Oral Contraceptive Formulations Research Articles

An Ethinyl Estradiol-Levonorgestrel Containing Oral Contraceptive Does Not Alter Cytochrome P4502C9 In Vivo Activity

Oral contraceptives have been in wide use for more than 50 years. Levonorgestrel, a commonly employed progestin component of combined oral contraceptives, was implicated in drug-drug interactions mediated via CYP2C9. Although in vitro studies refuted this interaction, there are no confirmatory in vivo studies. In the current study, we examined the phenotypic status of CYP2C9 using low-dose (125 mg) tolbutamide before and after oral contraceptive use in reproductive age women. Blood was collected 24 hours after the tolbutamide oral dose was administered, plasma was isolated, and tolbutamide concentration (C24) was measured using liquid chromatography-mass spectrometry. The natural logarithm of tolbutamide C24, a metric for CYP2C9 phenotype, was found to be equivalent (within 80%-125% equivalency boundaries) before and after oral contraceptive use. In conclusion, levonorgestrel-containing oral contraceptives, the most commonly used form of oral contraception, do not affect the status of the CYP2C9 enzyme. This suggests that it is safe to co-administer levonorgestrel-containing oral contraceptives and CYP2C9 substrates, which include a wide array of drugs.

Another Noncontraceptive Benefit of Hormonal Contraception

Although hormone levels in oral contraceptives (OCs) have been reduced dramatically during the last 50 years, concerns that OCs may cause cancer persist. To summarize the world literature on cancer risk associated with use of modern OC formulations, researchers analyzed pooled results from 50 observational studies (23 breast cancer, 9 cervical cancer, 11 colorectal cancer, and 7 endometrial cancers) published since 2000. Overall, OC use was associated with slightly …

Weight and body composition changes during oral contraceptive use in obese and normal weight women.

Oral contraceptive (OC) use seems to have little effect on weight change in normal weight women. Most previous studies have excluded obese women, so the effect of OC use on weight change in obese women is unknown. This analysis evaluates weight and body composition change with OC use among obese (body mass index [BMI] 30.0-39.9) and normal weight (BMI 19.0-24.9) women who were randomly assigned to two OC doses: 20 μg ethinyl estradiol (EE) and 100 μg levonorgestrel (LNG) OCs or 30 μg EE and 150 μg LNG OCs. Follow-up occurred after three to four OC cycles. Weight and body composition were measured at baseline and at follow-up using a bioelectrical impedance analyzer. Among 150 women (54 obese and 96 normal weight) who used OCs for 3 to 4 months, there were no clinically or statistically significant weight or body composition changes in the overall group or by BMI or OC formulation group. These findings add to evidence that EE/LNG OCs are not associated with short term weight or body composition change for normal weight women and suggest that OCs are also are not associated with short term weight or body composition change in obese women.

Risk of venous thrombosis in users of hormonal contraceptives in German gynaecological practices: a patient database analysis

Recent studies showed differences in the risk of venous thrombosis between different combined hormonal contraceptives. Database studies comprising large cohorts can add relevant aspects from daily clinical practice. The purpose of this study was to evaluate different progestogen in combination with ethinylestradiol on the risk of venous thrombosis in Germany. Computerized data from 68,168 contraceptive users in gynecological practices throughout Germany (Disease Analyzer Database) were analyzed. The adjusted odds ratios for risk of thrombosis were estimated in users of different oral contraceptive (OC) formulations relative to users of levonorgestrel-containing preparations. In total, 38 (0.06 %) of the 68,168 contraceptive users had a recorded diagnosis of thrombosis within 365 days after the initial prescription. The adjusted risk was 1.95 for desogestrel (95 % CI 0.52-7.29), 2.97 for dienogest (95 % CI 0.96-9.24), 1.57 for drospirenone (95 % CI 0.46-5.38), 2.54 for chlormadinone (95 % CI 0.72-9.04), and 3.24 for norgestimate (95 % CI 0.59-17.75) compared to levonorgestrel. None of those findings reached statistical significance. The maximum absolute increase versus levonorgestrel was 6 cases per 10,000 women (n.s.). The study shows the low incidence rates of thrombosis in OC users. Since there is no significant difference, this study does not confirm an increased risk but shows only a tendency for this risk of third- and fourth-generation OC versus levonorgestrel-containing products.

Effect of the Coadministration of Daclatasvir on the Pharmacokinetics of a Combined Oral Contraceptive Containing Ethinyl Estradiol and Norgestimate

Daclatasvir is a highly selective NS5A replication complex inhibitor currently in development for the treatment of chronic hepatitis C infection. Daclatasvir is active at picomolar concentrations and demonstrates in vitro activity against a broad range of HCV genotypes. The primary objective of this study was to assess the effect of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate (Ortho Tri-Cyclen(®)). In this open-label single-sequence study, 20 healthy female subjects received ethinyl estradiol and norgestimate for three cycles, with coadministration of daclatasvir in cycle 3. Pharmacokinetics of ethinyl estradiol and the active metabolites of norgestimate (norelgestromin and norgestrel) were assessed in cycles 2 and 3. Adjusted ratios of geometric means and 90% CIs were estimated for the maximum observed plasma concentration (ethinyl estradiol 1.11 [1.02, 1.20], norelgestromin 1.06 [0.99, 1.14] and norgestrel 1.07 [0.99, 1.16]) and area under the plasma concentration-time curve in one dosing interval (ethinyl estradiol 1.01 [0.95, 1.07], norelgestromin 1.12 [1.06, 1.17] and norgestrel 1.12 [1.02, 1.23]). Coadministration of daclatasvir resulted in no clinically relevant effects on exposure to ethinyl estradiol, norelgestromin or norgestrel.

An Evolutionary Approach Offers a Fresh Perspective on the Relationship Between Oral Contraception and Sexual Desire

Concern about the impact of oral contraceptive (OC) use on women’s sexual functioning, particularly lowered sexual desire (or libido), has been expressed for almost as long as OCs have been available. Despite numerous studies over several decades, however, we still do not know the underlying mechanism for negative effects nor can we predict which women will suffer from them (Sanders, Graham, Bass, & Bancroft, 2001). The research has consistently produced mixed evidence, of two kinds. First, there is mixed evidence across studies: some report negative associations between desire and OC use, others find no effect, and still others report positive effects (for recent reviews, see Burrows, Basha, & Goldstein, 2012; Davis & Castano, 2004; Pastor, Holla, & Chmel, 2013; Schaffir, 2006). Second, within their respective samples, studies also consistently report considerable individual variation in women’s experience: relatively large proportions of women experience a marked increase or decrease in desire, with others unaffected (Burrows et al., 2012; Davis & Castano, 2004; Pastor et al., 2013; Schaffir, 2006). For example, in a prospective study, 17 % had a higher frequency of sexual thoughts and 39 % had a lower frequency, following initiation of OC use (Sanders et al., 2001). Understanding this mixed pattern of results would likely benefit from a meta-analytical approach, although this would need to take into account the wide variation between studies in both methodologies and OC formulations under test. Currently, on the basis of these mixed effects, researchers typically conclude that the influence of OC use on sexual desire is complex and likely due to multiple psychosocial influences (Burrows et al., 2012; Davis & Castano, 2004; Pastor et al., 2013; Schaffir, 2006). Indeed, themostrecentreviewconcludedthat‘‘wecannot define a single indicator reliably and clearly characterizing a cause-effect relationship. This is mainly due to thesimultaneous and intertwined effects of a variety of complex biological, psychological, social, and multidimensional factors’’(Pastor et al., 2013). While thismaybeanaccurate reflectionof thecurrentempirical state of affairs, it is clearly unsatisfactory both to women concerned about possible consequences for their relationships and to healthcare providers who are unclear about what advice to give. Perceived changes in libido and arousal are important contributors to OC switching and discontinuation (Sanders et al., 2001). Understanding the mechanism underpinning these mixed effects is therefore of significant public health concern and this is a matter of global importance. According to the UN report on World Contraceptive Use 2011, 9 % of partnered women of reproductive age worldwide report using OC as their main contraceptive method, rising to 18 % in some regions. In the United States, 82 % of sexually experienced women, aged 18–44 years, had used OCat some stage of their lives (Mosher&Jones,2010). Against this background, new perspectives that might help to clarify the issue should be seized upon and scrutinized carefully. The possibilities that modulatory effects on mood or reduced circulatingtestosteronelevels(e.g., throughup-regulationofsex S. C. Roberts (&) School of Natural Sciences, University of Stirling, Stirling FK9 4LA, UK e-mail: craig.roberts@stir.ac.uk

Nomegestrol acetate-17b-estradiol for oral contraception.

Oral contraceptives remain a popular method of contraception over 50 years after their introduction. While safe and effective for many women, the failure rate of oral contraception is about 8%. Concerns about the risk of venous thromboembolism continue to drive the search for the safest oral contraceptive formulations. The oral contraceptive NOMAC-E2 contains nomegestrol acetate (NOMAC) 2.5 mg + 17b-estradiol (E2) 1.5 mg. The approved dosing regimen is 24 days of active hormone, followed by a 4-day hormone-free interval. NOMAC is a progestin derived from testosterone, which has high bioavailability, rapid absorption, and a long half-life. Estradiol, though it has a lower bioavailability, has been successfully combined with NOMAC in a monophasic oral contraceptive. Two recently published randomized controlled trials demonstrate that NOMAC-E2 is an effective contraceptive, with a Pearl Index less than one pregnancy per 100 woman-years. The bleeding pattern on NOMAC-E2 is characterized by fewer bleeding/spotting days, shorter withdrawal bleeds, and a higher incidence of amenorrhea than the comparator oral contraceptive containing drospirenone and ethinyl estradiol. The adverse event profile appears to be acceptable. Few severe adverse events were reported in the randomized controlled trials. The most common adverse events were irregular bleeding, acne, and weight gain. Preliminary studies suggest that NOMAC-E2 does not seem to have negative effects on hemostatic and metabolic parameters. While no one oral contraceptive formulation is likely to be the optimum choice for all women, NOMAC-E2 is a formulation with effectiveness comparable with that of other oral contraceptives, and a reassuring safety profile.

Detection of an estrogen derivative in two breast cancer cell lines using a single core multimodal probe for imaging (SCoMPI) imaged by a panel of luminescent and vibrational techniques

3-Methoxy-17α-ethynylestradiol or mestranol is a prodrug for ethynylestradiol and the estrogen component of some oral contraceptive formulations. We demonstrate here that a single core multimodal probe for imaging - SCoMPI - can be efficiently grafted onto mestranol allowing its tracking in two breast cancer cell lines, MDA-MB-231 and MCF-7 fixed cells. Correlative imaging studies based on luminescence (synchrotron UV spectromicroscopy, wide field and confocal fluorescence microscopies) and vibrational (AFMIR, synchrotron FTIR spectromicroscopy, synchrotron-based multiple beam FTIR imaging, confocal Raman microspectroscopy) spectroscopies were consistent with one another and showed a Golgi apparatus distribution of the SCoMPI-mestranol conjugate in both cell lines.

Benign Hepatocellular Tumors: A Multidisciplinary Approach

Benign Hepatocellular Tumors: A Multidisciplinary Approach

Treatment of Heavy Menstrual Bleeding with the Estradiol Valerate and Dienogest Oral Contraceptive Pill

The new estradiol valerate and dienogest oral contraceptive pill recently received U.S. Food and Drug Administration (FDA) approval to treat heavy menstrual bleeding in women without diagnosed uterine conditions.This oral contraceptive formulation combines estradiol valerate, which is metabolically identical to natural estradiol, with the potent new progestin, dienogest. The four-phasic pill is effective for pregnancy prevention and leads to significantly decreased menstrual bleeding among women with heavy periods, and shorter and lighter periods among women with normal periods. Studies indicate that this formulation may be associated with decreased hepatic activation compared to contraceptive pills that contain ethinyl estradiol. However, whether these findings translate to a decreased risk of thrombotic events has not been determined, and the pill carries the same contraindications as all other combined hormonal contraceptives.At least 10-15% of women suffer from heavy menstrual bleeding, defined as ≥80 mL of blood loss per cycle. In large clinical trials of women with heavy menstrual bleeding, the estradiol valerate and dienogest pill decreased blood loss volume by a median of 81%.Women with heavy menstrual bleeding treated with this contraceptive pill can expect a significant reduction in bleeding after just one cycle of use. This therapy leads to a decrease in bleeding that may be greater than that achieved by different oral contraceptive pills or other medical therapies, including tranexamic acid and nonsteroidal anti-inflammatory drugs.

Role of Inflammation and Aromatase Expression in the Eutopic Endometrium and its Relationship with the Development of Endometriosis

Epigenetic changes favoring the transcription of the aromatase gene in the endometrium allow endometrial cells to survive in ectopic locations by producing estrogens that spare them from destruction through activated macrophages. Local estrogen production hastens prostaglandin synthesis by stimulating COX-2 activity, thus creating a self-perpetuating sequence of augmented estrogen formation and enhanced inflammation. Repetitive retrograde menstruation reintroduces aromatase-positive endometrial cells endowed with the capacity to implant and invade the peritoneum. In order to control endometriosis, an effective medication must inhibit aromatase, block COX-2, decrease fibrosis and induce amenorrhea. Within this framework, progestins, either alone or in the form of oral contraceptives, appear as first-line treatment for endometriosis owing to their capacity to block enzymes such as aromatase and COX-2.

Magnetic Resonance Imaging (MRI) of hormone-induced breast changes in young premenopausal women

ObjectivesWe conducted a pilot study to identify whether MRI parameters are sensitive to hormone-induced changes in the breast during the natural menstrual cycle and whether changes could also be observed during an oral contraceptive (OC) cycle. Materials and MethodsThe New York University Langone Medical Center Institutional Review Board approved this HIPAA-compliant prospective study. All participants provided written informed consent. Participants were aged 24-31 years.We measured several non-contrast breast MRI parameters during each week of a single menstrual cycle (among 9 women) and OC cycle (among 8 women). Hormones were measured to confirm ovulation and classify menstrual cycle phase among naturally cycling women and to monitor OC compliance among OC users. We investigated how the non-contrast MRI parameters of breast fibroglandular tissue (FGT), apparent diffusion coefficient (ADC), magnetization transfer ratio (MTR), and transverse relaxation time (T2) varied over the natural and the OC cycles. ResultsWe observed significant increases in MRI FGT% and ADC in FGT, and longer T2 in FGT in the luteal vs. follicular phase of the menstrual cycle. We did not observe any consistent pattern of change for any of the MRI parameters among women using OCs. ConclusionsMRI is sensitive to hormone-induced breast tissue changes during the menstrual cycle. Larger studies are needed to assess whether MRI is also sensitive to the effects of exogenous hormones, such as various OC formulations, on the breast tissue of young premenopausal women.

Irritable Bowel Syndrome and Drospirenone-Containing Oral Contraceptives; A Comparative-Safety Study

Mineralocorticoids are thought to play a role in tissue repair, including fibrous tissue formation. The antimineralocorticoid activity of spironolactone has been linked to an increased risk of gastrointestinal bleeding. Drospirenone is a synthetic progestin approved in combination with ethinyl-estradiol as an oral contraceptive (OC). It is a spironolactone-derivative, and its antimineralocorticoid effects could irritate the gastrointestinal tract leading to symptoms of irritable bowel syndrome (IBS). A retrospective cohort study was conducted evaluating women 18-46 years of age in the IMS claims-database. New-users of progestin-based OCs were identified between 1997-2009. Ninety days of OC therapy and one year of prior enrollment with no prior diagnosis of IBS were required for inclusion. Cases were identified using a previously validated method for the diagnosis of IBS. Cox proportional hazards models were used to estimate the hazard ratio (HR) for developing IBS with the different OC formulations using levonorgestrel as a reference. The cohort included 939,281 women, averaging 29.1 years of age and 247 days of OC therapy. 3,050 incident cases of IBS were detected. The annualized incidence for IBS with drospirenone was 0.77% (1083 cases) while that for levonorgestrel was 0.46% (483 cases). The crude HR for development of IBS with drospirenone compared to levonorgestrel was 1.70 (95%CI 1.53-1.90), while the adjusted HR was 1.63 (95%CI 1.46-1.82). Multiple sensitivity analyses confirmed this association. Other OCs were unassociated with IBS. Our study found a positive association between drospirenone and a diagnosis of IBS that was not observed with other OCs.

Relationship Between Use of Different Oral Contraceptive Formulations and Breast Cancer Risk Among Young Women

Abstract Purpose: Prior studies suggest that recent oral contraceptive (OC) use is associated with a modest increased risk of breast cancer among young women. However, the majority of these reports have relied on self-reported use and have not characterized risks associated with newer OC formulations. Methods: We conducted a nested case-control study among health plan enrollees at a large health maintenance organization, Group Health Cooperative, which serves the greater Seattle-Puget Sound region. Cases consisted of 1,102 women 20–49 years of age diagnosed with invasive breast cancer from 1990–2009. We randomly selected 21,952 controls matched on age, year, and enrollment length. Detailed information on recent OC use, including formulation, dose, and duration was ascertained from electronic pharmacy records. Multivariate-adjusted conditional logistic regression was used to calculate odds ratios (ORs) as estimates of relative risks and 95% confidence intervals (CIs). Results: Recent OC use (within 1 year of diagnosis) was associated with a 60% (95% CI = 1.3–1.9) increased breast cancer risk. The association was slightly stronger for estrogen receptor (ER) positive compared to ER-negative disease (ER-positive OR = 1.7, 95% CI = 1.3–2.1 and ER-negative OR = 1.2, 95% CI = 0.8–1.8), though this difference was not statistically significant. The ORs varied somewhat by OC formulation, with recent use of OCs containing the progestin ethynodiol diacetate (OR = 2.6, 95% CI = 1.4–4.7) or high dose estrogen (OR = 2.7, 95% CI = 1.2–6.4) associated with particularly elevated risk estimates compared to non-use of OCs in the prior year. In contrast, risk estimates for recent use of OCs with the progestin norgestimate or low dose estrogen suggested either a modest association or no association (OR = 1.2, 95% CI = 0.6–2.2 and OR = 1.0, 95% CI = 0.6–1.7, respectively). Conclusions: These results suggest that recent use of contemporary OC formulations is associated with an elevated risk of breast cancer among women ages 20–49, with associations varying somewhat by OC formulation. Although breast cancer is rare among young women, the potential risk of breast cancer associated with certain formulations could impact OC recommendations by providers if these findings are confirmed.

Oral contraceptive formulation and risk of breast cancer

BackgroundWhile evidence on the association between oral contraceptive (OC) use and breast cancer generally suggests little or no increased risk, the question of whether breast cancer risk varies by OC formulation remains controversial. Few studies have examined this issue because large samples and extensive OC histories are required. Study DesignWe used data from a multicenter, population-based, case–control investigation. Women aged 35–64 years were interviewed. To explore the association between OC formulation and breast cancer risk, we used conditional logistic regression to derive adjusted odds ratios, and we used likelihood ratio tests for heterogeneity to assess whether breast cancer risk varied by OC formulation. Key OC exposure variables were ever use, current or former use, duration of use and time since last use. To strengthen inferences about specific formulations, we restricted most analyses to the 2282 women with breast cancer and the 2424 women without breast cancer who reported no OC use or exclusive use of one OC. ResultsThirty-eight formulations were reported by the 2674 women who used one OC; most OC formulations were used by only a few women. We conducted multivariable analyses on the 10 formulations that were each used by at least 50 women and conducted supplemental analyses on selected formulations of interest based on recent research. Breast cancer risk did not vary significantly by OC formulation, and no formulation was associated with a significantly increased breast cancer risk. ConclusionsThese results add to the small body of literature on the relationship between OC formulation and breast cancer. Our data are reassuring in that, among women 35–64 years of age, we found no evidence that specific OC formulations increase breast cancer risk.

Fifty Years of “the Pill”: Risk Reduction and Discovery of Benefits Beyond Contraception, Reflections, and Forecast

Widely regarded as a revolutionary drug in its early years, "the pill" may be considered the first designer or lifestyle drug. Approximately 85% of women in the United States will use an oral contraceptive (OC) for an average of 5 years. Since the introduction of OCs in the 1960s, both health benefits and safety concerns have been attributed to their use. Widespread use of OC formulations by women throughout their reproductive life cycle gave rise to concerns about the effects of OCs on risk factors for cardiovascular disorders and cancer. In most instances, the noncontraceptive benefits of OCs outweigh the potential risks. As with many first in class drugs, lessons can be learned from its development and use. Indeed, "the pill" played a significant role in reshaping the regulatory process for new drugs during the second half of the 20th century. The birth control pill celebrates its 50th birthday this year, as women and men celebrate five decades of this revolutionary method of family planning. Recent scientific and technological advances in genomics, proteomics, new materials, and new drug delivery systems, along with a new understanding of reproductive biology, offer the promise of new, safe, and effective forms of contraception. In addition to the history of OC therapeutic advances and unintended side effects, the noncontraceptive health benefits that women experience beyond pregnancy prevention are discussed. This article summarizes a symposium presented at the 50th Anniversary of the Society of Toxicology National Meeting, held from 6 to 10 March 2011 in Washington, DC.

Estradiol valerate and dienogest: a new approach to oral contraception

Most combination oral contraceptives contain ethinyl estradiol and a progestin. A new and novel oral contraceptive formulation combines estradiol valerate (E2V) with dienogest (DNG) in a four-phase dosing regimen. 17β-estradiol is a naturally-occurring estrogen, and a contraceptive pill containing such an estrogen offers potential benefits with regard to metabolic side effects and adverse events. Dienogest is derived from 19-nortestosterone and exerts profound progestational effects on the endometrium, but it differs from other progestins in its class by its antiandrogenic activity. Estradiol valerate plus dienogest (E2V/DNG) is now available in a four-phasic regimen that integrates an estrogen stepdown and progestin stepup dosing approach along with a short two-day hormone-free interval. This regimen offers safe, reliable contraception and has been shown to be an effective treatment for heavy menstrual bleeding. Metabolic effects and adverse events appear similar to those reported with oral contraceptives containing ethinyl estradiol.

Plasma factor VII-activating protease is increased by oral contraceptives and induces factor VII activation in-vivo

Oral contraceptive (OC) use influences the hemostatic system significantly and is a risk factor for development of cardiovascular disease. Factor VII-activating protease (FSAP) has potential effects on hemostasis. The 1601GA genotype of the 1601 G/A polymorphism in the FSAP gene expresses a FSAP alloenzyme with reduced pro-fibrinolytic activity. Presently, we address whether OC use and OC formulation affect FSAP measures in human blood. Healthy women (n = 588) were allocated to six cycles of OCs with estrogen contents of 20 μg (n = 158), 30 μg (n = 284), 35 μg (n = 79) or 50 μg (n = 67) combined with various progestins. FSAP genotypes, FSAP and factor VII (FVII) plasma measures were assessed at baseline and after 6 cycles of OC. The 1601GA genotype was present in 49 (8.3%) of the women and was associated with significantly reduced levels of FSAP (P ≤ 0.001). OC use increased FSAP antigen by 25% and FSAP activity by 59% (P < 0.001). The FSAP increase was comparable in the seven different OC treatment groups (P > 0.05). The relative increase in FSAP activity was significantly higher in women carrying the 1601GG genotype (63%) than in women carrying 1601GA genotype (50%) (P = 0.01) and was associated with an increased activation of FVII. In conclusion: OC use increases the plasma measures of FSAP. The increase in FSAP is comparable in the seven OC-groups studied but is more significant in women carrying the 1601GG genotype than in women with the 1601GA genotype and results in increased activation of FVII suggesting that FSAP-induced activation of FVII takes place in-vivo and not only in-vitro as hitherto described.

Influence of alitretinoin on the pharmacokinetics of the oral contraceptive ethinyl estradiol/norgestimate

Alitretinoin (9-cis retinoic acid) is currently registered in many European countries and in Canada as the only licensed treatment for severe chronic hand eczema unresponsive to potent topical corticosteroids. Alitretinoin, like all retinoids, is teratogenic, and women of child-bearing potential must strictly adhere to pregnancy-prevention measures. To investigate the influence of alitretinoin on the pharmacokinetics (PK) of ethinyl estradiol/norgestimate (Ortho Tri-Cyclen 28(®)), a commonly prescribed combination oral contraceptive. In total, 16 healthy premenopausal women received three consecutive cycles of the triphasic contraceptive ethinyl estradiol/norgestimate together with concomitant oral alitretinoin 40 mg once daily during cycle 2. Steady-state PK (noncompartmental analysis) of ethinyl estradiol, 17-deacetyl norgestimate, alitretinoin and its main metabolite 4-oxo-alitretinoin were assessed alone and in combination. The PK profiles of ethinyl estradiol and 17-deacetyl norgestimate were similar when contraceptives were given alone or with alitretinoin, and the area under the plasma concentration vs. time curve and the maximum concentration met the conventional criteria for PK equivalence. Similarly, the influence of ethinyl estradiol/norgestimate on systemic exposure to alitretinoin and 4-oxo-alitretinoin was not clinically relevant. Alitretinoin was well tolerated when given either alone or with ethinyl estradiol/norgestimate. There was no clinically relevant influence of alitretinoin on the PK of ethinyl estradiol/norgestimate, and no influence of ethinyl estradiol/norgestimate on systemic exposure to alitretinoin and 4-oxo-alitretinoin. Consequently, oral contraception with ethinyl estradiol/norgestimate is an appropriate primary method of birth control during alitretinoin treatment for women of childbearing potential.

Effect of raltegravir on estradiol and norgestimate plasma pharmacokinetics following oral contraceptive administration in healthy women

Oral contraceptives such as norgestimate-ethinyl estradiol (Ortho Tri-Cyclen®) are commonly prescribed in the HIV-infected patient population. A placebo-controlled, randomized, two-period crossover study in healthy HIV-seronegative subjects was conducted to assess the effect of raltegravir on the pharmacokinetics of the estrogen and progestin components of norgestimate-ethinyl estradiol [ethinyl estradiol (EE) and norelgestromin (NGMN), an active metabolite of norgestimate (NGT)]. In each of two periods, nineteen healthy women established on norgestimate-ethinyl estradiol contraception (21 days of active contraception; 7 days of placebo) received either 400 mg raltegravir or matching placebo twice daily on days 1-21. Pharmacokinetics were analysed on day 21 of each period. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the EE component of norgestimate-ethinyl estradiol when co-administrated with raltegravir relative to EE alone was 0.98 (0.93-1.04) for the area under the concentration-time curve from 0 to 24 h (AUC(0-24 h) ) and 1.06 (0.98-1.14) for the maximum concentration of drug in the plasma (C(max) ); the GMR (90% CI) for the NGMN component of norgestimate-ethinyl estradiol when co-administered with raltegravir relative to NGMN alone was 1.14 (1.08-1.21) for AUC(0-24 h) and 1.29 (1.23-1.37) for C(max) . There were no discontinuations due to a study drug-related adverse experience, nor any serious clinical or laboratory adverse experience. Raltegravir has no clinically important effect on EE or NGMN pharmacokinetics. Co-administration of raltegravir and an oral contraceptive containing EE and NGT was generally well tolerated; no dose adjustment is required for oral contraceptives containing EE and NGT when co-administered with raltegravir.