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Objective Evaluate bioequivalence, based on norelgestromin (NGMN) and ethinyl estradiol (EE) plasma concentrations, and adhesion of a transdermal contraceptive patch containing a newly sourced adhesive component (test) at end of shelf life (EOSL) vs. the marketed EVRA patch (reference) at beginning of shelf life (BOSL). Materials and methods In this randomized, double-blind, two-way crossover study, healthy women received a single, 7-day application of test and reference patches in 4 sequences: two 11-day treatment periods separated by a 21-day washout. Assessments included NGMN and EE pharmacokinetics (PK), adhesion (per European Medicines Agency (EMA) 5-point scale), irritation potential and application-site reactions, and tolerability. Patches were bioequivalent if 90% CIs of geometric mean ratios (GMRs) of test/reference for Cmax, AUC168h, AUC0-tlast, and AUC∞ were 80 - 125%. Patch adhesion was comparable if ratios of geometric mean cumulative adhesion percentages were ≥ 90%. Results 68 women were randomized, and 62 completed both treatments. 55 and 59 participants in the reference and test group, respectively, had patch adhesion ≥ 80% (EMA score 0 - 1) at end of treatment. Bioequivalence was demonstrated: GMRs for pharmacokinetic (PK) parameters ranged from 102.76 - 105.57% for NGMN and 93.78 - 94.80% for EE, and associated 90% CIs were fully within the bioequivalence acceptance range (80 - 125%) for both. The patches had comparable adhesion properties (GMR, 101.4% (90% CI: 99.2 - 103.6)) and incidences of treatment-emergent adverse events. Conclusion NGMN-EE transdermal test patch at EOSL was bioequivalent to the marketed patch at BOSL, supporting widening the product's shelf-life specification. Adhesive properties and safety profiles were comparable between patches.

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.

Delayed‐release dimethyl fumarate (DMF) is an oral therapy for relapsing multiple sclerosis with anti‐inflammatory and neuroprotective properties. This 2‐period crossover study was conducted to evaluate the potential for drug–drug interaction between DMF (240 mg twice daily) and a combined oral contraceptive (OC; norgestimate 250 μg, ethinyl estradiol 35 μg). Forty‐six healthy women were enrolled; 32 completed the study. After the lead‐in period (OC alone), 41 eligible participants were randomized 1:1 to sequence 1 (OC and DMF coadministration in period 1; OC alone in period 2) or sequence 2 (regimens reversed). Mean concentration profiles of plasma norelgestromin (primary metabolite of norgestimate) and ethinyl estradiol were superimposable following OC alone and OC coadministered with DMF, with 90% confidence intervals of geometric mean ratios for area under the plasma concentration–time curve over the dosing interval and peak plasma concentration contained within the 0.8–1.25 range. Low serum progesterone levels during combined treatment confirmed suppression of ovulation. The pharmacokinetics of DMF (measured via its primary active metabolite, monomethyl fumarate) were consistent with historical data when DMF was administered alone. No new safety concerns were identified. These results suggest that norgestimate/ethinyl estradiol–based OCs may be used with DMF without dose modification.

В основі статті – дослідження трансдермальної терапевтичної системи, що містить 600 мкг етінілестрадіолу та 6000 мкг норелгестроміну, яку використано для зменшення вегето-судинних і психоневрологічних проявів клімактеричного синдрому важкого та середньої важкості перебігу.Мета роботи – оцінити ефективність впливу ТТС, що містить 600 мкг етінілестрадіолу та 6000 мкг норелгестроміну, на прояви вегето-судинних і психоневрологічних порушень у жінок із клімактеричним синдромом важкого та середньої важкості перебігу.Матеріали та методи. Під спостереженням перебували 103 жінки постменопаузального віку з клімактеричними порушеннями важкого та середнього перебігу: 65 – основна група, 38 – група порівняння. Ступінь важкості клімактеричних проявів визначали за шкалою оцінювання менопаузи MRS до лікування та через один місяць після лікування. Жінкам основної групи запропоновано лікування клімактеричних розладів за допомогою ТТС, що містить 600 мкг етінілестрадіолу та 6000 мкг норелгестроміну, в режимі одна пластинка на один місяць. Жінкам групи порівняння призначали традиційну МГТ препаратом, що містить 1 мг естрадіолу та 5 мг дідрогестерону per os в безперервному режимі.Результати. На тлі здійсненого лікування відзначено вірогідне зниження бальної оцінки вегето-судинних та психоневрологічних симптомів менопаузи та зниження сумарного індексу менопаузи (з 25,9 ± 1,2 до 8,2 ± 0,9 – основна група; з 25,4 ± 1,6 до 9,9 ± 1,2 – група порівняння). Виявлено вірогідну різницю (p < 0,05) після лікування між показниками основної групи та групи порівняння за такими критеріями: припливи, проблеми зі сном, депресивний настрій, відчуття стурбованості, фізичного та психічного виснаження, неприємні відчуття в суглобах і м’язах. В основній групі ці показники були значно кращі.Висновки. При лікуванні клімактеричного синдрому важкого та середнього перебігу за допомогою TTC, що містить 600 мкг етінілестрадіолу та 6000 мкг норелгестроміну (пластир Evra), виявлено швидку та стійку корекцію вегето-судинних і психоневрологічних порушень. Вірогідне зниження сумарного індексу менопаузи через один місяць після лікування на 68,3 % (у групі порівняння – на 61 %) дає можливість рекомендувати ТТС з етінілестрадіолом і норелгестроміном як самостійний метод корекції клімактеричних порушень важкого та середнього ступенів важкості., The article presents data on a study of transdermal therapeutic system with 600 mkg ethinylestradiol and 6000 mkg norelgestromin, which was used for removal vasomotor and neuropsychiatric disorders of severe and middle course of climacteric syndrome.Purpose: to assess the effectiveness of influence of transdermal therapeutic system with 600 mkg ethinylestradiol and 6000 mkg norelgestromin for vasomotor and neuropsychiatric disorders of severe and middle climacteric syndrome.Materials and methods. 103 women of postmenopausal age with severe and middle climacteric disorders were under observation: 65 of them were included into the main group, 38 – the comparison group. Severity stage of climacteric manifestation was determined according to menopause rating scale (MRS) before treatment and a month after treatment. Women of the main group were offered to treat climacteric disorders with TTS, which contains 600 mkg ethinylestradiol and 6000 mkg norelgestromin, in regime 1 patch per 1 month. Traditional MHT preparation was prescribed to the women of the comparison group, this drug contains 1mg ethinylestradiol and 5 mg dydrohesteron, per os route in uninterrupted regime.Results. It was found reduction of vegetative, vascular and neuropsychiatric menopausal symptoms and total index of menopause from 25.9 ± 1.2 to 8.2 ± 0.9 – in the main group; and from 25.4 ± 1.6 to 9.9 ± 1.2 – in the comparison group. Reliable difference (p < 0.05) was found out after treatment between indexes of the main and comparison groups according to such criteria, as: hot flashes, sleeping disorders, joint and muscle complaints, depression, anxiety. These indexes were mush better in the main group.Conclusions. During treatment of severe and middle climacteric syndrome with TTS, which contains 600 mkg ethinylestradiol and 6000 mkg norelgestromin (Evra plaster), rapid and durable correction of vegetative, vascular and neuropsychiatric climacteric disorders was found out. Reliable reduction of total index of menopause in a month after treatment by 68.3 % from the first index (in the comparison group – 61 %) allows to recommend TTS with ethinylestradiol and norelgestromin as independent correction method for severe and middle climacteric disorders tratment., В основу статьи положено исследование трансдермальной терапевтической системы, содержащей 600 мкг этинилэстрадиола и 6000 мкг норэлгестромина, которую использовали для уменьшения вегето-сосудистых и психоневрологических проявлений тяжёлого и средней степени тяжести климактерического синдрома.Цель работы – оценить эффективность влияния ТТС, содержащей 600 мкг этинилэстрадиола и 6000 мкг норэлгестромина, на проявления вегето-сосудистых и психоневрологических нарушений у женщин с тяжёлым и средней степени тяжести климактерическим синдромом.Материалы и методы. Под наблюдением находилось 103 женщины постменопаузального возраста с тяжёлыми и средней степени тяжести климактерическими нарушениями: 65 – основная группа, 38 – группа сравнения. Степень тяжести климактерических проявлений определяли по шкале оценки менопаузы MRS до лечения и через один месяц после лечения. Женщинам основной группы предложено лечение климактерических нарушений с помощью ТТС, содержащей 600 мкг этинилэстрадиола и 6000 мкг норэлгестромина, в режиме одна пластинка на один месяц. Женщинам группы сравнения назначали традиционную МГТ препаратом, содержащим 1 мг эстрадиола и 5 мг дидрогестерона, per os в непрерывном режиме.Результаты. На фоне проведённого лечения отмечено достоверное снижение бальной оценки вегето-сосудистых и психоневрологических симптомов менопаузы и снижение суммарного индекса менопаузы (с 25,9 ± 1,2 до 8,2 ± 0,9 – основная группа; с 25,4 ± 1,6 до 9,9 ± 1,2 – группа сравнения). Выявлена достоверная разница (p < 0,05) после лечения между показателями основной группы и группы сравнения по таким критериям: приливы, проблемы со сном, депрессивное настроение, ощущение беспокойства, физическое и психическое истощение, неприятные ощущения в суставах и мышцах. В основной группе эти показатели были значительно лучше.Выводы. При лечении тяжёлого и средней степени тяжести климактерического синдрома с помощью ТТС, содержащей 600 мкг этинилэстрадиола и 6000 мкг норэлгестромина (пластырь Evra), выявлена быстрая и стойкая коррекция вегето-сосудистых и психоневрологических симптомов. Достоверное снижение суммарного индекса менопаузы через 1 месяц после лечения на 68,3 % (в группе сравнения – на 61 %) позволяет рекомендовать ТТС с этинилэстрадиолом и норэлгестромином как самостоятельный метод коррекции тяжёлых и средней степени тяжести климактерических нарушений.

Background: Dolutegravir (DTG; Tivicay; ViiV Healthcare, Research Triangle Park, NC) is an HIV-1-unboosted integrase inhibitor with no cytochrome P450 or uridine 5′diphosphate-glucuronosyltransferase inhibition or induction. As DTG is administered to HIV-1–infected women receiving oral contraceptives, assessing the potential for drug interactions was warranted. Objective: To determine the impact of DTG on the pharmacokinetics (PK) and pharmacodynamics (PD) of a common oral contraceptive, norgestimate/ethinyl estradiol (NGM/EE; Ortho-Cyclen; Ortho-McNeil-Janssen Pharmaceuticals, Inc, Raritan, NJ). Methods: This randomized, 2-period, double-blind, placebo-controlled study was conducted within 1 menstrual cycle at 1 clinical center in the United States; 16 women were enrolled. Participants received NGM 0.25 mg/EE 0.035 mg throughout the study. During days 1 to 10, they were randomized to receive twice-daily DTG 50 mg or matching placebo with food and switched to the other treatment during days 12 to 21. Results: Ratios of area under the concentration-time curve from time 0 until end of the dosage interval (AUC0-τ), maximum plasma concentration, and concentration at the end of the dosage interval of norelgestromin with DTG treatment to the same PK parameters with placebo treatment were 0.975, 0.890, and 0.932, respectively; for EE, ratios were 1.03, 0.99, and 1.02, respectively. No significant differences in luteinizing hormone, follicle-stimulating hormone, and progesterone were detected on days 1, 10, 11, 21, and 22. DTG steady-state AUC0-τ was similar to historical data. No severe or grade 3/4 adverse events occurred. Conclusions: DTG had no effect on NGM/EE PK or PD. NGM/EE can be administered with DTG without dose adjustment.

Objective: To determine the relative bioavailability of ethinyl estradiol (EE) and gestodene (GSD) after application of a novel transdermal contraceptive patch vs. a standard combined oral contraceptive (COC) pill (study 1), and to evaluate the pharmacokinetics (PK) of EE after application of the EE/GSD patch compared with an EE/norelgestromin (NGMN) patch (study 2). Materials: Participants were healthy, non-obese women aged 18 – 45 years (study 1) or 18 – 35 years (study 2). Compositions of study treatments were as follows: 0.55 mg EE/2.1 mg GSD (EE/GSD patch); 0.02 mg EE/0.075 mg GSD (standard COC); 0.6 mg EE/6 mg NGMN (EE/NGMN patch). Methods: In study 1, which consisted of 3 treatment periods (each followed by 7 patch- or pill-free days), treatments were administered in one of two randomized orders: either P–M–E (EE/GSD patch (P) every 7 days for 28 days → COC (M) once-daily for 21 days → two 7-day patch-wearing periods followed by one 10-day patch-wearing phase (E)), or the same treatments administered in sequence M–P–E. For study 2, participants received either the EE/GSD patch or EE/NGMN patch for seven treatment cycles (one patch per week for 3 weeks followed by a 7-day patch-free interval). Results: In study 1, average daily exposure to EE was similar for treatments P and M; the mean daily area under the concentration-time curve (AUC) ratio of treatment P vs. treatment M for EE was 1.06 (90% confidence interval (CI): 0.964 – 1.16), indicating average daily delivery similar to oral administration of 0.019 – 0.023 mg EE. For unbound GSD, average daily exposure was lower for treatment P vs. treatment M. The mean AUC ratio of treatment P vs. treatment M for unbound GSD was 0.820 (90% CI: 0.760 – 0.885), indicating average daily delivery from the patch of 0.057 – 0.066 mg GSD. Prolonged patch wearing did not result in a distinct decline in GSD and EE serum concentrations. In study 2, AUC at steady state (AUC0–168,ss), average steady-state serum concentration, and maximum steady-state serum concentration for EE was 2.0 – 2.7-fold higher for the EE/NGMN patch vs. the EE/GSD patch. The EE/GSD patch was well tolerated in both studies. Conclusions: Based on the 90% CI of the AUC ratio of oral treatment vs. patch application for unbound GSD and EE, the daily doses of GSD and EE released from the EE/GSD patch over the 7-day application period provided the same systemic exposure as those recorded after daily oral administration of a COC containing 0.02 mg EE and 0.06 mg GSD. The EE/GSD patch showed reduced EE exposure compared with the EE/NGMN patch. Together with its good tolerability, these properties support the EE/GSD patch as an effective and well-tolerated alternative to available transdermal and oral contraceptives.

The transdermal patch provides an effective and convenient option for hormonal contraception. The patch currently on the US market contains 150 µg norelgestromin and 35 µg ethinylestradiol (EE). The 20 cm2 patch is applied once weekly for 3 weeks, followed by a patch-free week, for a 21-7 cycle. Typical failure rates are similar to that of combined oral contraceptives (COCs). Transdermal delivery results in less peaks and troughs of estrogen, but a higher total estrogen exposure compared with COCs. Though studies show mixed results, the risk of developing venous thromboembolism (VTE) is about twice as high with the patch as with COCs; however, the absolute risk of VTE remains low. The side effect profile is similar to that of COCs, with slightly higher rates of breast tenderness plus a unique adverse effect of application site reactions. Two new patches have been developed, one containing gestodene and EE in Europe and another containing levonorgestrel and EE. Overall, the patch provides an alternative to COCs for women who want autonomy and the benefit of not needing to take a pill daily, with similar efficacy and tolerability.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Oral contraceptives are a widely prescribed means of birth control that requires the maintenance of adequate pharmacokinetics of the active components to maintain efficacy. • Oral contraceptive use in HIV-infected women is widespread and may often occur in women receiving raltegravir as part of their antiretroviral therapy. • Given the prevalence of oral contraceptive use and likely need for co-administration with raltegravir, combination administration should be studied to assess the safety and the pharmacokinetics of the oral contraceptive components. WHAT THIS STUDY ADDS • This study is the first to provide the practitioner with a detailed description of the influence of raltegravir on the pharmacokinetics of a triphasic oral contraceptive. • This study demonstrates that raltegravir does not meaningfully alter the pharmacokinetics of the estrogen or progestin components of such oral contraceptives. • This paper provides confidence to the practitioner that there will be no clinically meaningful interaction that would preclude the concurrent use of raltegravir and such oral contraceptives in combination. AIMS 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)]. METHODS 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. RESULTS 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 (AUC0–24 h) and 1.06 (0.98–1.14) for the maximum concentration of drug in the plasma (Cmax); 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 AUC0–24 h and 1.29 (1.23–1.37) for Cmax. There were no discontinuations due to a study drug-related adverse experience, nor any serious clinical or laboratory adverse experience. CONCLUSIONS 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.

Objective To investigate compliance, satisfaction, and preference in women using a transdermal contraceptive patch. Methods Women (18–6 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.

Objective: To document Canadian women's experience with the transdermal contraceptive patch, a method delivering 150 μg norelgestromin and 20 μg ethinyl estradiol daily. Methods: We conducted an open-label, multicentre, descriptive cohort study of the contraceptive patch over 9 cycles in 392 women requiring contraception. A single treatment cycle consisted of 3 consecutive 7-day patch applications followed by 1 patch-free week. At the final visit, overall satisfaction and preference for the patch was rated and compared with the previously used contraceptive method. Results: At baseline, 80.9% of participants were either very satisfied or somewhat satisfied with their previous contraceptive method, 89% having used oral contraceptives. At final observation, 60.6% of participants preferred the patch, 9.3% had no preference; and 30% preferred their previous method (n = 376). A total of 279 participants (71.2%) completed 9 cycles of patch use. Of these, 91% were satisfied with the patch and 74.9% preferred the patch to their previous contraceptive (43% strongly preferred and 31.9% preferred); 9% had no preference; and 16.1% preferred their previous method. Of those who preferred the patch, 82.7% preferred it because of its convenience or simplicity. Across all cycles, 88% of participants recorded perfect compliance. The most common adverse event was application site reactions (most of which were mild), experienced by 49% of participants: 33.7%, 16.5%, and 14.7% at cycles 1, 4, and 9, respectively. Conclusion: Both preference for and satisfaction with the transdermal contraceptive patch were high. Most participants found it easy to use and were highly compliant with the 7-day dosing regimen.

Objective To compare the effects of the contraceptive patch to oral contraceptives (OCs) on follicular size and incidence of ovulation in normal cycles and after dosing errors. Design Randomized, open-label. Setting Twelve centers. Patient(s) One hundred twenty-four ovulatory women. Intervention(s) Subjects received either the patch (groups 1 and 2) or one of three OCs. Correct dosing occurred in cycles 1, 2, 3, and 5. The following dosing errors were planned during cycle 4, a shortened 10-day cycle: [1] patch group 1 subjects wore one patch for 10 consecutive days; [2] for patch group 2 and OC subjects, 7 dosing days were followed by 3 drug-free days. Main outcome measure(s) Follicular size, as determined at each cycle by the maximum mean follicular diameter. Result(s) After a 3-day dosing error, follicular size was significantly smaller in the patch group (mean, 7.0 mm) vs. each OC group (range of means, 11.8–17.1 mm). Similar results were seen after proper dosing. The incidence of ovulation was significantly lower for the patch users than for women using OCs. Conclusion(s) Follicular size and incidence of ovulation were significantly reduced among contraceptive patch users compared with women using OCs in normal cycles and after planned dosing errors.

To review the safety and tolerability of the contraceptive patch (Ortho Evra/Evra) versus a standard oral contraceptive (Triphasil) and to present the pooled safety and tolerability of the patch across three pivotal studies.Three open-label, contraceptive studies of up to 13 treatment cycles.183 centers.Comparative study (812 patch, 605 oral contraceptive); pooled analysis (3,330 patch).The patch regimen was three consecutive 7-day patches (21 days) followed by 1 patch-free week per cycle; the oral contraceptive was dosed according to the U.S. physician package insert.Adverse events, laboratory tests, vital signs, and body weight.The incidence of most events was similar between the patch and oral contraceptive groups, with the exception of a higher incidence of application site reactions, breast discomfort (cycles 1 and 2 only), and dysmenorrhea in the patch group. Pooled analysis demonstrated that most application site reactions (92%) and breast symptoms (86%) were mild or moderate in severity, and2% of participants discontinued the patch because of either event. Only 7 (0.2%) participants experienced a serious adverse event classified as possibly, probably, or likely related to the patch. The mean change in body weight from baseline to the end of treatment was an increase of 0.3 kg.Overall, the contraceptive patch is well tolerated and has a side effect profile similar to an established oral contraceptive.

Objective: To assess the adhesive reliability of the contraceptive patch (Ortho Evra™/Evra™). Design: Pooled data of 3,319 women from three contraceptive studies of up to 13 treatment cycles; a subset of 325 women of the pooled data from warm and humid climates; and 30 women from a three-period, crossover exercise study. Setting: 184 centers. Patient(s): 3,349 healthy women. Intervention(s): In the contraceptive studies, each treatment cycle consisted of three consecutive 7-day patches (21 days) followed by one patch-free week. During each treatment period in the exercise study, women wore the patch for 7 days and participated in one of six activities (normal activity, excluding bathing; sauna; whirlpool; treadmill; cool-water immersion; or a combination of activities) each day at a supervised health center. Main Outcome Measure(s): Patch adhesion. Result(s): In the contraceptive studies, 4.7% of patches were replaced because they fell off (1.8% [1,297 of 70,552 patches]) or became partly detached (2.9% [2,050 of 70,552 patches]); patch replacement rates in centers from a warm, humid climate were 1.7% (85 of 4,877 patches) and 2.6% (128 of 4,877 patches), respectively. Only one of 87 patches (1.1%) completely detached in the exercise study. Conclusion(s): The reliability of adhesion of the contraceptive patch is excellent and consistent across all studies; only 1.8% and 2.9% of patches required replacement due to complete or partial detachment, respectively. Heat, humidity, and exercise do not affect adhesion.

Aims To determine the pharmacokinetic profile of norelgestromin (NGMN) and ethinyloestradiol (EE) following application of the contraceptive patch, Evra™/ Ortho Evra™, at each of four anatomic sites (abdomen, buttock, arm, and torso). Methods Thirty-seven healthy, nonpregnant women aged 20–45 years participated in this open-label, four-period crossover study. Subjects were randomized to one of four treatment (site of application) sequences. Each patch was worn for 7 days, with a 1 month washout between treatments. Blood samples were collected before and at various times up to 240 h after application of each patch. Serum samples were assayed for NGMN and EE by validated methods. Results The serum concentration reference ranges for NGMN and EE are 0.6–1.2 ng ml−1 and 25–75 pg ml−1, respectively, based on studies of the mean Cave of oral norgestimate 250 µg and EE 35 µg. For all application sites, mean concentrations of NGMN and EE remained within these ranges during the 7 day wear period. Absorption of NGMN and EE during patch application on the buttock, arm, and torso was equivalent. Absorption of NGMN and EE during patch application on the abdomen was approximately 20% less than observed for the other three sites, although mean serum concentrations were still within reference ranges. A previous study demonstrated therapeutic equivalence of patches worn on the abdomen vs other sites. Conclusions Serum concentrations of NGMN and EE from the contraceptive patch remain within the reference ranges throughout the 7 day wear period, regardless of the site of application (abdomen, buttock, arm, or torso).

Contraceptive patches have become a frequently used contraceptive method. We present a mathematical model that describes the serum concentration profiles of Norelgestromin (NGMN) and Ethinylestradiol (EE) released from the contraceptive patch Ortho Evra(®). We propose a simple one-compartment model based on pharmacokinetics data reported in previous studies. The model assumes a time-dependent release rate and a first order elimination rate for each of the active ingredients contained in the patch. The model was applied to noncompliance scenarios, such as total and partial detachment of the patch or prolonged use without patch replacement. The proposed model adequately describes the clinically observed evolution of NGMN and EE in serum. Predictions from the model were successfully validated using reported experimental data of serum concentrations of NGMN and EE. This simple model can be a valuable tool to predict pharmacokinetic profiles in diverse scenarios such us non-compliance situations. Alternatively, the model can be conveniently adapted to anticipate the effect of variations on patch characteristics such as differences in contact area, doses, materials, among others.

A randomized clinical trial was conducted with 239 women at nine clinical research sites to compare bleeding profile, headache frequency, and subject satisfaction with the transdermal contraceptive, ORTHO EVRA® (norelgestromin/ethinyl estradiol transdermal system) used in an extended regimen (84 days) with a traditional, 28-day cyclic regimen. In a majority of women studied, compared with cyclic use, extended use of transdermal norelgestromin/ethinyl estradiol delayed menses and reduced the total incidence of mean headache days during the hormone-free interval.

Objective To compare the effects of continuous use of oral (OC), transdermal, and vaginal combined contraceptives on the pituitary-ovarian axis and inhibition of follicular development. Design Spin-off study of a prospective, randomized trial. Setting University clinic. Patient(s) Forty-two of 54 healthy women completed the study. Intervention(s) Treatment with combined OCs (ethinyl E 2 [EE] and desogestrel), transdermal patches (EE and norelgestromin), or vaginal rings (EE and etonogestrel) for 9 weeks continuously. Blood sampling was performed before and at 5 and 9 weeks of treatment. Main Outcome Measure(s) Changes in serum hormone levels induced by combined contraceptives. Result(s) Serum antimullerian hormone (AMH), FSH, inhibin B, LH, and E 2 levels had decreased significantly in all study groups after 9 weeks of treatment. Significant declines were already detected after 5 weeks' use of combined contraceptives with regard to all hormone levels apart from those of serum AMH, where the decrease between baseline and 5 weeks was only moderate. Between groups, serum levels of AMH, inhibin B, LH, and E 2 were comparable at baseline and after 5 and 9 weeks of treatment. Conclusion(s) The decrease of serum AMH levels during the use of all combined contraceptives indicates that folliculogenesis is arrested independently of administration route. Clinical Trial Registration Number NCT01087879.

Background: Pharmacokinetic (PK) interactions between lopinavir/ ritonavir (LPV/r) and transdermally delivered ethinyl estradiol (EE) and norelgestromin (NGMN) are unknown. Methods: Using a standard noncompartmental PK analysis, we compared EE area under the time―concentration curve (AUC) and NGMN AUC during transdermal contraceptive patch administration in HIV-1―infected women on stable LPV/r to a control group of women not on highly active antiretroviral therapy (HAART). In addition, EE AUC after a single dose of a combination oral contraceptive pill including EE and norethindrone was measured before patch placement and was compared with patch EE AUC in both groups. Contraceptive effects on LPV/r PKs were estimated by measuring LPV/r AUC at baseline and during week 3 of patch administration. Results: Eight women on LPV/r, and 24 women in the control group were enrolled. Patch EE median AUC 0―168 h was 45% lower at 6010.36 pg·h·mL ―1 in those on LPV/r versus 10911.42 pg·h·mL ―1 in those on no HAART (P = 0.064). Pill EE median AUC 0―48 hours was similarly 55% lower at 344.67 pg·h·mL ―1 in those on LPV/r versus 765.38 pg·h·mL ―1 in those on no HAART (P = 0.003). Patch NGMN AUC 0―168 h however, was 138.39 ng·h·mL ―1 , 83% higher in the LPV/r group compared with the control AUC of 75.63 ng·h·mL ―1 (P = 0.036). After 3 weeks on the patch, LPV AUC 0―8 h decreased by 19%, (P = 0.156). Conclusions: Although PKs of contraceptive EE and NGMN are significantly altered with LPV/r, the contraceptive efficacy of the patch is likely to be maintained. Larger studies are indicated to fully assess contraceptive efficacy versus risks of the transdermal contraceptive patch when co-administered with protease inhibitors.

BACKGROUND: The delivery of combination contraceptive steroids from a transdermal contraceptive patch or a contraceptive vaginal ring offers potential advantages over the traditional oral route. The transdermal patch and vaginal ring could require a lower dose due to increased bioavailability and improved user compliance. OBJECTIVES: To compare the contraceptive effectiveness, cycle control, compliance (adherence), and safety of the contraceptive patch or the vaginal ring versus combination oral contraceptives (COCs). SEARCH METHODS: Through February 2013, we searched MEDLINE, POPLINE, CENTRAL, LILACS, ClinicalTrials.gov, and ICTRP for trials of the contraceptive patch or the vaginal ring. Earlier searches also included EMBASE. For the initial review, we contacted known researchers and manufacturers to identify other trials. SELECTION CRITERIA: We considered randomized controlled trials comparing a transdermal contraceptive patch or a contraceptive vaginal ring with a COC. DATA COLLECTION AND ANALYSIS: Data were abstracted by two authors and entered into RevMan. For dichotomous variables, the Peto odds ratio (OR) with 95% confidence intervals (CI) was calculated. For continuous variables, the mean difference was computed. We also assessed the quality of evidence for this review. MAIN RESULTS: We found 18 trials that met our inclusion criteria. Of six patch studies, five examined the marketed patch containing norelgestromin plus ethinyl estradiol (EE); one studied a patch in development that contains levonorgestrel (LNG) plus EE. Of 12 vaginal ring trials, 11 examined the same marketing ring containing etonogestrel plus EE; one studied a ring being developed that contains nesterone plus EE. Contraceptive effectiveness was not significantly different for the patch or ring versus the comparison COC. Compliance data were limited. Patch users showed better compliance than COC users in three trials. For the norelgestromin plus EE patch, ORs were 2.05 (95% CI 1.83 to 2.29) and 2.76 (95% CI 2.35 to 3.24). In the levonorgestrel plus EE patch report, patch users were less likely to have missed days of therapy (OR 0.36; 95% CI 0.25 to 0.51). Of four vaginal ring trials, one found ring users had more noncompliance (OR 3.99; 95% CI 1.87 to 8.52), while another showed more compliance with the regimen (OR 1.67; 95% CI 1.04 to 2.68). More patch users discontinued early than COC users. ORs from two meta‐analyses were 1.59 (95% CI 1.26 to 2.00) and 1.56 (95% CI 1.18 to 2.06) and another trial showed OR 2.57 (95% CI 0.99 to 6.64). Patch users also had more discontinuation due to adverse events than COC users. Users of the norelgestromin‐containing patch reported more breast discomfort, dysmenorrhea, nausea, and vomiting. In the levonorgestrel‐containing patch trial, patch users reported less vomiting, headaches, and fatigue. Of 11 ring trials with discontinuation data, two showed the ring group discontinued less than the COC group: OR 0.32 (95% CI 0.16 to 0.66) and OR 0.52 (95% CI 0.31 to 0.88). Ring users were less likely to discontinue due to adverse events in one study (OR 0.32; 95% CI 0.15 to 0.70). Compared to the COC users, ring users had more vaginitis and leukorrhea but less vaginal dryness. Ring users also reported less nausea, acne, irritability, depression, and emotional lability than COC users. For cycle control, only one trial study showed a significant difference. Women in the patch group were less likely to have breakthrough bleeding and spotting. Seven ring studies had bleeding data; four trials showed the ring group generally had better cycle control than the COC group. AUTHORS' CONCLUSIONS: Effectiveness was not significantly different for the methods compared. Pregnancy data were available from half of the patch trials but two‐thirds of ring trials. The patch could lead to more discontinuation than the COC. The patch group had better compliance than the COC group. Compliance data came from half of the patch studies and one‐third of the ring trials. Patch users had more side effects than the COC group. Ring users generally had fewer adverse events than COC users but more vaginal irritation and discharge. The quality of the evidence for this review was considered low for the patch and moderate for the ring. The main reasons for downgrading were lack of information on the randomization sequence generation or allocation concealment, the outcome assessment methods, high losses to follow up, and exclusions after randomization.

Objective To evaluate the efficacy and tolerability of a contraceptive vaginal ring and transdermal patch in the treatment of endometriosis-associated pain. Design Patient preference cohort study. Setting Academic center. Patient(s) Two-hundred and seven women with recurrent moderate or severe pelvic pain after conservative surgery for symptomatic endometriosis. Intervention(s) Continuous, 12-month treatment with a vaginal ring supplying 15 mcg of ethinyl E and 120 mcg of etonogestrel per day or a transdermal system delivering 20 mcg of ethinyl E and 150 mcg norelgestromin per day. Main Outcome Measure(s) Satisfaction with treatment. Result(s) One-hundred and twenty-three women preferred the ring, and 84 preferred the patch. Forty-four ring users (36%) and 51 patch users (61%) withdrew. Thirty-six of 79 subjects (46%) in the ring group and 14 of 33 (42%) in the patch group shifted from continuous to cyclic use because of irregular bleeding. Pain symptoms were reduced by both treatments, with the ring being more effective than the patch in patients with rectovaginal lesions. According to an intention-to-treat analysis, 88 of 123 ring users (72%) and 40 of 84 patch users (48%) were satisfied with the treatment received. Conclusion(s) Patients who preferred the ring were significantly more likely to be satisfied and to comply with treatment than those who chose the patch. Both systems were associated with poor bleeding control when used continuously.

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.

Objective: The pharmacokinetics of norelgestromin, the primary active metabolite of norgestimate, plus ethinyl estradiol (EE), delivered by the once-weekly contraceptive patch (Ortho Evra™/Evra™), have been studied in eight trials. This overview summarizes the relevant pharmacokinetic data for the contraceptive patch. Design: Review article. Result(s): The amount of norelgestromin and EE absorbed from the patch is proportional to patch size: the 20-cm 2 patch (Ortho Evra™) delivers norelgestromin, 150 μg/d, and EE, 20 μg/d, to the systemic circulation. After single and multiple applications of the contraceptive patch, daily serum concentrations (area under the serum concentration-versus-time curve) of norelgestromin and EE were within the ranges generally seen with oral norgestimate, 250 μg/EE 35 μg (Ortho-Cyclen®/Cilest®), but without the peaks and troughs characteristic of oral dosing. Moreover, the contraceptive patch maintains serum concentrations of norelgestromin and EE within these ranges for up to 10 days, suggesting that clinical efficacy would be maintained even if a scheduled change is missed for as long as two full days. Regardless of the location of patch application (abdomen, buttock, upper outer arm, or torso [excluding breasts]) and even under conditions of heat, humidity, exercise, and cool-water immersion, efficacious concentrations of norelgestromin and EE are achieved. Coadministration of the patch with tetracycline did not affect the pharmacokinetics of norelgestromin and EE. Conclusion(s): The contraceptive patch exhibits an excellent pharmacokinetic profile, maintaining efficacious serum hormone concentrations under varying conditions.

Objective: To determine compliance with the contraceptive patch (Ortho Evra™/Evra™) overall and by age among women in North America and to compare rates of perfect use with those of an established oral contraceptive. Design: Data were pooled for three contraceptive studies in which women participated for up to 13 cycles; the subset of centers in North America was used in this analysis. Setting: 76 North American centers. Patient(s): Healthy women 18–45 years of age. Intervention(s): In all studies, the patch regimen was three consecutive 7-day patches (21 days) followed by 1 patch-free week per cycle. Main Outcome Measure(s): Perfect use for the patch or oral contraceptive, defined as 21 consecutive days of drug-taking followed by a 7-day drug-free period; for contraceptive patch users, no patch could be worn for more than 7 days. Oral contraceptives were used according to package labeling. Results: For all contraceptive patch users in North America (n = 1,785), perfect use was consistent across age groups. The percentage of cycles with perfect use of the patch ranged within age groups from 88.1% to 91.0%. In the comparative study conducted only in North America, perfect use was also consistent across age groups for the patch (n = 812), but rates of perfect use for the oral contraceptive (n = 605) differed significantly by age. Conclusion(s): Age did not affect compliance with the patch among all North American women studied. In a comparative study of women at North American centers, compliance with the weekly contraceptive patch was significantly better than with an established oral contraceptive. The contraceptive patch is uniformly easy to use across all ages.

To present efficacy and cycle control data pooled from three pivotal studies of the contraceptive patch (Ortho Evra/Evra).Three multicenter, open-label, contraceptive studies that included up to 13 treatment cycles.183 centers.3,319 women.Three consecutive 7-day patches (21 days) with 1 patch-free week per cycle.Contraceptive efficacy and cycle control.Overall and method failure life-table estimates of contraceptive failure through 13 cycles were 0.8% (95% CI, 0.3%-1.3%) and 0.6% (95% CI, 0.2%-0.9%), respectively. Corresponding Pearl indices were 0.88 (95% CI, 0.44-1.33) and 0.7 (95% CI, 0.31-1.10). Contraceptive failure among women with a body weight90 kg (198 lb) was low and uniformly distributed across the weight range. A subgroup of women with body weightor = 90 kg (or = 198 lb) may have increased risk of pregnancy. The incidence of breakthrough bleeding was low and decreased over time.In contraceptive patch users, the overall annual probability of pregnancy was 0.8% and the method failure probability was 0.6%. The efficacy of the patch was high and similar across age and racial groups. Among women90 kg (198 lb), contraceptive failure was low and uniformly distributed across the range of body weights. In womenor = 90 kg (or = 198 lb), contraceptive failures may be increased. Efficacy and cycle control have been shown to be comparable to an established oral contraceptive.

Transdermal contraception is a convenient way of hormonal contraception that allows weekly application of a patch for 3 consecutive weeks followed by a patch-free week. Efficacy side effects advantages and disadvantages as well as patient satisfaction with this formulation are discussed in this short review. The first patch introduced in 2002 contained ethinylestradiol and norelgestromin. Recently a new patch containing gestodene as the gestagen component has been developed. Early data for this formulation are presented.