 versus 6.5 ± 1.15, p 0.07) and for albumin (5.4 ± 0.92 versus 5.3 ± 1.08; p 0.30). The current study also indicates the level of hepatic function test alteration is related to the type of hormonal contraceptives, duration of usage, and level of adherence to a specific class of contraceptives. CONCLUSION AND RECOMMENDATION: Hormonal contraceptive use was observed to affect hepatic function. Based on this finding, we strongly recommend to closely monitor liver function tests in women using hormonal contraceptives.

Disparities in utilisation of combined oral contraceptives in Aotearoa New Zealand: A cross-sectional whole-of-population study.

AIMS: The combined oral contraceptive (COC) is the most commonly used hormonal contraceptive in Aotearoa New Zealand (Aotearoa/NZ). Currently there is limited data available on who uses COC in Aotearoa/NZ. The aims were to (i) define the population of reproductive-aged females in Aotearoa/NZ in 2018 and identify the rate of COC use among this group and (ii) describe the sociodemographic and geographic characteristics of the population of COC users compared to the general population of reproductive-aged females in 2018. METHODS: This whole-of-population cross-sectional study used the Integrated Data Infrastructure, a large research database managed by Statistics New Zealand. Females aged 16-50 years with complete sociodemographic and geographic information in 2018 from Aotearoa/NZ's estimated resident population were included. COC dispensing records to this cohort were identified from the national Pharmaceutical Collection. This paper reports descriptive counts of COC use and employs generalised linear regression with a binomial distribution and a log link to estimate adjusted risk ratios (aRR) of COC use for key sociodemographic and geographic subgroups. RESULTS: Of 1 113 750 individuals in the study, 159 789 (14.3%) were dispensed as COC in 2018. European/other individuals were most likely to use COC (aRR: 2.72, 2.67-2.78), and Pacific Peoples were least likely (aRR: 0.56, 0.55-0.58) to use COC. Individuals residing in the most deprived quintile had less COC use than individuals in the least deprived quintile (aRR: 0.73, 0.72-0.74). CONCLUSION: Our study is able to highlight significant disparities in use by ethnicity, area-level deprivation, and geographic factors.

Cost-effectiveness Analysis of Dienogest Compared with Combined Oral Contraceptives after Surgery for Endometriosis.

STUDY OBJECTIVE: To assess the cost-effectiveness of different strategies, including the dienogest (DNG) and combined oral contraceptives (COC) therapy, for the prevention of endometriosis recurrence after surgery. DESIGN: A decision tree model was created. The analysis was based on data from a healthcare provider in China. Model inputs were derived from published data. The end points included incremental cost effectiveness ratio, net monetary benefit (NMB), and incremental NMB associated with prevention of recurrence. The uncertainty was assessed through one way and probabilistic sensitivity analysis. The Consolidated Health Economic Evaluation Reporting Standards 2022 checklist was used to assess quality of the reporting. SETTING: China healthcare system. PATIENTS: Individuals undergoing laparoscopic surgery for endometriosis. INTERVENTIONS: DNG vs COC. MEASUREMENTS AND MAIN RESULTS: The base case analysis showed that hormone supression via DNG resulted in 0.7493 quality-adjusted life years (QALYs) at a cost of $1625.49 compared with COC, which resulted in 0.7346 QALYs at a cost of $343.61. The incremental cost effectiveness ratio was $87 679.89 per additional QALY gained and the DNG treatment was associated with an incremental NMB of -$731.39. Probabilistic sensitivity analysis indicated that DNG is not cost-effective in most cases at a threshold consistent with World Health Organisation recommendations of $37 653/QALY. CONCLUSION: The result of our present analysis suggests that the DNG might not be cost-effective for the prevention of endometriosis recurrence after surgery in China.

Assessment of Quality of Life, Sexual Quality of Life, and Pain Symptoms in Deep Infiltrating Endometriosis Patients With or Without Associated Adenomyosis and the Influence of a Flexible Extended Combined Oral Contraceptive Regimen: Results of a Prospective, Observational Study.

BACKGROUND: The quality of life of women with deep infiltrating endometriosis (DIE) is impaired and may improve with combined oral contraceptives (COCs). AIM: To compare the overall and sexual quality of life of patients diagnosed with DIE with or without associated adenomyosis (AD) with that of healthy controls and determine the influence of a COC containing 2 mg dienogest/30 µg ethinyl estradiol on these aspects. METHODS: We enrolled 42 women diagnosed with DIE; 31 diagnosed with DIE + AD by transvaginal ultrasound, and 39 non-AD/DIE controls. All patients were interviewed regarding pain symptoms (dysmenorrhea, dyspareunia, dyschezia, and dysuria), heavy menstrual bleeding using the Pictorial Blood Loss Assessment Chart, quality of life using the Short Form-36 questionnaire (SF-36), and sexual quality of life using the Sexual Quality of Life-Female questionnaire (SQOL-F) and the Brief Profile of Female Sexual Function (B-PFSF) before starting COCs and after 12 months of treatment. OUTCOMES: There was significant improvement in overall and sexual quality of life after treatment in DIE and DIE + AD patients. RESULTS: Non-AD/DIE controls showed significantly higher scores in the B-PFSF, the SQOL-F and the SF-36 questionnaires (P < .05) at baseline versus the other groups. DIE + AD patients showed poorer quality of sexual life and greater intensity in pain symptoms compared with DIE patients. After 12 months of treatment, there was a significant improvement in overall and sexual quality of life in the DIE and DIE + AD groups, with improvement in sexual quality of life being slightly greater in DIE + AD patients compared with DIE patients. Pain symptoms also decreased in both groups. CLINICAL IMPLICATIONS: Patients with DIE + AD showed greater impairment in overall and sexual quality of life compared with patients with isolated DIE which seems to improve with a COC containing 2 mg dienogest/30 µg ethinyl estradiol. STRENGTHS & LIMITATIONS: Strengths include the long-term follow up, assessment of the impact of two associated conditions, and administration of the same COC in all patients. Limitations include the relatively small sample size, and the fact that we did not assess the effectiveness of a flexible extended COC regimen containing 2 mg dienogest/30 µg ethinyl estradiol since the groups were different at baseline. CONCLUSION: Patients diagnosed with DIE with or without AD have a decreased quality of life which may improve with a COC containing 2 mg dienogest/30 µg ethinyl estradiol. Further research is needed to confirm our results. Alcalde AM, Martínez-Zamora MÁ, Gracia M, et al. Assessment of Quality of Life, Sexual Quality of Life, and Pain Symptoms in Deep Infiltrating Endometriosis Patients With or Without Associated Adenomyosis and the Influence of a Flexible Extended Combined Oral Contraceptive Regimen: Results of a Prospective, Observational Study. J Sex Med 2022;19:311-318.

Knowledge and beliefs about the use/abuse of oral contraceptive pills among males: A mixed-method explanatory sequential study in community pharmacy settings.

BACKGROUND: Oral contraceptive pills (OCPs) are considered one of the most important birth control methods globally. However, these pills were designed for female administration rather than males. This study was designed to investigate patterns of OCPs use and abuse among Jordanian males, according to the community pharmacists' observations. METHOD: A mixed-method explanatory sequential study was conducted using an online self-administered survey, followed by semi-structured in-depth interviews for registered pharmacists, assistant pharmacists and pharmacy interns. The interviews were utilized using a conceptual framework. Inductive thematic analysis and descriptive/regression analyses were completed using Nvivo and SPSS, respectively. RESULTS: A total of 158 questionnaire responses and 22 interviews were included in our analysis. Around half (48.4%) of the questionnaire responses confirmed that males could use OCPs for hair growth enhancement, muscle gain and acne treatment 12.7%, 31.7% and 4.4%, respectively. Through the interviews, the participating pharmacists highlighted that males use OCPs mostly for bodybuilding purposes, according to recommendations by their coaches at the gym. The most abused OCPs containing estrogen (Ethinyl estradiol) and progestins (Drospirenone or Levonorgestrel). CONCLUSION: This study provided insight into unexpected uses of OCPs by males in Jordan. Community pharmacists have a crucial role in the management of OCPs use and abuse. However, restricted regulations and monitoring must be released and implemented on the community to limit such practices.

Quantitative Assessment of Levonorgestrel Binding Partner Interplay and Drug-Drug Interactions Using Physiologically Based Pharmacokinetic Modeling.

Levonorgestrel (LNG) is the active moiety in many hormonal contraceptive formulations. It is typically coformulated with ethinyl estradiol (EE) to decrease intermenstrual bleeding. Due to its widespread use and CYP3A4-mediated metabolism, there is concern regarding drug-drug interactions (DDIs), particularly a suboptimal LNG exposure when co-administered with CYP3A4 inducers, potentially leading to unintended pregnancies. The goal of this analysis was to determine the impact of DDIs on the systemic exposure of LNG. To this end, we developed and verified a physiologically-based pharmacokinetic (PBPK) model for LNG in PK-Sim (version 8.0) accounting for the impact of EE and body mass index (BMI) on LNG's binding to sex-hormone binding globulin. Model parameters were optimized following intravenous and oral administration of 0.09 mg LNG. The combined LNG-EE PBPK model was verified regarding CYP3A4-mediated interaction by comparing to published clinical DDI study data with carbamazepine, rifampicin, and efavirenz (CYP3A4 inducers). Once verified, the model was applied to predict systemic LNG exposure in normal BMI and obese women (BMI ≥ 30 kg/m2 ) with and without co-administration of itraconazole (competitive CYP3A4 inhibitor) and clarithromycin (mechanism-based CYP3A4 inhibitor). Total and free LNG exposures, when co-administered with EE, decreased 2-fold in the presence of rifampin, whereas they increased 1.5-fold in the presence of itraconazole. Although changes in total and unbound exposure were decreased in obese women compared with normal BMI women, the relative impact of DDIs on LNG exposure was similar between both groups.

Decreasing utilization and increasing prices of brand-name oral contraceptive pills: Implications to societal costs and market competition.

The affordability of pharmaceuticals has been a major challenge in US health care. Generic substitution has been proposed as an important tool to reduce the costs, yet little is known how the prices of more expensive brand-name drugs would be affected by an increased utilization of generics. We aimed to examine the trend of overall utilization and the total costs of brand-name oral contraceptive pills (OCPs), the most widely used form of contraception, and its association with the pharmaceutical market concentration among the OCPs. Data from the Medical Expenditure Panel Survey (MEPS) 2011-2014, a nationally representative survey of healthcare utilization, were extracted on the utilization of generic and brand-name OCPs. A multiple logit regression analysis was conducted to assess the trend in utilization of brand-name OCPs over time. Total costs, including the costs to the payers and consumers, were synthesized. The Herfindahl-Hirschman Index (HHI), an index describing market concentration, was constructed, and a multiple regression analysis was conducted to evaluate the association between the brand-name OCP prices and the market share of individual brand-name drugs. The odds of utilizing brand-name drugs decreased steadily in 2012, 2013, and 2014 compared to 2012 (AOR 0.87, 0.73, 0.55, respectively, p<0.05) controlling for patient mix. Despite significant decline in total utilization, there was a 90% increase in the price of brand-name OCPs, resulting an 18% increase in revenue from 2011 to 2014 for the industry. During this time, pharmaceutical market concentration for OCPs increased (HHI increased from 1105 in 2011 to 2415 in 2014). Each percentage point increase in the market share by a brand-name OCPs was associated with a $3.12 increase in its price. Market mechanisms matter. Practitioners and policy makers need to take market mechanisms into account in order to realize the benefits of generic substitutions.

A cohort study of the service-users of online contraception.

BACKGROUND: In January 2017, the first free service providing oral contraceptive pills (OCPs) ordered online and posted home became available in the London boroughs of Lambeth and Southwark - ethnically and socioeconomically diverse areas with high rates of unplanned pregnancy. There are concerns that online services can increase health inequalities; therefore, we aimed to describe service-users according to age, ethnicity and Index of Multiple Deprivation (IMD) quintile of area of residence and to examine the association of these with repeated use. METHODS: We analysed routinely collected data from January 2017 to April 2018 and described service-users using available sociodemographic factors and information on patterns of use. Logistic regression analysis examined factors associated with repeat ordering of OCPs. RESULTS: The service was accessed by 726 individuals; most aged between 20 and 29 years (72.5%); self-identified as being of white ethnic group (58.8%); and residents of the first and second most deprived IMD quintiles (79.2%). Compared with those of white ethnic group, those of black ethnic group were significantly less likely to make repeat orders (adjusted OR 0.53, 95% CI 0.31 to 0.89; p=0.001), as were those of Asian and mixed ethnic groups. CONCLUSIONS: These are the first empirical findings on free, online contraception and suggest that early adopters broadly reflect the population of the local area in terms of ethnic diversity and deprivation as measured by IMD. Ongoing service development should prioritise the identification and removal of barriers which may inhibit repeat use for black and minority ethnic groups.

Economic evaluation of a novel genetic screening test for risk of venous thromboembolism compared with standard of care in women considering combined hormonal contraception in Switzerland.

AIM: The aim of this study was to assess the cost effectiveness of the Pill Protect (PP) genetic screening test for venous thromboembolism (VTE) risk compared with standard of care (SoC), for women considering combined hormonal contraceptives (CHCs) in Switzerland. METHODS: A two-part microsimulation model was developed to estimate VTE events, costs and quality-adjusted life years (QALYs) associated with the PP and SoC strategies. In the first portion of the model, a cohort of 1 million Swiss first-time seekers of a CHC were simulated. It was determined whether each women would receive a CHC or non-CHC by using prescribing patterns elicited from a modified Delphi study. These results formed the basis of the SoC strategy. For the PP strategy, a PP test was included and the results considered in addition to SoC practice. Each woman then entered a Markov model that captured morbidity and mortality over a lifetime. The risk of having a VTE was derived from the risk algorithm that underpins the PP test. The remaining model inputs relating to population characteristics, costs, health resource use, mortality and utilities were derived from published studies or national sources. The model was validated and calibrated to align with population-based studies. Extensive uncertainty analyses were conducted. RESULTS: From a Swiss health system perspective, the PP strategy in comparison with the SoC strategy generated an additional CHF 231, and gained 0.003 QALYs per woman, leading to an incremental cost-effectiveness ratio of CHF 76 610 per QALY gained. Assuming a threshold of CHF 100 000 per QALY gained, the PP strategy is likely to be cost effective. Our results were generally robust to variations in the parameter values. CONCLUSIONS: The PP test may be cost effective in Switzerland for screening women seeking CHCs for their risk of VTE based on the current evidence.

Actualización en anovulatorios orales combinados (AOC) / Update on combined oral anovulatory (AOC)

INTRODUCCIÓN: La anticoncepción, es única entre las intervenciones médicas por sus beneficios potenciales en la salud de las mujeres. Usar métodos eficaces y seguros, reduce la mortalidad materna, da libertad, calidad de vida y mejora la salud y sobrevida de los niños. Prevenir embarazos no planeados es una prioridad para Salud Pública. Por tratarse de una medida preventiva y de uso masivo, deben seleccionarse las prácticas con el mejor balance riesgo/beneficio. Los Anovulatorios Orales combinados (AOC), son los más usados y conocidos en nuestro país. ANTICONCEPCIÓN CON AOC: Es la anticoncepción con píldoras orales que contienen etinil estradiol (EE) combinado con un progestágeno en diferentes formulaciones. Los progestágenos existentes son: norgestrel y levonorgestrel, Desogestrel, Norgestimato, Gestodeno, Drospirenona y los más recientes: Dienogest, Nomegestrol y norelgestromin. AOC DISPONIBLES EN ARGENTINA: La mayoría de las formulaciones contienen EE más levonorgestrel, EE más desogestrel, EE más gestodeno, EE más norgestimato y EE más drospirenona en preparados monofásicos (la misma dosis todos los comprimidos) y bifásicos, trifásicos y multifásicos. Actualmente han sido autorizados para su comercialización en nuestro país, nuevos AOC conteniendo estrógenos diferentes del EE. Los estrógenos usados son: de Estradiol y 17 beta estradiol junto a dos nuevos progestágenos el Dienogest y el nomegestrol. Su efectividad anticonceptiva está probada pero sus perfiles de seguridad no han sido establecidos aún con respecto al EE. RIESGOS PARA LA SALUD: Los riesgos severos para la salud de los AOC están representados por incremento de trombosis venosa profundas y trombosis arteriales. Existe un aumento pequeño del RR de cáncer de mama y cáncer de cuello uterino.4,5. El riego absoluto de trombosis es pequeño, pero es mucho menor en las no usuarias o en las usuarias de progestágenos solos. El riego de trombosis también está asociado al tipo de progestágeno usado, es claramente menor con Levonorgestrel y noretisterona que con cualquiera de los otros progestágenos. BENEFICIOS NO ANTICONCEPTIVOS PARA LA SALUD: Se asocian a reducción del riesgo de cáncer de endometrio y cáncer colorrectal y varios efectos beneficiosos no contraceptivos como: regulación del ciclo con patrones de sangrado menores y predecibles, disminución del dolor menstrual y efectos beneficiosos en el síndrome de ovario poliquístico y la endometriosis. CRITERIOS DE ELEGIBILIDAD: Son los criterios establecidos por La OMS para determinar quiénes pueden o no usar determinados métodos de contracepción según algunas características personales (edad, estado puerperal, etc.) o condiciones de salud. PROVISIÓN Y ACCESIBILIDAD: Los AOC con mejor relación riesgo/beneficio se encuentran en el Formulario Terapéutico Provincial de Neuquén y están disponibles en los centros de salud.

Patterns of prescription and discontinuation of contraceptives for Swedish women with obesity and normal-weight women.

Purpose: This study aimed to explore the prescription of different contraceptive methods to Swedish women with obesity and to compare the pattern of prescription and adherence to treatment between this group and normal-weight women. Materials and methods: This study included 371 women with obesity and 744 matched normal-weight women, aged 18-40. Medical records were scrutinised for the period 1 January 2010 to 31 December 2014. The retrieved variables included: background characteristics, prescribed contraceptive methods, adverse effects, duration of treatment, reason for discontinuation and bleeding pattern. Result: Progestin-only pills were mainly prescribed to women with obesity (44% vs. 20%, p = 0.001) whereas combined hormonal contraception was mainly prescribed to normal-weight women (60% vs. 21%, p < 0.0001). Thirty-three percent vs. 25% (p = 0.003) discontinued their contraceptive method within 1 year. The most commonly declared reason for discontinuation was bleeding disturbance (14.7% vs. 9.6%, p = 0.008). Conclusion: The most commonly prescribed contraceptive method in women with obesity was progestin-only pills, but surprisingly many women with obesity were prescribed combined hormonal contraception despite current Swedish and European guidelines. Incident users with obesity were significantly more likely to discontinue their contraceptive method within the first year of the study period, compared with incident normal-weight users.

Ulipristal acetate compared to levonorgestrel emergency contraception among current oral contraceptive users: a cost-effectiveness analysis.

OBJECTIVE: To estimate the cost-effectiveness of ulipristal acetate (UPA) and levonorgestrel (LNG) emergency contraception (EC) on pregnancy prevention among combined oral contraceptive (COC) pill users with an extended pill-free interval. We accounted for the potential interaction of COCs and obesity on EC efficacy. METHODS: We built a decision-analytic model using TreeAge software to evaluate the optimal oral EC strategy in a hypothetical cohort of 100,000 twenty-five-year-old women midcycle with a prolonged "missed" pill episode (8-14 days). We used a 5-year time horizon and 3% discount rate. From a healthcare perspective, we obtained probabilities, utilities and costs inflated to 2018 dollars from the literature. We set the threshold for cost-effectiveness at a standard $100,000 per quality-adjusted life-year. We included the following clinical outcomes: number of protected cycles, unintended pregnancies, abortions, deliveries and costs. RESULTS: We found that UPA was the optimal method of oral EC, as it resulted in 720 fewer unintended pregnancies, 736 fewer abortions and 80 fewer deliveries at a total cost savings of $50,323 and 79 additional adjusted life-years. UPA continued to be the optimal strategy even in the case of obesity or COCs impacting UPA efficacy, in which a COC interaction would have to change efficacy of UPA by 160% before LNG was the dominant strategy. CONCLUSION: Our models found that UPA was the dominant choice of oral EC among COC users with a prolonged "missed" pill episode, regardless of body mass index or an adverse interaction of COCs on UPA. IMPLICATIONS: Ulipristal acetate is the dominant choice of oral emergency contraception among combined oral contraceptive users.

Effects of Estrogen Therapies on Outcomes in Turner Syndrome: Assessment of Induction of Puberty and Adult Estrogen Use.

CONTEXT: Turner syndrome (TS) is often associated with delayed puberty. To induce puberty, estrogen is administered in incremental doses at an age determined by age of presentation. After puberty, various types of maintenance estrogen replacement therapy (ERT) are used. OBJECTIVE: We sought associations between age of induction of puberty and type of ERT on adult health outcomes. DESIGN: Health surveillance data included blood profiles, bone density, and blood pressure. We assessed interactions between these data and age at first estrogen exposure in women with primary amenorrhea. We also assessed these data according to ERT subgroups [combined oral contraceptive pill (OCP), oral estrogen (OE), and transdermal estradiol (TE)] using data from each of 6679 clinic visits, controlling for age, body mass index, and height. SETTING: Adult TS clinic at University College London Hospital. PATIENTS: Of 799 women with TS, 624 had primary amenorrhea and 599 had accurate maintenance ERT data. MAIN OUTCOME MEASURES: Parameters of health surveillance derived from clinical guidelines. RESULTS: Estrogen start age was negatively correlated with adult bone density (spine: r = -0.20 and hip: r = -0.022; P ≤ 0.001). OCP users had higher blood pressure and an adverse lipid profile compared with other ERT subgroups. TE was associated with elevated liver enzymes and hemoglobin A1c compared with OE (P ≤ 0.01). CONCLUSIONS: An earlier age of induction of puberty may be beneficial for adult bone density. Given the high prevalence of hypertension in TS, the use of OCP for ERT should be limited. OE may be a benefit for steatohepatitis.

Altered pharmacokinetics of combined oral contraceptives in obesity - multistudy assessment.

OBJECTIVE: The objective was to evaluate the pharmacokinetics (PKs) of levonorgestrel (LNG)-containing combined oral contraceptives (COCs) in obese women. STUDY DESIGN: We pooled and reanalyzed data from 89 women with different body mass index (BMI) categories from four clinical studies. The LNG and ethinyl estradiol (EE) PKs were analyzed utilizing a zero-order absorption (K0), two-compartment PK model to evaluate key PK parameters in relation to a range of weights, BMI and body surface area (BSA). RESULTS: Increasing of body habitus metrics is correlated with decreasing Cmax (p<.0001) and AUCτ (p<.05) for both LNG and EE, but no correlation was found for Cmin (p≥.17). Increasing weight and BMI were associated with a modest increase (p≤.056) of clearance (CL) and appreciable increases of central volume (V1, p<.05), distribution clearance (CLd, p≤.001) and peripheral volume (V2, p<.0001) for LNG. For EE, increases in CL (p≤.009) were found with greater weight, BMI and BSA. Values of V1, CLd and V2 also increased (p<.0001) in obese subjects. The half-life and steady-state volume were greater among obese women (p<.0001) for both LNG and EE. LNG and EE PK parameters correlated well (p≤.006 for all), indicating that individual subject physiology affected both drugs similarly. CONCLUSIONS: The primary effects of obesity on LNG and EE were a modest increase in CL and a marked increase in distribution parameters. We observed no obesity-related differences in trough LNG and EE concentrations. IMPLICATIONS: This population PK analysis demonstrated reduced systemic exposure to LNG/EE oral contraceptives in obese subjects (Cmax and AUCτ); these particular differences are unlikely to lower contraceptive effectiveness among obese women who are correctly using LNG-containing contraceptives.

Impact of EU risk assessment process and administrative regulations for manufacturers of combined hormonal contraceptive prescribing. An analysis of developments in Germany and the implications.

OBJECTIVE: Combined hormonal contraceptives (CHC) exhibit differing risks for cardiovascular and thrombotic events (VTE). A European referral process confirmed higher VTE risks for 3rd generation gestagens and drospirenone. CHC are now grouped in risk classes (RC) I, II, and III, with RC III having a higher risk than RC I and X (risk not yet known). Marketing authorization holders were obliged to implement pharmacovigilance measures and risk minimization measures including changes of prescribing information. The study assessed whether these activities induced changes in prescription patterns. METHODS: German prescription data for 1.1 million women below 20 years of age were used to analyze the effects of interventions and potential influence factors using logistic regression. Descriptive statistics were calculated for prescriptions for 3.3 million women from January 2011 to March 2016. RESULTS: Shares of RC I and RC X recipients rose substantially over the observation period, while RC III recipient share showed a steady decrease. The referral induced a slightly faster decrease in RC III and increase in RC X. The implementation of pharmacovigilance measures manifested no additional effect. CONCLUSION: The decrease in RC III share already observed before the referral process can be explained with pre-existing discussions around CHC. The effect attributable to the referral was statistically significant, although very small. While evidence for a connection between interventions and prescription change is only indirect, the study shows that routine data are suitable for impact analyses, and monitoring prescribing patterns can be recommended as feedback after regulatory or political interventions. This is being followed up.

Prescription pattern and trend of oral contraceptives in Japan: A descriptive study based on pharmacy claims data (2006 - 2014).

OBJECTIVE: The use of combined oral contraceptives (COC) as a contraceptive method is still limited in Japan, used only by 1.1% of women of reproductive age. The usage pattern of COC, such as continuation and preparation switch, between COC generations was investigated using large datasets. METHODS: This descriptive study spanning from 2006 to 2014 used nationwide prescriptions based on administrative databases, including both reimbursed and non-reimbursed drugs. All the first-time COC users were included as a cohort. Usage patterns considering trends, continuation, and switch of COC generations were also investigated. RESULTS: Of the 38,123 patients, the overall mean age at initial use of COC was 32.9 years. Of the first-time users, 51.2%, 23.7%, 5.6%, and 19.5% received first-, second-, third-, and fourth-generation COCs, respectively. The overall rate of continuation was 59.1%, and the rate of first-time use with switching to other generations within 180 days was 3.1%. CONCLUSION: We revealed the actual usage of COC in Japan with frequent prescriptions of first- or fourth-generation COCs and relatively high age at initial use. Moreover, the COC continuation rate was low, and switch was limited. Further studies into its proper usage are recommended.

A Longitudinal Assessment of Cervical Inflammation and Immunity Associated with HIV-1 Infection, Hormonal Contraception, and Pregnancy.

Hormonal contraception (HC), particularly injectable depot-medroxyprogesterone acetate (DMPA), has been associated with increased HIV acquisition and higher levels of cervical regulated upon activation, normal T-cell expressed, and secreted (RANTES), also associated with HIV seroconversion. Longitudinal changes in cervical immunity associated with DMPA and combined oral contraceptives (COCs) have not been studied. Cervical samples from 216 HIV seroconverters in Uganda and Zimbabwe with matched samples from 727 HIV-uninfected controls were collected at two quarterly visits before (t - 2, t - 1), at (t0), and two visits following (t + 1, t + 2) HIV seroconversion and corresponding visits for HIV-negative controls. We measured 10 biomarkers of inflammation and immunity and used generalized linear models to estimate and compare biomarker levels across HIV status, contraceptive, and pregnancy groups. Biomarkers remained relatively stable across visits for controls, while in HIV-infected women cervical immunity started to change before seroconversion with RANTES and BD-2 increased and secretory leukocyte protease inhibitor (SLPI) decreased at t - 1 and continued to change at t0 with ICAM-1 up and IL-8 down and with more biomarkers after seroconversion (IL-1ß, IL-6, MIP-3α, VEGF, and IL-1RA down and IL-1RA:IL-1ß ratio up). In multivariable analyses, seroconverters had higher BD-2 at t - 1, higher RANTES and lower SLPI from t - 1 through t + 2, and lower IL-8 and IL-1RA at and/or after seroconversion compared to nonseroconverters. Compared to non-HC users, DMPA users had higher RANTES at all visits and lower BD-2 at t - 2 through t0, while COC users and pregnant women had higher IL-8 and SLPI at all visits; COC users also had lower BD-2 preseroconversion; pregnant women had lower RANTES at t0 - t + 2. Longitudinal patterns of cervical immunity differ between HIV seroconverters and HIV-negative women; seroconverters demonstrate increased RANTES and decreased SLPI starting before and continuing postseroconversion. Furthermore, these patterns are differentially regulated by DMPA, COC, and pregnancy.

A systematic review of cost-effectiveness analysis of screening interventions for assessing the risk of venous thromboembolism in women considering combined oral contraceptives.

Use of combined oral contraceptives (COCs) by women increases the risk of venous thromboembolism (VTE), which can have a major impact on an individuals' quality of life. VTE is also associated with an increase in healthcare costs. Our aim was to systematically review cost-effectiveness analyses (CEAs) considering any screening for risk of VTE in women using COCs. The quality of reporting in each study was assessed, a summary of results was prepared, and the key drivers of cost effectiveness in each of the eligible CEAs were identified. A search strategy using MeSH terms was performed in MEDLINE, Embase, the Centre for Review and Dissemination (CRD) database including the Economic Evaluation Database from the UK National Health Service, and Cochrane reviews. Two reviewers independently screened and determined the final articles, and a third reviewer resolved any discrepancies. Consolidated Health Economic Evaluation Reporting Standards was used to assess the quality of reporting in terms of perspective, effectiveness measures, model structure, cost, time-horizon and discounting. Four publications (three from Europe, one from the United States) were eligible for inclusion in the review. According to current criteria, relevant elements were sometimes not captured and the sources of epidemiological and effectiveness data used in the CEAs were of limited quality. The studies varied in terms of type of costs assessed, country settings, model assumptions and uncertainty around input parameters. Key drivers of CEAs were sensitivity and specificity of the test, incidence rate of VTE, relative risk of prophylaxis, and costs of the test. The reviewed studies were too dissimilar to draw a firm conclusion on cost-effectiveness analysis about universal and selective screening in high-risk groups. The new emerging diagnostic tools for identifying women at risk of developing VTE, that are more predictive and less costly, highlight the need for more studies that apply the latest evidence and utilize robust methods for cost-effectiveness analysis. This information is required to improve decision making for this pertinent issue within personalized medicine.