Safety and tolerability of a new low-dose contraceptive patch in obese and nonobese women.

OBJECTIVE: The safety and tolerability of a new low-dose levonorgestrel/ethinyl estradiol (LNG/EE) contraceptive patch was compared with 2 combination oral contraceptives in 2 clinical studies in which approximately 30% of enrolled participants were obese. STUDY DESIGN: Two phase 3, open-label, randomized, parallel-group, multicenter trials compared the LNG/EE contraceptive patch (n = 1579) with combination oral contraceptives (n = 581) in healthy women 17-40 years of age. Combination oral contraceptives were LNG 100 µg per EE 20 µg (combination oral contraceptive 20; n = 375) or LNG 150 µg per EE 30 µg (combination oral contraceptive 30; n = 206). Safety and tolerability data from the 2 trials were evaluated in integrated safety analyses. RESULTS: Treatment-emergent adverse events of 2% or greater in the LNG/EE contraceptive patch were nasopharyngitis (5.2%), nausea (4.1%), upper respiratory infection (3.5%), headache (3.4%), sinusitis (2.9%), cervical dysplasia (2.3%), and urinary tract infection (2.1%). Including skin reaction-related treatment-emergent adverse events, the proportion of women who experienced any treatment-emergent adverse event was similar among women randomized to the contraceptive patch (47.5%), the combination oral contraceptive 20 (47.4%), or the combination oral contraceptive 30 (46.8%). The incidence of treatment-emergent adverse events was similar in obese vs nonobese participants in all groups. Serious adverse events occurred in less than 1% of participants in any of the treatment groups. CONCLUSION: The LNG/EE contraceptive patch and combination oral contraceptives were well tolerated and associated with similar treatment-emergent adverse event incidences in obese and nonobese women.

Hypercoagulability in adolescent girls on oral contraceptives-global coagulation profile and estrogen receptor polymorphisms.

Oral contraceptive (OCP) induced changes on coagulation are complex with high inter-individual variability. The precise reason for differences in this variability is unknown. We hypothesized that global coagulation assays better delineate these changes and variability in hypercoagulability may be the result of differences in estrogen metabolism and thrombophilia. Fifty-two adolescents initiating OCPs were prospectively enrolled; 33 subjects completed the study. Samples were analyzed prior to and after OCPs for procoagulant and anticoagulant factor activities and thrombin generation (TG) +/-thrombomodulin. Participants were genotyped for common thrombophilia and estrogen receptor-α (ESR-α) single nucleotide polymorphisms (SNPs). SNP genotypes were compared to coagulation parameters; TG parameters and differences pre and post OCPs were examined. At baseline, a striking finding was elevated FVIII levels. FVL was absent in all and F2 G20210A was present in one participant. The ESR-α polymorphism was present in heterozygous state in 59% and homozygous state in 21% participants. There were no differences in VWF levels and FVIII: C after being on OCPs. Protein S levels decreased with OCPs. Sixty percent of participants showed evidence of hypercoagulability on TG testing on OCPs. Higher thrombin peak and endogenous thrombin potential (ETP) were seen on TG after OCPs. With thrombomodulin, ETP and thrombin peak did not decrease after OCPs, signifying 'thrombomodulin resistance'. We demonstrated that OCPs induce a state of "variable" hypercoagulability in adolescents, predominantly through the protein S pathway. Genetic and nongenetic factors may account for the variable increase in hypercoagulability. Further research is needed to understand this.

Metabolic effects of the contraceptive skin patch and subdermal contraceptive implant in Mexican women: a prospective study.

BACKGROUND: The contraceptive skin patch (CSP) accepted by the U.S. FDA in 2001 includes ethinylestradiol and norelgestromine, whereas the subdermal contraceptive implant (SCI) has etonogestrel and is also approved by the FDA. In Mexico, both are now widely used for contraception but their effects on Mexican population are unknown. The objective of the study was to evaluate if these treatments induce metabolic changes in a sample of indigenous and mestizo Mexican women. METHODS: An observational, prospective, longitudinal, non-randomized study of women between 18 and 35 years of age assigned to CSP or SCI. We performed several laboratory tests: clinical chemistry, lipid profile, and liver and thyroid function tests. Also, serum levels of insulin, C-peptide, IGF-1, leptin, adiponectin, and C reactive protein were assayed. RESULTS: Sixty-two women were enrolled, 25 used CSP (0 indigenous; 25 mestizos) and 37 used SCI (18 indigenous; 19 mestizos). Clinical symptoms were relatively more frequent in the SCI group. Thirty-four contraceptive users gained weight without other clinical significant changes. After 4 months of treatment, significant changes were found in some biochemical parameters in both treatment groups. Most were clinically irrelevant. Interestingly, the percentage of users with an abnormal atherogenic index diminished from 75% to 41.6% after follow-up. CONCLUSIONS: The CSP slightly modified the metabolic variables. Most changes were nonsignificant, whereas for SCI users changes were more evident and perhaps beneficial. Results of this attempt to evaluate the effects of contraceptives in mestizo and native-American populations show that clinical symptoms are frequent in Mexican users of CSP and SCI. Although these medications may affect some metabolic variables, these changes seem clinically irrelevant. Induction of abnormalities in other physiological pathways cannot be ruled out.

Hormone withdrawal-associated symptoms: comparison of oestradiol valerate/dienogest versus ethinylestradiol/norgestimate.

OBJECTIVES: To determine the effect of oestradiol valerate/dienogest (E2V/DNG) versus ethinylestradiol/norgestimate (EE/NGM) on hormone-withdrawal associated symptoms (HWAS) in otherwise healthy women who had experienced at least one of these symptoms when using 21/7-day combined oral contraceptives (COCs). METHODS: This phase III, parallel-group study randomised 409 women aged 18 to 50 years to E2V/DNG or EE/NGM. The primary efficacy variable was the change from baseline to cycle 6 in the average of the three highest visual analogue scale values for headache and/or pelvic pain during cycle days 22 to 28. RESULTS: In total, 395 were included in the full analysis set (E2V/DNG, n = 191; EE/NGM, n = 204). E2V/DNG reduced the symptoms of headache or pelvic pain during cycle days 22 to 28 from baseline to cycle 6 to a significantly greater extent than EE/NGM (mean decrease 43.6 vs. 35.5 mm; p = 0.0024). Both treatments were well tolerated with a similar proportion of women experiencing adverse events that were considered at least possibly related to treatment (35% E2V/DNG vs. 34% EE/NGM). CONCLUSIONS: E2V/DNG reduces the frequency and intensity of headache and pelvic pain to a greater extent than EE/NGM, and may be a good option for women susceptible to HWAS with conventional 21/7-day COCs.

Differences in prescription rates and odds ratios of antidepressant drugs in relation to individual hormonal contraceptives: a nationwide population-based study with age-specific analyses.

OBJECTIVES: To examine, among young women, the association of individual hormonal contraceptives, within two broad groupings, with antidepressant therapy. METHODS: In a nationwide register-based study, we examined the prescription rates of antidepressant drugs in relation to individual combined hormonal and progestin-only contraceptives among Swedish women aged 16-31 years (N = 917,993). Drug data were obtained from the Swedish Prescribed Drug Register for the period 1 July 2005-30 June 2008. Data on the total population of women aged 16-31 in 2008 were obtained from the Total Population Register of Statistics Sweden. The proportion of women using both hormonal contraception and antidepressants, and odds ratios (ORs) for antidepressant use for hormonal contraceptive users versus non-users, were calculated, the latter by logistic regression, for each formulation. RESULTS: The highest antidepressant OR in all age groups, particularly in the 16-19 years age group, related to medroxyprogesterone-only, followed by etonogestrel-only, levonorgestrel-only and ethinylestradiol/norelgestromin formulations. Oral contraceptives containing ethinylestradiol combined with lynestrenol or drospirenone had considerably higher ORs than other pills. ORs significantly lower than 1 were observed when ethinylestradiol was combined with norethisterone, levonorgestrel or desogestrel. CONCLUSION: The association between use of hormonal contraceptives and antidepressant drugs varies considerably within both the combined hormonal contraceptive and the progestin-only groups.

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

BACKGROUND: 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. AIM: To investigate the influence of alitretinoin on the pharmacokinetics (PK) of ethinyl estradiol/norgestimate (Ortho Tri-Cyclen 28(®)), a commonly prescribed combination oral contraceptive. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

High levels of women's satisfaction and compliance with transdermal contraception: results from a European multinational, 6-month study.

OBJECTIVE: To investigate compliance, satisfaction, and preference in women using a transdermal contraceptive patch. METHODS: Women (18-46 years) from eight European countries used contraceptive patches (norelgestromin 6 mg, ethinylestradiol 600 µg) for six, 4-week treatment cycles. Compliance, satisfaction, and preference were assessed after 3 and 6 cycles and study completion using self-report methods. RESULTS: Of the 778 participants, 36.8% (n = 287) used no contraception at baseline. The most common methods were oral contraceptives (67.9%, n = 334) and barrier methods (21.5%, n = 106). Of oral contraception users, 63.5% (n = 212) were satisfied or very satisfied with their previous method, but compliance was poor with 77.8% (n = 260) reporting missed doses. After 3 and 6 cycles, >80% of all included women were satisfied or very satisfied with the patch. At study completion, most participants (73.7%) reported a preference for the patch compared to their previous method. Of 4107 cycles, 3718 (90.5%) were completed with perfect compliance. Two pregnancies occurred during this study, representing a Pearl Index of 0.63. No new safety issues were identified and the patch was well tolerated. CONCLUSION: Women were highly satisfied with transdermal contraception and preferred this form of family planning over their previous method. Transdermal contraception represents a valuable addition to contraceptive options with potential to offer high compliance and efficacy.

The paradigm of norgestimate: a third-generation testosterone-derivative progestin with a peripheral anti-androgenic activity and the lowest risk of venous thromboembolism.

INTRODUCTION: Norgestimate (NGM) is a testosterone derivative with peculiar receptor activities. AREAS COVERED: This is a narrative review of the available data on the pharmacotherapy of NGM in combined hormonal contraceptives (CHCs) in terms of contraceptive efficacy, venous thromboembolism (VTE) risk, safety, tolerability and bleeding patterns. A comprehensive literature review was conducted in August 2020 using PubMed with the keyword 'norgestimate'. EXPERT OPINION: NGM shows a mild estrogenic activity associated with anti-mineralocorticoid and anti-androgenic properties, largely responsible for the cardiovascular safety profile. The anti-androgenic property depends on the androgen receptor (AR) nuclear translocation (AR trafficking and its subnuclear distribution), the inhibition of 5α-reductase activity (it possesses higher activity compared to other available progestins), and the increase on sexual hormone binding globulin (SHBG) levels if combined with an estrogenic counterpart. NGM is one of the molecules that best modulates the power of ethinyl-estradiol on the thromboembolic risk, being associated with the lowest VTE risk between different CHCs. NGM has the advantage of retaining peripheral anti-androgenic activity, demonstrated by the impact on lipid and glucose metabolism, and it should be preferred if compared with other similar progestins of the same class of risk which are much more androgenic, such as levonorgestrel.

[Combined hormonal contraception in cycles artificially extended]. / Anticoncepción con hormonales combinados en ciclos extendidos artificialmente.

OBJECTIVE: To compare the bleeding patterns, satisfaction and tolerability of 3 different contraceptive in an extended regimens in the service of Family Planning of the North Central Hospital of PEMEX. MATERIAL AND METHODS: Healthy, adult women with desire of contraception for one year (N 120) were randomly assigned to receive oral contraceptive drospirenone/ethinyl E2 (group1), the norelgestromin/ethinyl E2 transdermal patch (group 2) and vaginal ring etonogestrel/ ethinyl E2 (group 3) in an extended regimen (42 consecutive days, 1 hormone-free week). Study assessments were conducted at scheduled visits at the time of initial screening, at baseline after 1, 3, 6, and 12 months. Subjects recorded menstrual associated symptoms bleeding data and completed satisfaction questionnaires. Subjects and investigators provided overall assessments of the regimens. RESULTS: Extended use of 3 different contraceptive resulted in fewer bleeding days in every group (66.6%, 55% and 58.3% P 0.0024), and less mastalgia and menstrual pain. Subjects were highly satisfied with three regimens (93.3%, 96.6% and 91.6% P 0.00421). Although not mayor adverse events were reported with this regimen, there was an increase in spotting days; it decreased with each successive cycle of therapy. Efficacy and safety were similar to those reported for traditional cycle. CONCLUSION: Extended-contraceptive regimen delays menses and reduces bleeding, a profile that may be preferred by women who seek flexibility with their contraceptive method.

Comparison of a transdermal contraceptive patch with a newly sourced adhesive component versus EVRA patch: A double-blind, randomized, bioequivalence and adhesion study in healthy women.

OBJECTIVE: To evaluate the bioequivalence of norelgestromin and ethinyl estradiol (NGMN-EE) and adhesion of a transdermal contraceptive patch containing a newly sourced adhesive component (test) compared with the marketed (reference) patch. STUDY DESIGN: In this randomized, double-blind, 2-way crossover study, healthy women received single 7-day application of both test and reference patches. Treatment phase included two treatment periods of 11 days each separated by a 21-day washout period starting from day of patch removal (day 8) of treatment period 1. Assessments included NGMN and EE pharmacokinetics (PK), adhesion using European Medicines Agency (EMA) 5-point scale, irritation potential and application-site reactions, and safety. Patches were bioequivalent if 90% CIs of ratios of means of test/reference for AUC168h, AUCinf, and Css fell within 80-125%. Patch adhesion was comparable if ratios of mean cumulative adhesion percentage values of test/reference were ≥90.0%. RESULTS: Seventy women were randomized; 57 completed both treatments with ≥80% adhesion (score 0-1). Bioequivalence of test and reference patches was demonstrated as 90% CI of ratio of geometric means for AUC168h, AUCinf, and Css for NGMN and EE fell within 80-125%. Both patches had similar adhesion properties (geometric mean ratio was 100.3% [90% CI, 93.2-107.9]). Similar rates of mild-to-moderate itching (11% vs 10%) and erythema events (79% vs 74%) were reported for test and reference patches, respectively, on day 8. CONCLUSIONS: The test patch with the newly sourced adhesive component is bioequivalent to the currently marketed NGMN-EE transdermal patch and has similar adhesion and irritation potential. IMPLICATIONS STATEMENT: The norelgestromin and ethinyl estradiol transdermal patch containing a newly sourced adhesive component is bioequivalent to the currently marketed patch for both active moieties. Both patches had similar adhesion, irritation potential, and safety profiles.

Confronting the legal risks of prescribing the contraceptive patch with ongoing litigation.

Recent changes in U.S. Food and Drug Administration (FDA) labeling and news reports of lawsuits resulting in million-dollar settlements understandably may deter gynecologists from prescribing the transdermal contraceptive patch Ortho Evra (Ortho-McNeil Pharmaceutical, Inc., Titusville, NJ). Gynecologists who, with all good intentions, prescribe an FDA-approved drug such as the contraceptive patch potentially could find themselves liable for an adverse drug reaction. Although much of the current focus by plaintiff attorneys and the news media is on the contraceptive patch, no prescription contraceptive method is without medical risks to the patient or legal risks to the prescribing gynecologist. The purpose of this commentary is to provide an overview of the medical-legal controversies and pitfalls in prescribing the contraceptive patch as well as to outline how gynecologists can avert legal liability by providing proper informed consent. Despite FDA labeling changes and ongoing litigation, with proper informed consent, the contraceptive patch still may be the best choice for many patients who prefer the convenience of a weekly patch over a daily oral contraceptive. Also, regardless of the contraceptive option chosen, the principles of providing and documenting proper informed consent in medical records are applicable not only to providing quality care to patients, but also to protecting the legal interests of the prescribing gynecologist. By documenting proper informed consent in medical records, gynecologists should feel more at ease in prescribing the contraceptive method that best fits their individual patients' needs, even in the presence of ongoing litigation.

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.

Adhesion Evaluation of AG200-15: An Investigational Transdermal Contraceptive Delivery System.

INTRODUCTION: AG200-15, an investigational transdermal contraceptive delivery system or patch, is designed to be a low-dose, non-daily, combined hormonal contraceptive option for women. In this phase 1 study, the in vivo adhesion of the AG200-15 patch was compared to Xulane®, the only contraceptive patch available in the USA. METHODS: This phase 1, randomized, open-label, single-dose, two-treatment, two-period crossover adhesion study compared the 7-day adhesion of the AG200-15 and Xulane contraceptive patches. Eighty-three women, ages 18 to 35 years old, with body mass index (BMI) ≥ 19 kg/m2 and < 35 kg/m2, and weight ≥ 48 kg and < 90 kg were enrolled. Trained study site personnel used a five-point scale to assess patch adhesion daily. A score of 0 reflected at least 90% adhesion; while a score of 4 represented complete detachment of the patch. The primary objective was to compare the adhesion properties of the two patches; AG200-15 would be considered statistically non-inferior to Xulane if the upper 95% confidence limit (CL) of the mean difference in adhesion scores was below + 0.15. RESULTS: The overall mean (standard deviation) scores for AG200-15 (N = 78) and Xulane (N = 77) were 0.14 (0.28) and 0.39 (0.40), respectively (lower scores on the adhesion scale indicate better adhesion). The study demonstrated a difference in mean adhesion scores of - 0.24, meeting the prespecified non-inferiority criterion by demonstrating a one-sided upper CL of - 0.16. Thus, the in vivo adhesion of AG200-15 was shown to be non-inferior to that of Xulane. Most subjects experienced no skin irritation at the application site for either patch and no serious adverse event was reported in the study. CONCLUSION: The in vivo adhesion of AG200-15 is non-inferior to that of Xulane on the basis of the prespecified criterion of the upper bound of the one-sided 95% CL for the mean adhesion score difference being below + 0.15. Both patches were generally well tolerated. FUNDING: Agile Therapeutics, Inc.

A Multi-Center, Open-Label, Pharmacokinetic Drug Interaction Study of Erenumab and a Combined Oral Contraceptive in Healthy Females.

BACKGROUND: Erenumab is a human anti-calcitonin gene-related peptide monoclonal antibody developed for migraine prevention. Migraine predominately affects women of childbearing age; thus, it is important to determine potential drug-drug interactions between a common oral contraceptive and drugs used to treat migraine. OBJECTIVES: We sought to evaluate potential drug-drug interactions between erenumab and a common oral contraceptive. METHODS: Healthy women received three cycles of a norgestimate/ethinyl estradiol-containing oral contraceptive with a single 140-mg subcutaneous dose of erenumab during cycle three. Norgestimate metabolites (norgestrel and norelgestromin) and ethinyl estradiol pharmacokinetics were evaluated in the absence and presence of erenumab. Primary endpoint was peak plasma concentration (Cmax) and area under concentration-time curve from time 0 to 24 h (AUCtau). Luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations were evaluated as pharmacodynamic markers. RESULTS: Erenumab did not influence the pharmacokinetics of norelgestromin, norgestrel, or ethinyl estradiol. Least-squares mean estimates (90% confidence interval) for Cmax ratios were 1.05 (0.90-1.23), 1.06 (0.97-1.16), and 1.04 (0.88-1.22) for norelgestromin, norgestrel, and ethinyl estradiol, respectively. Respective AUCtau ratios were 1.02 (0.94-1.12), 1.03 (0.96-1.10), and 1.02 (0.91-1.14). Luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations were similar after exposure to oral contraceptive alone and with erenumab. CONCLUSION: Erenumab did not alter the pharmacokinetics of the active components of an estrogen/progestin combination oral contraceptive. Thus, no change in contraceptive efficacy is expected with erenumab. TRIAL REGISTRATION: ClinicalTrials.gov NCT02792517.

Effects of oral and transdermal hormonal contraception on vascular risk markers: a randomized controlled trial.

OBJECTIVE: To compare the effects of oral and transdermal contraceptives containing similar hormone formulations on vascular risk markers. METHODS: We conducted a randomized, investigator-blinded, crossover, clinical trial with 24 healthy women, aged 18-35 years, who received 2 months of transdermal or oral contraceptive, 2 months washout, then 2 months of the alternative medication. The transdermal contraceptive contained 0.75 mg ethinyl estradiol and 6 mg norelgestromin. The oral contraceptive contained 35 mcg ethinyl estradiol and 250 mcg norgestimate. Blood samples taken before and after each treatment were analyzed in batch for D-dimer, von Willebrand factor, factor VIII, total and free protein S, antithrombin, fibrinogen, C-reactive protein, and normalized activated protein C sensitivity ratio (nAPCsr) determined with two thrombin generation-based assays, the alpha2macroglobulin-thrombin end point method (alpha2M-IIa) and calibrated automated thrombinography. Repeated measures analysis of variance was used for analysis. RESULTS: For both contraceptives (transdermal, oral) there were significant declines in free (19%, 11%) and total protein S (19%, 13%) and antithrombin (13%, 10%); increases in fibrinogen (8%, 10%), C-reactive protein (220%, 292%), nAPCsr alpha2M-IIa (81%, 61%), and nAPCsr calibrated automated thrombinography (102%, 68%), all P<.05. Transdermal contraceptives had a greater effect than oral contraceptives on free protein S (P=.07), nAPCsr alpha2M-IIa (P=.06), and nAPCsr calibrated automated thrombinography (P=.03). CONCLUSION: Oral and transdermal contraception with similar hormones had similar adverse effects on vascular risk markers. This suggests that this transdermal contraceptive has at least a similar thrombosis risk as its oral counterpart. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00554632 LEVEL OF EVIDENCE: I.

Effect of the ethinylestradiol/norelgestromin contraceptive patch on body composition. Results of bioelectrical impedance analysis in a population of Italian women.

BACKGROUND: As weight gain is one of the most frequently cited reasons for not using and for discontinuing hormonal contraceptives, in an open-label, single-arm, multicentre clinical study we evaluated the effect of the ethinylestradiol/norelgestromin contraceptive patch (EVRA, Janssen-Cilag International, Belgium) on body composition using bioelectrical impedance analysis (BIA). METHODS: Body weight and impedance vector components (resistance (R) and reactance (Xc), at 50 kHz frequency, Akern-RJL Systems analyzer) were recorded before entry, after 1, 3 and 6 months in 182 Italian healthy women aged 29 yr (18 to 45), and with BMI 21.8 kg/m2 (16 to 31). Total body water (TBW) was estimated with a BIA regression equation. Vector BIA was performed with the RXc mean graph method and the Hotelling's T2 test for paired and unpaired data. RESULTS: After 6 months body weight increased by 0.64 kg (1.1%) and TBW increased by 0.51 L (1.7%). The pattern of impedance vector displacement indicated a small increase in soft tissue hydration (interstitial gel fluid). Body composition changes did not significantly differ among groups of previous contraceptive methods. Arterial blood pressure did not significantly change over time. CONCLUSION: After 6 months of treatment with the ethinylestradiol/norelgestromin contraceptive patch we found a minimal, clinically not relevant, increase in body weight less than 1 kg that could be attributed to an adaptive interstitial gel hydration. This fluctuation is physiological as confirmed by the lack of any effect on blood pressure. This could be useful in increasing women's choice, acceptability and compliance of the ethinylestradiol/norelgestromin contraceptive patch.

A clinical study of transdermal contraceptive patch in Thai adolescence women.

OBJECTIVE: To study cycle control, compliance and safety of a transdermal contraceptive patch in adolescent Thai women. MATERIAL AND METHOD: Fifty-eight healthy women were assigned to receive 3 cycles of contraceptive patch (ethinyl estradiol 20 microg and norelgestromin 150 microg/day). All participants aged 16-20 years were invited to participate from the family planning clinic at King Chulalongkorn Memorial Hospital. Data were collected on adverse effects, perceived advantages and disadvantages, body weight, blood pressure, patch detachments and compliance. Data were analyzed using mean, percentage and student's t-test. RESULTS: The participants' average age was 19.4 years, height 158.8 cm, weight 51.8 kg, BMI 20.8 Kg/m2. The most location of patch application was the abdomen and the most adverse event was breast tenderness (31.0%) followed by application site reaction, nausea vomiting and headache respectively. The breast symptom was mild in severity. The participants reported decrease in dysmenorrhea and shorter duration of bleeding. There were no significant changes in body weight and blood pressure. The improvement of their facial acne was reported. There were no pregnancies during use and the adhesion of the contraceptive patch is excellent. Partial patch detachment was reported in only 6.9%. No completed patch detachment was found. CONCLUSION: The present study found an overall positive impression of a new transdermal contraceptive patch. The good compliance and few side effects were demonstrated. The adhesive patch contraceptive was excellent.

[Acute cholestasis following treatment with nimesulide and oral contraception: case report and review]. / Akútna cholestáza po uzívaní nimesulidu a kontraceptív: kazuistika a prehl'ad literatúry.

Our case report of acute cholestatic liver injury highlights the potential hepatotoxicity of nimesulide treatment in combination with oral contraception. Rarely occuring histological findings of "pure" cholestasis without any inflammatory or necrotic changes with favourable outcome following ursodeoxycholic acid administration are described. It was not possible to distinguish the separate role of any of these two drugs on hepatotoxicity according to the available information. Based on the known similarities in hepatotoxic profile of nimesulide and oral contraceptives, it can be assumed that their interaction could increase the risk of liver damage, although the precise mechanisms are not ellucidated yet. Nimesulide toxicity however is often reported in cases taking several potentially hepatotoxic drugs. It is therefore prudent to reconsider any concommitant treatment and closely monitor liver function tests in patients requiring nimesulide treatment.

Transdermal hormonal contraception: benefits and risks.

Transdermal drug delivery systems have been available in the United States for >20 years. Since the introduction of the first transdermal patch (scopolamine) for the treatment of motion sickness, >35 transdermal patch products have been approved by the US Food and Drug Administration for a variety of indications that include hormone replacement therapy, nicotine replacement therapy, chronic pain (fentanyl), angina (nitroglycerin), hypertension (clonidine), and more recently, overactive bladder (oxybutynin), and contraception (ethinyl estradiol/norelgestromin). Clinical data demonstrated the efficacy and safety of the contraceptive patch; however, concerns regarding estrogen levels and reports of venous thromboembolism led to the development of 2 epidemiologic studies and, subsequently, revised product labeling. Despite this, the contraceptive patch may be an appropriate option for some patients.

The contraceptive patch in relation to ischemic stroke and acute myocardial infarction.

STUDY OBJECTIVE: To compare rates of stroke and acute myocardial infarction in users of the Ortho EVRA contraceptive patch with these rates in users of norgestimate-containing oral contraceptives (OCs) with 35 microg of ethinyl estradiol. DESIGN: Retrospective, population-based, epidemiologic study. DATA SOURCE: PharMetrics database. SUBJECTS: Females aged 15-45 years in the PharMetrics database who had filled at least one prescription for the Ortho EVRA contraceptive patch or a norgestimate OC between April 1, 2002, and March 31, 2005. MEASUREMENTS AND MAIN RESULTS: Incidence rates and 95% confidence intervals (CI) were estimated for the outcomes of ischemic stroke and acute myocardial infarction by exposure. Crude incidence rates of ischemic stroke among users of the patch and users of norgestimate OCs were 13.6/100,000 woman-years (95% CI 5.9-26.8) and 11.3/100,000 woman-years (95% CI 5.4-20.8), respectively. The crude incidence rate of acute myocardial infarction was 1.7/100,000 woman-years (95% CI 0.04-9.5) in current patch users and 7.9/100,000 woman-years (95% CI 3.2-16.3) in current users of norgestimate OCs. Incidence rate ratios (IRRs) were estimated for the outcomes by comparing data for users of the patch and users of a norgestimate OC. The IRR for stroke was 1.2 (95% CI 0.41-3.4) and for acute myocardial infarction was 0.2 (95% CI 0.004-1.7). CONCLUSION: Ischemic stroke and acute myocardial infarction are rare among young women who use hormonal contraceptives, and the current data provide no suggestion of an increased risk of either ischemic stroke or acute myocardial infarction in users of the Ortho EVRA contraceptive patch compared with users of norgestimate OCs.