Oral Contraceptive Formulations Research Articles

Protective role of Eclipta alba L. extract against ethinylestradiol induced genotoxic damage in cultured human lymphocytes

In India, natural preparations derived from plants are widely used for the treatment of various diseases. Hence it becomes necessary to assess the modulating action of the plant extracts when associated with other substances. Ethinylestradiol is not only a genotoxic agent but also a tumor initiating agent. It is widely used in oral contraceptive formulations and also for the treatment of various sexual and metabolic disorders. In the present study, the antigenotoxic effect of Eclipta alba was evaluated against the genotoxic effect induced by 10 μM of ethinylestradiol in the presence of metabolic activation using mitotic index (MI), chromosomal aberrations, sister chromatid exchanges and replication index (RI) as parameters. The treatment of 10 μM of ethinylestradiol along with 1.02x10–4, 2.125x10–4, 3.15x10–4 and 4.17x10–4 g/mL of Eclipta alba (E. alba) extract in culture medium results in a significant dose dependent decrease in the genotoxic effects induced by the treatment of 10 μM of ethinylestradiol. The results of the present study suggest that the plant extract per se does not have genotoxic potential, but can modulate the genotoxicity of ethinylestradiol in cultured human lymphocytes.

Use of nitroanilines for spectrophotometric determination of ethinylestradiol in pharmaceutical formulations

Three nitroanilines (2-methoxy-4-nitroaniline, 2,4-dinitroaniline and 2-methyl-4-nitroaniline) were tested as spectrophotometric reagents for determination of ethinylestradiol (ETE). The determinations were based on absorbance measurments of the reaction product obtained from the coupling of each diazotized nitroaniline with ETE. Optimization of temperature, pH and diazotization coupling reaction time was realized. 2-Methyl-4-nitroaniline provided the more sensitive system for ETE spectrophotometric determination at 531 nm and the analytical response was linear in the concentration range of 0.65–10.0 µg ml−1. The limit of detection and coefficient of variation were estimated as 197 µg l−1 and 4.5%, respectively. The results showed that the proposed method is simple and rapid, allowing selective determination of analyte. The method successfully determined ETE in oral contraceptive formulations.

Oral Contraceptive Use and Breast Cancer: A Prospective Study of Young Women

Previous studies convincingly showed an increase in risk of breast cancer associated with current or recent use of oral contraceptives from the 1960s to 1980s. The relation of contemporary oral contraceptive formulations to breast cancer risk is less clear. We assessed lifetime oral contraceptive use and the specific formulations used among 116,608 female nurses ages 25 to 42 years at enrollment in 1989, and subsequently updated this information every 2 years. We related this information to risk of breast cancer up to June 1, 2001. During 1,246,967 person-years of follow-up, 1,344 cases of invasive breast cancer were diagnosed. Past use of any oral contraceptive was not related to breast cancer risk [multivariate relative risk (RR), 1.12; 95% confidence interval 0.95-1.33]. Current use of any oral contraceptive was related to a marginally significant higher risk (multivariate RR, 1.33; 95% CI, 1.03-1.73). One specific formulation substantially accounted for the excess risk: the RR for current use of triphasic preparations with levonorgestrel as the progestin was 3.05 (95% CI, 2.00-4.66; P < 0.0001). Current use of oral contraceptives carries an excess risk of breast cancer. Levonorgestrel used in triphasic preparations may account for much of this elevation in risk. Different oral contraceptive formulations might convey different risks of breast cancer; ongoing monitoring of these associations is necessary as oral contraceptive formulations change.

Oral Contraceptive Use and Estrogen/Progesterone Receptor–Negative Breast Cancer among African American Women

Oral contraceptive formulations have changed over time, making it relevant to assess the effect of more recent formulations on breast cancer risk. In addition, some studies have found stronger positive associations of oral contraceptive use with estrogen receptor-negative (ER(-)) than with ER-positive (ER(+)) breast cancer. We carried out the first assessment of the effect of oral contraceptive use on the incidence of breast cancer classified by receptor status among African American women, a group disproportionately affected by ER(-) cancer. We followed 53,848 Black Women's Health Study participants from 1995 to 2007 through biennial health questionnaires, in which participants reported information about incident breast cancer, oral contraceptive use, and breast cancer risk factors. Pathology information was obtained on receptor status for 789 incident cases. Incidence rate ratios (IRR) with 95% confidence intervals (95% CI) were derived from Cox regression models with control for confounding factors. Ever use of oral contraceptives was more strongly associated with ER(-)PR(-) breast cancer (279 cases; IRR, 1.65; 95% CI, 1.19-2.30) than with ER(+)PR(+) cancer (386 cases; IRR, 1.11; 95% CI, 0.86-1.42). The risk of ER(-)PR(-) breast cancer increased with increasing duration of use among recent users. These results indicate that the oral contraceptive formulations used in recent decades increase breast cancer risk in African American women, with a greater effect for ER(-) than ER(+) cancer. Mechanisms to explain the adverse influence of oral contraceptive use on ER(-) breast cancer need to be elucidated.

Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: A meta-analysis

Background Women with BRCA1 or BRCA2 mutations are at increased risk of breast and ovarian cancer. Oral contraceptives (OC) use has been associated with a reduction in ovarian cancer risk and with a moderately increased breast cancer risk, which tends to level off in the few years after stopping. The association between oral contraceptive and BRCA1 or BRCA2 gene mutations carriers is unclear. Methods We performed a comprehensive literature search updated to March 2010 of studies on the associations between OC users and breast or ovarian cancer for ascertained BRCA1/2 carriers. We obtained summary risk estimated for ever OC users, for duration of use and time since stopping. Results A total of 2855 breast cancer cases and 1503 ovarian cancer cases, carrying an ascertained BRCA1/2 mutation, were included in our meta-analyses, based on overall 18 studies. Use of OC was associated with a significant reduced risk of ovarian cancer for BRCA1/2 carriers (summary relative risk (SRR) = 0.50; 95% confidence interval (CI), 0.33–0.75). We also observed a significant 36% risk reduction for each additional 10 years of OC use (SRR: 0.64; 95% CI, 0.53–0.78; P trend < 0.01). We found no evidence of a significant association between OC and breast cancer risk in carriers (SRR: 1.13; 95% CI, 0.88–1.45) and with duration of use. OC formulations used before 1975 were associated with a significant increased risk of breast cancer (SRR: 1.47; 95% 1.06, 2.04), but no evidence of a significant association was found with use of more recent formulations (SRR: 1.17; 95% 0.74, 1.86). Conclusions OC users carrying an ascertained BRCA1/2 mutation have a reduced risk of ovarian cancer, proportional to the duration of use. There is no evidence that recent OC formulations increase breast cancer risk in carriers.

New low-dose, extended-cycle pills with levonorgestrel and ethinyl estradiol: an evolutionary step in birth control

To review milestones in development of oral contraceptive pills since their introduction in the US 50 years ago in order to better understand how a new formulation with low-dose estrogen in an extended-cycle pattern fits into the evolution of birth control pills. This is a review of trends in the development of various birth controls pills and includes data from phase III clinical trials for this new formulation. The first birth control pill was a very high-dose monophasic formulation with the prodrug estrogen mestranol and a first-generation progestin. Over the decades, the doses of hormones have been markedly reduced, and a new estrogen and several different progestins were developed and used in different dosing patterns. The final element to undergo change was the 7-day pill-free interval. Many of these same changes have been made in the development of extended-cycle pill formulation. The newest extended-cycle oral contraceptive formulation with 84 active pills, each containing 20 μg ethinyl estradiol and 100 μg levonorgestrel, represents an important evolution in birth control that incorporates lower doses of estrogen (to reduce side effects and possibly reduce risk of thrombosis), fewer scheduled bleeding episodes (to meet women's desires for fewer and shorter menses) and the use of low-dose estrogen in place of placebo pills (to reduce the number of days of unscheduled spotting and bleeding). Hopefully, this unique formation will motivate women to be more successful contraceptors.

Endocrinological, metabolic and clinical features of treatment with oral contraceptive formulation containing ethinylestradiol plus chlormadinone acetate in nonobese women with polycystic ovary syndrome

Background Chlormadinone acetate (CMA) is a progestin compound similar to progesterone, with antiandrogenic properties. In healthy eumenorrheic women, it was demonstrated that the monophasic estroprogestin formulation containing CMA (2 mg) plus ethinyl estradiol (EE) (30 mcg) (EE30+CMA) is efficacious both in reducing hyperandrogenic symptoms, fat mass and in improving lipoprotein panel, without changes in insulin-glucose metabolism. These metabolic properties are important for women affected by polycystic ovary syndrome (PCOS) in whom there is a predisposition to insulin resistance. Study Design We studied whether in young nonobese women with PCOS (15 subjects, EE30+CMA-PCOS group) a six-cycle treatment with EE30+CMA can reduce androgen levels, androgen bioavailability and the score of hirsutism and acne, and modify glucose-insulin metabolism evaluated by the oral glucose tolerance test and the body composition evaluated by bio-impedenziometry. These parameters were evaluated before (first visit) and during the sixth cycle of EE30+CMA (second visit). All the results were compared with those of a matched-age-group of nonobese PCOS women (15 subjects, no OC-PCOS group) evaluated before (first visit) and after six menstrual cycles in which they did not use any drug or oral contraceptive (second visit). Results In the EE30+CMA-PCOS group women, androgen levels and bioavailability, hirsutism and acne score were significantly lower at the second than at the first visit, whereas they did not change in no OC-PCOS group. At the second visit, in both groups, glucose-insulin metabolism and body composition parameters were not affected. Conclusions A six-cycle treatment with EE30+CMA is efficacious in nonobese PCOS women to improve hyperandrogenic symptoms, without negative interferences both on body composition and on insulin-glucose metabolism.

The Effect of Atazanavir/Ritonavir on the Pharmacokinetics of An Oral Contraceptive Containing Ethinyl Estradiol and Norgestimate in Healthy Women

Coadministration of oral contraceptives with protease inhibitors is complicated by drug interactions. An open-label three-period single-sequence study assessed the effect of coadministration of atazanavir (ATV)/ritonavir (RTV) with Ortho Tri-Cyclen(®) and with Ortho Tri-Cyclen(®) LO (Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ, USA) on the pharmacokinetics (PK) of ethinyl estradiol (EE), norgestimate (NGM), ATV and RTV. A total of 20 healthy women aged 18-45 years received study treatments. In the lead-in period and in period 1, participants received a full cycle of Ortho Tri-Cyclen (EE 35 μg with NGM 0.18/0.215/0.25 mg) from days 1-28. In period 2, participants received a full cycle of Ortho Tri-Cyclen LO (EE 25 μg with NGM 0.18/0.215/0.25 mg) plus ATV/RTV (300/100 mg once daily) on days 29-42. PK assessments were performed on days 14 and 42 in periods 1 and 2, respectively. ATV/RTV with dose-normalized EE/NGM resulted in geometric mean reductions of 16% in EE peak plasma concentration (C(max)), 19% in EE area under the concentration-time curve for a dosing interval (AUC([τ])) and 37% in EE lowest plasma concentration (C(min)), compared with EE 35 μg with NGM in the absence of ATV/RTV. NGM with EE and ATV/RTV 300/100 mg once daily resulted in increases of approximately 68%, 85% and 102% in 17-deacetyl NGM C(max), AUC((τ)) and C(min), respectively. Two participants discontinued the study because of adverse events. ATV/RTV with Ortho Tri-Cyclen was well-tolerated and reductions in EE were not predicted to decrease contraceptive efficacy if the formulation contained ≥30 μg of EE.

High-calcium diet reduces blood pressure, blood volume and preserves vasorelaxation in oral contraceptive-treated female rats

Cardiovascular complications are the major clinical challenges among users of synthetic steroids in oral contraceptive (OC) formulations. Interventions that reduce blood volume and improve vasorelaxation have been shown to reduce hypertension and the associated risk factors. The aim of the present study was to investigate the influence of increasing dietary calcium from 0.9 to 3.0% on the development of OC-induced high blood pressure and associated changes in female Sprague-Dawley rats treated with a combination of OC steroids (1 μg ethinyl estradiol and 10 μg norgestrel; p.o.) daily for 10 weeks. Results showed that OC administration led to significant increases in blood pressure, blood volume and cardiac weight. Conversely, OC caused significant reductions in body weight, urinary excretion of water, plasma levels of calcium, 17β-estradiol and progesterone. Increased dietary calcium attenuated the elevation in blood pressure induced by OC and abrogated the associated changes in blood volume, cardiac weight, plasma calcium and urinary excretion of water. The endothelium-dependent relaxation responses to acetylcholine and endothelium-independent relaxation responses to sodium nitroprusside in noradrenaline-precontracted aortic rings were not significantly different among the groups. The results indicate that increased calcium intake abrogated the development of high blood pressure and associated increased blood volume and cardiac weight during OC treatment. The beneficial effect of increased dietary calcium during OC use may be explained by improved diuretic and preserved vasorelaxant responses.

International Active Surveillance Study of Women Taking Oral Contraceptives (INAS-OC Study)

BackgroundA 24-day regimen of contraceptive doses of drospirenone and ethinylestradiol (DRSP/EE 24d) was recently launched. This regimen has properties which may be beneficial for certain user populations (e.g., women suffering from premenstrual dysphoric disorder or acne). However, it is unknown whether this extended regimen has an impact on the cardiovascular risk associated with the use of oral contraceptives (OCs). The INternational Active Surveillance study of women taking Oral Contraceptives (INAS-OC) is designed to investigate the short- and long-term safety of the new regimen in a population which is representative for the typical user of oral contraceptives.Methods/DesignA large, prospective, controlled, non-interventional, long-term cohort study with active surveillance of the study participants has been chosen to ensure reliable and valid results. More than 2,000 gynecologists in the US and 5 European countries (Austria, Germany, Italy, Poland, and Sweden) will recruit more than 80,000 OC users. The two to five year follow-up of these women will result in at least 220,000 documented women-years.The main clinical outcomes of interest for the follow-up are deep venous thrombosis, pulmonary embolism, acute myocardial infarction and cerebrovascular accidents. Secondary objectives are general safety, effectiveness and drug utilization pattern of DRSP/EE 24d, return to fertility after stop of OC use, as well as the baseline risk for users of individual OC formulations.Because of the non-interference character of this study, potential participants (first-time users or switchers) are informed about the study only after the decision regarding prescription of a new OC. There are no specific medical inclusion or exclusion criteria. Study participation is voluntary and a written informed consent is required. After the baseline questionnaire, follow-up questionnaires will be mailed to the participants every 6 months for up to 5 years after baseline. Self-reported serious adverse events will be validated by contacting the relevant physician and by reviewing relevant source documents. At the end of the study an independent blinded adjudication of relevant clinical outcomes will be conducted.Meanwhile, this study has received ethical approval from the Western Institutional Review Board (USA) and the Medical Association in Berlin (Germany).DiscussionThe feasibility of the study is considered to be very high because of its similar design to the EURAS-OC study. All relevant methodological and logistical features of the study were successfully tested in the EURAS study.The chosen design minimizes the impact of referral and misclassification bias, healthy user effect and loss to follow-up. Overall, it is expected that the study design is robust enough to interpret hazard ratios of 1.5 or higher.

Effect of Laropiprant, a PGD2 Receptor 1 Antagonist, on Estradiol and Norgestimate Pharmacokinetics After Oral Contraceptive Administration in Women

Laropiprant is a prostaglandin D2 receptor 1 antagonist that is being developed in combination with niacin for the treatment of dyslipidemia. This randomized clinical study evaluated the effect of laropiprant on the pharmacokinetics of ethinyl estradiol (EE) and norelgestromin (NGMN), the principal circulating metabolite of norgestimate, in healthy women receiving 3 or more months of an oral contraceptive (Ortho Tri-Cyclen; Ortho-McNeil Pharmaceutical, Raritan, NJ), which contains EE and norgestimate. Twenty-one female subjects with normal menstrual cycles received the oral contraceptive on Days 1 to 21 during two consecutive contraceptive cycles. Subjects received double-blind 40 mg/day laropiprant or placebo on Days 1 to 21 of each contraceptive cycle. Plasma samples were collected predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose on Day 21 to measure area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24hr) and maximum concentration observed in plasma (Cmax) of EE and NGMN. Comparability would be declared if the 90% confidence intervals for the geometric mean ratio of AUC0-24hr and Cmax in the absence and presence of laropiprant were within predefined bounds (0.80-1.25). The estimated geometric mean ratios (90% confidence intervals) of EE and NGMN, respectively, were 1.08 (1.04-1.13) and 0.97 (0.94-0.99) for AUC0-24hr and 1.16 (1.06-1.27) and 1.00 (0.94-1.06) for Cmax. The 90% confidence intervals for the geometric mean ratio of EE Cmax minimally exceeded the prespecified bounds; the other relevant pharmacokinetic parameters fell within the predefined bounds. Coadministration of 40 mg laropiprant with the oral contraceptive did not lead to clinically meaningful alterations in the pharmacokinetics of EE or NGMN.

Oral contraceptives in migraine

Combined oral contraceptives are a safe and highly effective method of birth control, but they can also raise problems of clinical tolerability and/or safety in migraine patients. It is now commonly accepted that, in migraine with aura, the use of combined oral contraceptives is always contraindicated, and that their intake must also be suspended by patients suffering from migraine without aura if aura symptoms appear. The newest combined oral contraceptive formulations are generally well tolerated in migraine without aura, and the majority of migraine without aura sufferers do not show any problems with their use; nevertheless, the last International Classification of Headache Disorders identifies at least two entities evidently related to the use of combined oral contraceptives: exogenous hormone-induced headache and estrogen-withdrawal headache. As regards the safety, even if both migraine and combined oral contraceptive intake are associated with an increased risk of ischemic stroke, migraine without aura per se is not a contraindication for combined oral contraceptive use. Other risk factors (tobacco use, hypertension, hyperlipidemia, obesity and diabetes) must be carefully considered when prescribing combined oral contraceptives in migraine without aura patients, in particular in women aged over 35 years. Furthermore, the exclusion of a hereditary thrombophilia and of alterations of coagulative parameters should precede any decision of combined oral contraceptive prescription in migraine patients.

Follicular development in a 7-day versus 4-day hormone-free interval with an oral contraceptive containing 20 mcg ethinyl estradiol and 1 mg norethindrone acetate

Background Combined oral contraceptive (COC) formulations with 20 mcg ethinyl estradiol (EE) have a greater incidence of ovarian hormone production and follicular development, which can be managed by shortening the number of hormone-free days per COC cycle. This study evaluates differences in follicular development during a 7-day versus 4-day hormone-free interval in a COC regimen with 20 mcg EE and 1 mg norethindrone acetate. Study Design Forty-one healthy women were randomized in an open-label fashion to this formulation in either a 24/4 or a 21/7 day regimen for three cycles. Estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone and inhibin B were measured daily from Cycle 2, Day 21 to Cycle 3, Day 3 and on Day 7 of Cycle 3. Follicular diameter and Hoogland score were calculated on Cycle 2, Days 21, 24 and 28 and Cycle 3, Days 3 and 7. Results Sixty-six percent of subjects in the 21/7 group and 70% of the subjects in the 24/4 group developed a follicle greater than 10 mm diameter. Ovarian steroid hormone levels, Hoogland scores and bleeding patterns were not statistically significant between the groups. Conclusion In contrast to prior studies, this analysis suggests no difference in follicle development or bleeding patterns among women receiving a 21/7 or 24/4 regimen of a 20-mcg EE/1-mg norethindrone acetate COC.

Liver Dysfunction in Turner Syndrome: Prevalence, Natural History and Effect of Exogenous Estrogen

Women with Turner syndrome (TS), one of the commonest sex chromosomal abnormalities, are at increased risk of impaired liver function as manifested by elevated liver enzymes, but its clinical significance remains uncertain. Factors contributing to increased liver function tests (LFTs) were investigated in 3 studies: A cross-sectional review of liver function in 125 women with TS whose median age was 31 years. A longitudinal study of 30 women with TS who were followed-up for 8 years on average. A dose-response study of 14 women with TS and 11 control women with hypogonadism who received 17-β-estradiol in doses of 1, 2, and 4 mg daily cyclically for 12 weeks each. The enzymes measured included γ-glutamyl transferase (GGT), alanine aminotransferase (ALT), and alkaline phosphatase. Compared with a control population, 91% of women with TS had elevated liver enzymes. The annual incidence was 2.1%. In the cross-sectional study, the enzyme most frequently elevated was GGT. LFTs correlated positively with cholesterol levels and body mass index. Increasing doses of hormone replacement therapy were associated with significant reductions in GGT, ALT, bilirubin, and albumin. Exogenous estrogen, whether in the form of oral contraception or HRT, improved liver function. There was no evidence of hepatic autoimmunity apart from anti-smooth muscle antibodies in 2.2% of individuals. Previous studies using reference ranges rather than matched control subjects may have underestimated the frequency of elevated liver enzymes in women with TS. The investigators believe that hepatic dysfunction in women with TS is probably a form of hepatic steatosis. Estrogen therapy should continue despite the presence of liver dysfunction, and there may be reason to increase the estrogen replacement dose.

Oestrogens and Crohn’s disease: the missed link

Observational studies, sometimes, can not provide us with clear answers for very important questions. The answer for a question on whether sex hormones in general, and oestrogen in particular, play some role in inducing and development of Crohn's disease is uncertain. Study design, inclusion criteria, and different formulations of oral contraceptives may partly explain the conflict results of the published reports. But these may be due to the divergent effects of oestrogen, which are based on dose, tissue specificity and cellular environment. This paper is aimed at examining the influence of androgens on the prognosis of Crohn's disease.

Hormonal contraceptive discontinuation patterns according to formulation: investigation of associations in an administrative claims database

Background Hormonal contraceptive use is generally characterized by poor adherence and relatively high discontinuation. This study investigated whether specific hormonal contraceptive formulations and/or delivery systems might be correlated with discontinuation of contraception. Study Design This was a retrospective descriptive analysis within a large administrative claims database. The sample included women aged 15–40 years with a pharmacy benefit and at least one new hormonal contraception prescription during the study period and no prescription in the previous 6 months. Filled contraceptive prescriptions were grouped into several categories of delivery system, dosage, progestin type and monophasic vs. triphasic formulations. In each, a baseline number of women was established who filled a first prescription for a contraceptive formulation in the specified category. Then, the percentage of these women who filled a prescription for a contraceptive in the same category within 3 months' time was determined. Continuation or change rates were compared within each group. Results Oral contraceptives (OCs) were the least likely to be discontinued at 3 months; injectables were the most likely. OC formulations associated with increased risk of discontinuation (odds ratios above 1.3 representing a 5% or higher increased discontinuation) included very-low-dose (20–25 mcg ethinyl estradiol) pills containing norethindrone acetate or norgestimate, as compared to a preparation with the same progestin type but with a higher dose of estrogen. Desogestrel and norethindrone-containing triphasics were more likely to be discontinued than other triphasic progestins. OC formulations with desogestrel and norethindrone/norethindrone acetate were more likely than formulations with other progestins to be discontinued overall. Conclusions This investigation in a sample of nearly 250,000 women suggests possible associations between discontinuation of hormonal contraception and factors such as estrogen dosing, progestin type and changes in dosage during the cycle. Identification of factors correlated with contraceptive discontinuation may inform management and improve adherence.

Novel ethinyl estradiol-beta-cyclodextrin clathrate formulation does not influence the relative bioavailability of ethinyl estradiol or coadministered drospirenone

Background A new combined oral contraceptive formulation has been developed consisting of a beta-cyclodextrin (betadex) clathrate formulation of ethinyl estradiol in combination with drospirenone (EE-betadex clathrate/drsp). In this novel EE-betadex clathrate/drsp preparation, betadex serves as an inert complexing agent to enhance stability and shelf-life. The study was conducted to investigate the relative bioavailability and pharmacokinetic parameters of EE and drsp after oral administration of EE-betadex clathrate/drsp. Methods This was an open-label, randomized, single-dose, three-period, three-treatment, crossover study conducted in 18 healthy postmenopausal women aged 45–75 years. The women received single oral doses of 40 mcg EE/6 mg drsp formulated as EE-betadex clathrate/drsp or EE/drsp (EE as a free steroid) tablets, or as a microcrystalline suspension on three separate occasions. Serum samples were collected for pharmacokinetic analyses. Results The relative bioavailability of EE and drsp after EE-betadex clathrate/drsp tablet administration was comparable with that achieved with the EE/drsp tablet (107% and 101%, respectively). In addition, the inclusion of EE in a betadex clathrate does not affect the pharmacokinetics of either EE or drsp. There were no safety concerns with any of the medications. Conclusion The betadex clathrate formulation of EE, when combined with DRSP, does not affect the pharmacokinetics and relative bioavailability of either EE or drsp.

Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol for contraception and control of menstrual symptoms

Considerable recent interest has focused on new methods of delivery of oral contraceptives that reduce or eliminate the hormone-free interval in order to improve convenience and acceptability, but maintain contraceptive efficacy, minimize side effects and reduce or eliminate the frequency of withdrawal bleeding episodes. Studies in several countries, including the US, have documented that many women would prefer to have no episodes of withdrawal bleeding when using oral contraceptives. This review focuses on a unique oral contraceptive formulation containing levonogestrel 90 μg and ethinyl estradiol 20 μg, approved for use in a continuous dosing regimen designed to eliminate withdrawal bleeding throughout the entire year.

A continuous regimen of levonorgestrel/ethinyl estradiol for contraception and elimination of menstruation

Clinicians and patients desiring amenorrhea for therapeutic or social reasons will find continuous-use 90 microg levonorgestrel/20 microg ethinyl estradiol to be an attractive oral contraceptive dosing option. Although other formulations of oral contraceptives can be dosed in a continuous manner off-label, the convenience of a 28-day dose pack represents a major advance that will likely increase acceptability of the strategy. The availability of FDA-approved continuous-use 90 microg levonorgestrel/20 microg ethinyl estradiol will help mainstream continuous oral contraception in the same way that Preven and Plan B helped legitimize and mainstream emergency contraception. Patients wishing to use continuous 90 microg levonorgestrel/20 microg ethinyl estradiol must recognize and accept that unscheduled breakthrough bleeding is typical during the first four to six cycles of use. Control of cycle-related symptoms may emerge as an off-label indication for use.

Drospirenone/ethinyl estradiol

Drospirenone 3 mg/ethinyl estradiol 20 microg (24/4) is a new unique oral contraceptive formulation that combines in a novel dosing regimen the lowest dosage of ethinyl estradiol commonly used today with drospirenone, an innovative progestin. Drospirenone is a compound closely resembling progesterone, but with the antimineralocorticoid and antiandrogenic properties of a related therapeutic agent, the diuretic, antihypertensive and androgen receptor antagonist, 17alpha-spironolactone. The prolongation of hormonally active pills in the monthly drospirenone/ethinyl estradiol cycle from 21 days to 24 days, followed by 4 days of inactive pills, is an interesting variant of the recently developed extended pill regimens (1). Recent contraceptive research has focused on improving side effect profiles and providing noncontraceptive health and lifestyle advantages. Many of these benefits are now supported with evidence-based medicine (2). Most available oral contraceptives improve cycle regularity, menstrual pain, excessive menstrual flow and acne. However, weight gain, bloating, food cravings, breast tenderness and mood alterations (especially irritability and depression and the complex of affective, behavioral and somatic symptoms of premenstrual syndrome [PMS] and the severe form of PMS, premenstrual dysphoric disorder [PMDD]) are not generally improved with the traditional oral contraceptive formulations (3). Drospirenone/ethinyl estradiol 24/4 is currently the only hormonally based contraceptive regimen with large, randomized, controlled trials demonstrating efficacy for PMDD. It has received U.S. Food and Drug Administration (FDA) indications not only for the prevention of pregnancy but also for PMDD and for moderate acne vulgaris in women who choose oral contraception for birth control (4, 5).