Risk-Benefit Assessment of Ethinylestradiol Using a Physiologically Based Pharmacokinetic Modeling Approach.

Current formulations of combined oral contraceptives (COC) containing ethinylestradiol (EE) have ≤35 µg due to increased risks of cardiovascular diseases (CVD) with higher doses of EE. Low-dose formulations however, have resulted in increased incidences of breakthrough bleeding and contraceptive failure, particularly when coadministered with inducers of cytochrome P450 enzymes (CYP). The developed physiologically based pharmacokinetic model quantitatively predicted the effect of CYP3A4 inhibition and induction on the pharmacokinetics of EE. The predicted Cmax and AUC ratios when coadministered with voriconazole, fluconazole, rifampicin, and carbamazepine were within 1.25 of the observed data. Based on published clinical data, an AUCss value of 1,000 pg/ml.h was selected as the threshold for breakthrough bleeding. Prospective application of the model in simulations of different doses of EE (20 µg, 35 µg, and 50 µg) identified percentages of the population at risk of breakthrough bleeding alone and with varying degrees of CYP modulation.

Regulamentação do estrogênio sintético 17-etinilestradiol em matrizes aquáticas na Europa, Estados Unidos e Brasil / Regulación del estrógeno sintético 17-etinilestradiol en matrices acuáticas en Europa, Estados Unidos y Brasil / Regulation of the synthetic estrogen 17-ethinylestradiol in water bodies in Europe, the United States, and Brazil

O estrogênio sintético 17α-etinilestradiol, principal componente utilizado em formulações de contraceptivos orais, tem sido apontado como um dos principais compostos responsáveis por provocar efeitos adversos no sistema endócrino de várias espécies. O objetivo deste estudo foi analisar o estado da arte dos dispositivos legais e normativos referentes ao controle desse estrogênio sintético nas águas da Europa e dos Estados Unidos, e traçar um paralelo com a realidade brasileira. No geral, os países têm buscado ampliar a regulamentação e monitoramento de alguns micropoluentes emergentes que antes não eram objeto de atenção por parte dos dispositivos legais. A Europa está mais avançada no que tange à qualidade dos corpos hídricos, enquanto que nos Estados Unidos esta substância é alvo de regulamentação apenas para a água destinada ao consumo humano. No Brasil, ainda não há nenhum dispositivo legal ou normativo que aborde esse estrogênio, o que pode ser associado a uma baixa maturidade do sistema brasileiro quanto ao controle de poluentes hídricos.

El estrógeno sintético 17α-etinilestradiol, principal componente utilizado en fórmulas de contraceptivos orales, ha sido apuntado como uno de los principales compuestos responsables por provocar efectos adversos en el sistema endócrino de varias especies. El objetivo de este estudio fue analizar el estado de la cuestión de los dispositivos legales y normativos referentes al control de este estrógeno sintético en las aguas de Europa y de los Estados Unidos, y trazar un paralelo con la realidad brasileña. En general, los países han buscado ampliar la regulación y el monitoreo de algunos microcontaminantes emergentes que antes no eran objeto de atención por parte de los dispositivos legales. Europa está más avanzada en lo que se refiere a la calidad de los cuerpos hídricos, mientras que en los Estados Unidos esta substancia es objeto de regulación solamente para el agua destinada al consumo humano. En Brasil todavía no existe ningún dispositivo legal o normativo que aborde este estrógeno, lo que puede ser asociado a una inmadurez del sistema brasileño respecto al control de contaminantes hídricos.

The synthetic estrogen 17α-ethinylestradiol, the principal component of oral contraceptives, has been identified as one of the main compounds accounting for adverse effects on the endocrine system in various species. This study aimed to analyze the state-of-the-art in legislation and guidelines for the control of this synthetic estrogen in water bodies in Europe and the United States and to draw a parallel with the Brazilian reality. Countries have generally attempted to expand the regulation and monitoring of certain emerging micropollutants not previously covered by legislation. Europe is more advanced in terms of water quality, while in the United States this estrogen is only regulated in water for human consumption. Brazil still lacks legal provisions or standards for this estrogen, which can be explained by the relatively limited maturity of the country's system for controlling water pollutants.

Reflections after the Diane affair.

The Pharmacovigilance Centre Lareb received 621 reports of possible adverse drugs reactions on Diane-35® . Of all reports, 388 were received after media attention. Of the 309 reports of thromboembolic adverse drugs reactions, 18 cases were fatal. In 31 cases the thromboembolic adverse drugs reaction was initially not recognized as such. The analysis and the turmoil of the 'Diane affair' gave rise to the following reflections: Reflection 1. Continuous awareness and attention of risk of medicines is needed, also for known risks, for timely recognition of adverse drugs reactions. Reflection 2. Reporting side effects should be part of the professional attitude. Reports play a pivotal role in the detection of new adverse drugs reactions and the conditions under which known adverse drugs reactions occur. Reflection 3. Improvement of adequate use of drugs. Pharmacovigilance not only has the aim to improve knowledge on risk of medicines, but also the aim of getting this knowledge into Health Care practice.

Ethinyl estradiol and 17ß-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment.

The need to seek improved combined oral contraceptive (COC) efficacy, with fewer health risks and better acceptability, has been ongoing since the introduction of COCs more than 50 years ago. New progestin formulations combined with lower doses of ethinyl estradiol (EE), the predominant estrogenic component of COCs, have reduced the incidence of venous thromboembolism and other negative outcomes of COC treatment. Previous attempts to use endogenous 17ß-estradiol (E2) instead of EE were limited primarily by poor cycle control. The recent introduction of E2-based formulations has renewed interest to determine if there are potential benefits of using E2 in COCs. These formulations have been shown to have similar efficacy and cycle control as EE-based COCs. This review provides a brief summary of the pharmacology of EE and E2, including metabolism, pharmacokinetics and pharmacodynamics, as well as adverse effects of these estrogens.

Quantification of the adverse effect of ethinylestradiol containing oral contraceptive pills when used in conjunction with growth hormone replacement in routine practice.

OBJECTIVE: Oestrogen antagonizes the action of growth hormone (GH). For women with combined GH and oestrogen deficiency, transdermal oestradiol is more favourable in this regard compared to oral oestradiol. Oral contraceptive pills containing ethinylestradiol (EE) are commonly used in young women with GHD and there is little information on the impact of this form of oestrogen. DESIGN: A case note review of women with growth hormone deficiency (GHD) attending a tertiary endocrine clinic comparing the dose of GH and serum insulin-like growth factor 1 concentrations and the type of exogenous oestrogen. METHODS: All women with GHD between the ages of 18 and 47 attending University College London Hospitals (UCLH) were included and grouped according to type of oestrogen replacement. Weight, GH dose and serum IGF-I concentrations were recorded at 121 visits in 88 women. RESULTS: The daily dose of GH was significantly higher and the GH responsivity was significantly lower in the EE group compared to those taking no oestrogen and transdermal oestrogen. The additional cost of GH for women using EE compared to transdermal oestradiol was £6016 per patient per year. Effectiveness of GH improved in all women changing from EE to another form of oestrogen. CONCLUSION: Use of oral contraceptive pills containing EE should be avoided in women receiving treatment with GH. Alternative options include oral or transdermal hormone replacement therapy (HRT) preparations for those that require oestrogen replacement or a progesterone-based regimen for contraceptive purposes.

SOGC clinical practice guideline. No. 252, December 2010. Oral contraceptives and the risk of venous thromboembolism: an update.

OBJECTIVE: To provide current and emerging evidence on oral contraceptives and the risk of venous thromboembolism. EVIDENCE: Articles published in English from 2005 were retrieved through searches of PubMed and Medline, using the following terms: venous thromboembolism, VTE, contraception, oral contraceptives, hormonal contraception. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated in the guideline to May 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of evidence was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table). SUMMARY STATEMENTS: 1. Modern oral contraceptives offer highly effective contraception and a range of non-contraceptive benefits. (I) 2. Venous thromboembolism, although rare, remains one of the serious adverse consequences of hormonal contraception. Best evidence indicates that venous thromboembolism rates in non-users of reproductive age approximate 4-5/10 000 women per year; rates in oral contraceptive users are in the range of 9-10/10 000 women per year. For comparison, venous thromboembolism rates in pregnancy approach 29/10 000 overall and may reach 300-400/10 000 in the immediate postpartum period. (II-1) 3. Research demonstrates that oral contraceptives with ≤ 35 µg of ethinyl estradiol carry a lower risk of venous thromboembolism than oral contraceptives with 50 µg. (II-2) Although preliminary data suggest a possible further reduction in venous thromboembolism with oral contraceptives with < 35 µg ethinyl estradiol, robust data to support this conclusion are presently lacking. 4. Recent contradictory evidence and the ensuing media coverage of the venous thromboembolism risk attributed to the progestin component of certain newer oral contraceptive products have led to fear and confusion about the safety of oral contraceptives in general and drospirenone-containing oral contraceptives in particular. "Pill scares" of this nature have occurred in the past, with panic stopping of the pill, increased rates of unplanned pregnancy, and no subsequent decrease in venous thromboembolism rates. (II-3) 5. Two high quality research studies that addressed the venous thromboembolism risk associated with various oral contraceptives found comparable venous thromboembolism rates with drospirenone-containing oral contraceptives and other approved products. (II-1) 6. Two reports suggesting an increased risk of venous thromboembolism with drospirenone-containing oral contraceptives have significant methodological flaws that render their conclusions suspect. It seems likely that residual confounding could have distorted both the results and the conclusions of these reports. (II-3).

A randomized controlled trial of a low-dose combined oral contraceptive containing 3 mg drospirenone plus 20 microg ethinylestradiol in the treatment of acne vulgaris: lesion counts, investigator ratings and subject self-assessment.

OBJECTIVE: To assess the efficacy of a combined oral contraceptive (COC) containing 3 mg drospirenone (drsp) plus 20 microg ethinylestradiol (EE) administered in 24 days of active treatment followed by a four-day hormone-free interval (24/4 regimen) compared with placebo for the treatment of moderate acne vulgaris. METHODS: Healthy females (14-45 years old) with moderate facial acne were randomized to 3 mg drsp/20 microg EE 24/4 (n = 270) or placebo (n = 268) for six cycles. The secondary efficacy variables measured included change from baseline to endpoint (cycle 6) in individual lesion count for nodules, papules, pustules, open and closed comedones. RESULTS: There were significantly greater reductions in individual lesion counts from baseline to endpoint in the 3 mg drsp/20 microg EE group than in the placebo group (P < 0.05 from parametric model). CONCLUSION: The 3 mg drsp/20 microg EE COC administered in a 24/4 regimen significantly reduced acne lesions.

Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol.

CONTEXT: In 2006, we published a study that indicated that the new transdermal contraceptive patch containing ethinyl estradiol (EE) and the progestin norelgestromin did not increase the risk for venous thromboembolism (VTE) compared to oral contraceptive containing norgestimate and 35 microg of EE. OBJECTIVE: This report updates information on the risk of nonfatal VTE in women using the contraceptive patch in comparison to women using oral contraceptives containing norgestimate (either monophasic or triphasic) and 35 microg of EE (norgestimate-35) using an additional 17 months of data. DESIGN, SETTING AND PARTICIPANTS: Nested case-control design based on information from PharMetrics, a US-based company that collects and organizes information on claims paid by managed care plans. The study was nested among all women, aged 15 to 44 years, who started either the contraceptive patch or norgestimate-35 after April 1, 2002. Cases were women with current use of one of these two study drugs and a documented diagnosis of VTE in the absence of identifiable clinical risk factors (idiopathic VTE) who were not in the earlier study. Up to four controls were matched to each case by age and calendar time. MAIN OUTCOME MEASURES: Odds ratios (ORs) comparing the risk of nonfatal VTE in new users of the two contraceptives. RESULTS: We identified 56 new cases of newly diagnosed, idiopathic VTE in the updated study population. The OR comparing the contraceptive patch to norgestimate-35 was 1.1 (95% CI 0.6-2.1). CONCLUSIONS: After evaluating an additional 17 months of data, the results indicate that the risk of nonfatal VTE for the contraceptive patch is closely similar to the risk for oral contraceptives containing 35 mug of EE and norgestimate.

Serum potassium monitoring for users of ethinyl estradiol/drospirenone taking medications predisposing to hyperkalemia: physician compliance and survey of knowledge and attitudes.

PURPOSE: Yasmin-28 [ethinyl estradiol 0.03 mg/drospirenone 3 mg (EE/DRSP)] contains drospirenone, a progestin component that possesses antimineralocorticoid activity with a potassium-sparing diuretic effect similar to that in spironolactone. Product labeling recommends potassium monitoring in the first month of use for women concurrently receiving medication that may increase serum potassium. METHODS: We evaluated compliance with this recommendation by measuring monitoring around the date of oral contraceptive (OC) initiation in women who received EE/DRSP while being treated with medications predisposing to hyperkalemia and in similar women who received other OCs. Because preliminary analyses indicated incomplete compliance, we surveyed physicians who prescribed EE/DRSP to women receiving drugs predisposing to hyperkalemia on their knowledge and attitudes with regard to the recommendation. We conducted this study using data from the Ingenix Research Datamart, which includes insurance claims for reimbursement for medical services and prescription medications for approximately 8,000,000 members of a large nationally dispersed health plan. We used claims for pharmacy dispensings of prescription medications to identify all women aged 10-59 years old who initiated EE/DRSP or other OCs during the first 3 years of EE/DRSP availability (July 2001 to June 2004). The frequency of potassium monitoring was measured by identifying claims for serum potassium tests. We conducted a telephone survey of 58 physicians who had prescribed EE/DRSP up to June 2003 to women who received concomitant hyperkalemic drugs. RESULTS: Although potassium monitoring was generally more frequent among EE/DRSP initiators receiving concomitant hyperkalemic drugs than among other OC initiators receiving similar medications, only 40% of 466 EE/DRSP initiators with concurrent hyperkalemic treatment had potassium tests. More than 98% of surveyed physicians were aware of the potassium-sparing property of EE/DRSP. Compared with physicians whose patients had potassium tests, physicians of patients without such tests were more likely to disagree with the recommendation for users of angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, heparin and nonsteroidal anti-inflammatory drugs. Patient barriers and health plan restrictions were other factors possibly contributing to noncompliance. CONCLUSION: This study demonstrates incomplete physician compliance with a labeling recommendation of potassium monitoring for initiators of EE/DRSP receiving concomitant therapy predisposing to hyperkalemia. The limited compliance was likely due to a combination of selective physician acceptance of the recommendations and specific patient and health plan barriers to testing.

Economic evaluation of norethisterone acetate/ethinylestradiol (FemHRT) for women with menopausal symptoms.

INTRODUCTION: The objective of this study was to assess the cost effectiveness of a continuous combined oral preparation of norethisterone (norethindrone) acetate and ethinylestradiol (NA/EE) [FemHRT] as both a first-line and second-line therapy for menopausal women. PERSPECTIVE: Third-party payer. METHODS: The cost effectiveness of NA/EE was assessed as both a first- and second-line therapy in comparison with conjugated equine oestrogen 0.625mg and medroxyprogesterone acetate 2.5mg (CEE/MPA) and no therapy. Analysis was conducted within a Markov model with states relating to the presence and absence of vaginal bleeding, menopausal symptoms and hip fracture. Analysis forecasted life expectancy, QALYs and lifetime costs for a 50-year-old menopausal woman. Compliance was modelled related to menopausal symptoms and vaginal bleeding. For the base-case analysis, it was assumed that compliant women would take therapy for up to 5 years. Sensitivity analysis assumed therapy was taken only for 1 year. RESULTS: Compared with both CEE/MPA and no therapy, NA/EE led to an increase in both costs and QALYs, both as a first- and second-line therapy. For first-line therapy, the incremental cost per QALY gained for NA/EE was $2200 Canadian dollars ($Can; 1999 values) [compared with no therapy] and was $Can20 300 (compared with CEE/MPA). For second-line therapy, the incremental cost per QALY gained for NA/EE was $Can900 (compared with no therapy) and was $Can16 400 (compared with CEE/MPA). Results were robust to most sensitivity analyses. CONCLUSIONS: NA/EE is a cost-effective therapy for women with menopausal symptoms both as a first-line and second-line therapy.

Evra--a patch on oral contraception?

Evra (Janssen-Cilag) is the first contraceptive to be available as a skin patch. In promotional material aimed at healthcare professionals, the company claims that Evra offers a "once-weekly method of contraception" with "more than 99% effectiveness and excellent compliance". The company's website for women using Evra carries the slogan "Evra The Right Contraceptive Choice" and claims that the patch is "just as effective as the contraceptive pill". Each patch is intended to be worn for 7 days, in contrast to combined oral contraceptives (COCs), which need to be taken daily. Here we assess whether Evra offers real advantages over COCs and consider its place as a contraceptive option.