Comparison of Combined Parenteral and Oral Hormonal Contraceptives: A Systematic Review and Meta-Analysis of Randomized Trials.

BACKGROUND: Delivering contraceptive hormones through a transdermal patch or a vaginal ring might have advantages over the traditional oral route. OBJECTIVES: To compare the effectiveness, compliance, and side effect profile of oral and parenteral drug administration methods. METHODS: We performed a systematic literature search in four medical databases-MEDLINE (via PubMed), Cochrane Library (CENTRAL), Embase, and Scopus-from inception to 20 November 2022. Randomized controlled trials assessing the efficacy, compliance, and adverse event profile of combined parenteral and oral hormonal contraceptives were included. RESULTS: Our systematic search provided 3952 records; after duplicate removal, we screened 2707 duplicate-free records. A total of 13 eligible studies were identified after title, abstract, and full-text selection. We observed no significant difference in contraceptive efficacy (Pearl Index) between oral and parenteral drug administration (MD = -0.06, CI: -0.66-0.53; I2 = 0%). We found significant subgroup differences between parenteral methods in terms of compliance (χ2 = 4.32, p =0.038, I2 = 80%) and certain adverse events: breast discomfort (χ2 = 19.04, p =0.001, I2 = 80%), nausea (χ2 = 8.04, p =0.005, I2 = 75%), and vomiting (χ2 = 9.30, p =0.002; I2 = 72%). CONCLUSION: Both parenteral and oral contraceptives can be used as an effective contraceptive method, and the route of administration should be tailored to patient needs and adverse event occurrence.

[Combined Hormonal Contraception - Which Pill for Which Patient?] / Kombinierte hormonelle Kontrazeption ­ welches Präparat für welche Indikation?

Combined Hormonal Contraception - Which Pill for Which Patient? Abstract. Combined hormonal contraceptives (CHC) are a valuable and highly effective option in contraceptive counseling. Methods and preparations available in Switzerland are combined oral contraceptives (COC), vaginal rings and transdermal patches. All preparations contain an estrogen and a progestin component. The estrogen component mainly consists of the synthetically produced ethinylestradiol (EE), although newer COC may contain natural estrogens such as estradiol (E2) and estetrol (E4). For the progestin component, a variety of luteal body hormones are available, which enable the health care professional to prescribe a "tailored" product for the patient due to their different partial effects. The individual thromboembolism (TE) risk should always be considered and taken into account when prescribing CHC.

New Contraception Update - Annovera, Phexxi, Slynd, and Twirla.

Purpose of Review: In this review, we discuss the efficacy, safety, and benefits of four new contraceptive products available in the USA, specifically Annovera, Phexxi, Slynd, and Twirla. Recent Findings: Annovera is a vaginal ring releasing ethinyl estradiol and segesterone acetate that can be used for up to one year (13 cycles), offering patients an effective, user-controlled option that may improve contraceptive access for those in low-resource settings or those with barriers to retrieving monthly prescriptions; however, given limited efficacy and safety data in people with body mass index (BMI) > 29 kg/m2, clinicians may consider whether Annovera is an appropriate contraceptive method for obese patients if there are other acceptable alternatives. Phexxi prescription-only vaginal gel is a user-controlled, non-hormonal, on-demand contraceptive method that represents a novel addition to the market with its additional uses as a personal lubricant and as a potential microbicide for urogenital infection prevention. Slynd, a drospirenone-only pill, provides more flexibility for delayed or missed pills while maintaining efficacy and a more favorable bleeding profile compared with previously available progestin-only pills. Lastly, Twirla is a transdermal patch releasing ethinyl estradiol and levonorgestrel that offers users an additional option for a user-controlled, combined hormonal contraceptive method without daily dosing; however, prescription is limited to patients with BMI < 30 kg/m2 due to decreased efficacy and VTE events in people with obesity. Summary: The addition of these products expands the available options for pregnancy prevention to address unmet contraceptive needs.

The new low-dose transdermal contraceptive system (Twirla®): results from preclinical and Phase III trials.

A new low-dose, once-a-week contraceptive transdermal delivery system (TDS) with 2.3-mg ethinyl estradiol (EE) and 2.6-mg levonorgestrel (LNG; Twirla®) has recently been approved by the US FDA for contraception of women with BMI <30 kg/m2. The rationale for developing this new patch, the preclinical study results and the results from two innovative Phase III clinical trials demonstrate that this patch has an acceptable Pearl index (4.3%) for its indicated users and has safety and tolerability comparable to other similar dose oral combined hormonal contraceptives. This new TDS provides an improvement over the existing TDS products, with significantly lower steady-state estrogen exposure, a level equal to that with 30-µg EE containing oral contraceptives.

Lay abstract A new patch with lower doses of estrogen than existing contraceptive patches has been approved by the US FDA for birth control for women who are not obese. It has been tested in two large clinical trials that included women who are like the general population of reproductive age women in the USA. Up-to-date electronic diaries were used to get the most accurate information to use to counsel women who might appreciate the convenience of once-a-week patch use. The patch worked better in lighter women than those who were heavier, and it appears to be safer in women with lower BMIs too.

Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: Phase 3 clinical trial results.

OBJECTIVE: To assess the contraceptive efficacy, safety, and tolerability of a contraceptive transdermal delivery system, (TDS; TWIRLAⓇ) containing levonorgestrel (LNG) and ethinyl estradiol (EE). STUDY DESIGN: This single-arm, open-label, multicenter, 1-year (13 cycle), phase 3 study enrolled sexually active women ≥18 years old at risk for pregnancy irrespective of body mass index (BMI). Women used patches in 28-day cycles (3 consecutive administrations of 7-day patches followed by 7 days off-treatment/patch-free week). We assessed contraceptive efficacy by the Pearl Index (PI) in women 18 to 35 years, excluding cycles without intercourse or when other contraceptive methods were used. RESULTS: The study enrolled 2032 demographically diverse women in the US, of which 35.3% had a BMI ≥30 kg/m2. In the primary efficacy analysis, the PI (95% confidence interval) was 5.8 (4.5-7.2) pregnancies per 100 woman-years. PIs trended higher as BMI increased; the PI was 4.3 (2.9-5.8) in women with BMI <30 kg/m2 and 8.6 (5.8-11.5) in women with BMI ≥30 kg/m2. Hormone-related treatment-emergent adverse events included nausea (4.1%) and headache (3.6%); 11% of women discontinued due to adverse events. Four women (all with BMIs ≥30 kg/m2) reported thromboembolic events considered related to treatment. CONCLUSIONS: The low-dose LNG/EE TDS was effective in preventing pregnancy in a population of women representative of US demographics. Efficacy was reduced in women with BMI ≥30 kg/m2. The TDS safety and tolerability profile was consistent with other similar dose combined hormonal contraceptives. Results of this phase 3 study supported the US Food and Drug Administration approval of TWIRLAⓇ for prevention of pregnancy in women with BMI <30 kg/m2. IMPLICATIONS: TDS (120 µg/day levonorgestrel and 30 µg/day ethinyl estradiol) is an effective, low-dose transdermal contraceptive patch with favorable tolerability profile approved for prevention of pregnancy in women with BMI <30 kg/m2. TDS has reduced effectiveness in women with BMI ≥30 kg/m2.

Pill, patch or ring? A mixed methods analysis of provider counseling about combined hormonal contraception.

OBJECTIVE: In this study we aimed to investigate the content and process of contraceptive counseling surrounding combined hormonal contraceptive (CHC) methods (combined oral contraceptives, the ring, and the patch). STUDY DESIGN: We performed a mixed methods analysis of data collected as part of the Patient-Provider Communication about Contraception study, in which reproductive age women and their providers were recruited at several San Francisco Bay Area clinics from 2009-2012. Participants completed pre- and post-visit surveys, and had their visits audio recorded and transcribed. We performed descriptive and bivariate analyses of the entire cohort to examine associations between demographic characteristics and pre-existing method preferences with method selection and counseling content, and coded transcripts of a subset of the sample for salient themes related to content and process of counseling about combined hormonal contraceptive methods using a directed content analysis approach. RESULTS: The overall sample included 342 women, with 152 women (44%) having a preference for a specific CHC prior to their visit, 127 women (37%) had a preference for a non-CHC method, and 63 (18%) having no existing method preference. Of the women who reported preferring a CHC in their pre-visit survey, the majority (72%) chose that method. We found that women were inconsistently counseled about the range of CHC methods. For example, women who had no pre-visit method preference (52%) or who preferred the ring (54%) or the patch (73%) were more likely to receive comprehensive counseling about the three CHC methods than were women who preferred combined oral contraceptives (35%) or non-CHC methods (33%). Providers mentioned the patch the least often, and in qualitative analysis indicated discomfort with prescribing this method. Side effects and benefits of methods, as well as strategies to enhance successful use of the chosen method, were inconsistently discussed. In only 73% of visits in which a woman chose a CHC did the provider assess the patient's ability to use the chosen method correctly, and in 66% of all visits in which women chose a CHC method, providers discussed what to do if she was dissatisfied with the method. CONCLUSIONS: Counseling about combined hormonal contraceptive methods often does not include information about all available methods, or comprehensive information about side effects, benefits, or logistics of use. As this counseling can impact patient's satisfaction with and continuation of their chosen method of contraception, future work should focus on designing interventions to improve providers' ability to meet patients' needs. IMPLICATIONS: Short acting hormonal contraception is widely used, but counseling for these methods often neglects key features. Comprehensive counseling about all methods and their individual features can improve contraceptive selection and use.

Phase I/II pharmacokinetic and pharmacodynamic evaluation of two levonorgestrel-only contraceptive patches in a multicenter randomized trial.

OBJECTIVES: To evaluate the pharmacokinetic and pharmacodynamic effects of two novel levonorgestrel (LNG)-only contraceptive patches. STUDY DESIGN: This multi-center Phase I/II trial randomized participants to use a 7-day transdermal patch designed to deliver a 40 mcg or 75 mcg daily LNG dose for 11 consecutive weeks; randomization was stratified by body mass index (BMI) <32 or 32-40 kg/m2. Evaluations occurred twice weekly for 5 weeks, then once weekly with supplemental visits for participants reporting a urinary LH surge. We evaluated pharmacokinetics via the weekly trough serum LNG concentrations (≥180 pg/mL considered therapeutic). The primary pharmacodynamic outcomes were cervical mucus and ovulation, evaluated using modified Insler cervical mucus scores and serum markers of ovulation. RESULTS: Randomization yielded similar groups. Of 121 enrolled women, 117 contributed analyzable data. Overall, mean LNG concentrations achieved with use of the 75 mcg patch [value] were roughly double those seen with the 40 mcg dose. Concentrations achieved in higher-BMI women (BMI=32-40 kg/m2) were 50% lower compared to lower-BMI women for both patches. During the study, 94/117 (80%) participants had at least one LNG concentration <180 pg/mL. Insler scores were ≥5 at least once in 102/117 (87%) of participants, and ovulation occurred at least once in 81/117 (69%). Sixty participants (51%) had at least one ovulation following an Insler score ≥5; this occurred most frequently among higher-BMI participants using the lower-dose patch (19/25, 76%). CONCLUSIONS: Women using two investigational LNG patches did not achieve consistent concentrations of LNG >180 pg/mL, an efficacy benchmark established in other studies with LNG implants, and they experienced high rates of ovulation as well as cervical mucus scores not supportive of high contraceptive efficacy. IMPLICATIONS: The novel LNG-only patches in this study may not adequately decrease pregnancy risk, particularly for higher-BMI women. Future studies of LNG-only contraceptive patches will need to employ higher LNG doses and assess the acceptability and safety of such dosing.

Transdermal delivery of combined hormonal contraception: a review of the current literature.

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.

No. 329-Canadian Contraception Consensus Part 4 of 4 Chapter 9: Combined Hormonal Contraception.

OBJECTIVE: To provide guidelines for health care providers on the use of contraceptive methods to prevent pregnancy and on the promotion of healthy sexuality. OUTCOMES: Overall efficacy of cited contraceptive methods, assessing reduction in pregnancy rate, safety, and side effects; the effect of cited contraceptive methods on sexual health and general well-being; and the availability of cited contraceptive methods in Canada. EVIDENCE: Medline and the Cochrane Database were searched for articles in English on subjects related to contraception, sexuality, and sexual health from January 1994 to December 2015 in order to update the Canadian Contraception Consensus published February-April 2004. Relevant Canadian government publications and position papers from appropriate health and family planning organizations were also reviewed. VALUES: The quality of the evidence is rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice are ranked according to the method described in this report. SUMMARY STATEMENTS: RECOMMENDATIONS.

No 329-Consensus canadien sur la contraception (4e partie de 4) : chapitre 9 ­ contraception hormonale combinée.

OBJECTIF: Mettre à la disposition des fournisseurs de soins des lignes directrices concernant le recours à des méthodes contraceptives pour prévenir la grossesse et la promotion d'une sexualité saine. ISSUES: Efficacité globale des méthodes contraceptives citées : évaluation de l'innocuité, des effets indésirables et de la baisse du taux de grossesse; effet des méthodes contraceptives citées sur la santé sexuelle et le bien-être général; disponibilité des méthodes contraceptives citées au Canada. RéSULTATS: Des recherches ont été effectuées dans MEDLINE et la base de données Cochrane afin d'en tirer les articles en anglais publiés entre janvier 1994 et décembre 2015 traitant de sujets liés à la contraception, à la sexualité et à la santé sexuelle, dans le but de mettre à jour le consensus canadien sur la contraception paru de février à avril 2004. Nous avons également passé en revue les publications pertinentes du gouvernement canadien, ainsi que les déclarations de principes issues d'organisations compétentes vouées à la santé et à la planification familiale. VALEURS: La qualité des résultats a été évaluée au moyen des critères décrits par le Groupe d'étude canadien sur les soins de santé préventifs. Les recommandations quant à la pratique sont classées en fonction de la méthode décrite dans le rapport du Groupe. DéCLARATIONS SOMMAIRES: RECOMMANDATIONS.

The pharmacokinetics of 12-week continuous contraceptive patch use.

OBJECTIVES: We sought to assess the change in serum ethinyl estradiol (EE2) and norelgestromin (NGMN) levels over 12 weeks of continuous contraceptive patch use. STUDY DESIGN: We asked participants (n=30) to apply consecutive patches to be worn continuously (without a patch-free interval) for 12 weeks. We collected blood samples at the end of each patch week and two times during weeks 4, 8, and 12 (with the additional blood draw occurring mid-week). Liquid chromatography-tandem triple quadrupole mass spectrometry (LC-MS/MS) was utilized to assess EE2 and NGMN levels. RESULTS: Twenty-seven women completed the study; 26 were compliant with patch use. Ethinyl estradiol levels ranged from 0 to 193 pg/mL over the period. We observed an accumulation over the 12-week time at an estimated rate of 2.15 pg/mL per week (95% confidence interval 0.95-3.35, p<.001). The change in NGMN levels ranged from 0 to 2.52 ng/mL over the 12 weeks (95% confidence interval 0.021-0.019, p=.915). The most common side effects reported were vaginal spotting, breast tenderness and abdominal pain/cramping. There were no serious adverse events reported. CONCLUSION: While the range of weekly EE2 values was quite wide, the absolute values remain low and generally within the expected range described in product labeling. Providers may consider prescribing continuous use of the patch, but given the slow accumulation of EE2 over time, 12 weeks should not be exceeded in the absence of safety data.

An open-label, two-period comparative study on pharmacokinetics and safety of a combined ethinylestradiol/gestodene transdermal contraceptive patch.

We investigated the pharmacokinetics and safety profiles of a newly developed combined ethinylestradiol (EE)/gestodene (GSD) transdermal contraceptive patch after a single-dose administration and compared with the market available tablet formulation in healthy adult subjects. An open-label, two-period comparative study was conducted in 12 healthy women volunteers. A single dose of the study combined EE/GE transdermal contraceptive patch and oral tablet (Milunet®) were administered. Blood samples at different time points after dose were collected, and concentrations were analyzed. A reliable, highly sensitive and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS) assay method was developed in this study to determine the plasma concentrations of EE and GSD. Compared to the tablet, the study patch had a significantly decreased maximum plasma concentration (Cmax), extended time to reach the Cmax and half-life, as well as increased clearance and apparent volume of distribution. The half-lives of EE and GSD of the patch were 3.3 and 2.2 times, respectively, than the half-life of the tablet. The areas under the plasma concentration-time curve (AUCs) of EE and GSD of the patch were 8.0 and 16.2 times, respectively, than the AUC of the tablet. No severe adverse event was observed during the whole study, and the general safety was acceptable. In conclusion, compared to the oral tablet Milunet, the study contraceptive patch was well tolerated and showed potent drug exposure, significant extended half-life and stable drug concentrations.

Simultaneous determination of levonorgestrel and ethinylestradiol in New Zealand rabbit plasma by liquid chromatography-tandem mass spectrometry and their pharmacokinetics / 中国药理学与毒理学杂志

OBJECTIVE To establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous determinations of concentrations of levonorgestrel (LNG) and ethinylestradiol (EE) in New Zealand rabbit plasma, and to study their pharmacokinetics in New Zealand rabbits after multiple dosing. METHODS Six female New Zealand rabbits were given LNG/EE patches ten times (5 cm × 4 cm, each patch contained LNG 5.35 mg and EE 0.11 mg), 1 patch every 3 d, for 30 consecutie days. Blood samples were collected at different time points before and after drug administration. The plasma samples were derived with dansyl chloride and then analyzed by HPLC-MS/MS method. The main pharmacokinetic parameters were calculated using DAS3.0 software. RESULTS The linear concentra-tion range of LNG was 0.10-20.00μg · L-1. The lower limit of quantitation was 0.10μg · L-1. The extrac-tion recovery was more than 78.30％. The intra-day and inter-day precisions were both less than 12.89％. The first-dosing pharmacokinetic parameters for LNG were as follows:Cmax (8.10±2.38)μg·L-1, Tmax (2.38±1.45) h, and AUC(0-768) (142.35±36.99) h·μg·L-1. The last administration pharmacokinetic parameters for LNG were as follows:Cmax (7.05±1.07)μg·L-1, Tmax (2.71±1.83) h, and AUC(0-768) (141.95±22.31) h·μg·L-1. The linear concentration range of EE was 0.02-5.00μg·L-1. The lower limit of quantitation was 0.02μg·L-1. The extraction recovery was above 79.99％. The intra-day and inter-day precisions were both less than 12.76％. The first-dosing pharmacokinetic parameters for EE were as follows: Cmax (0.18 ± 0.04)μg · L-1, Tmax (2.50±1.30) h, and AUC(0-768) (2.65±0.56) h·μg·L-1. The last administration pharmacokinetic parame-ters for EE were as follows:Cmax (0.17 ± 0.07)μg · L-1, Tmax (2.17 ± 0.26)h, and AUC(0-768) (2.02 ± 0.82) h ·μg · L-1. CONCLUSION The HPLC-MS/MS determination method is accurate and sensitive, which can be used to simultaneously determine the concentration of LNG and EE. There are no significant differences in main pharmacokinetic parameters between the first dose and the last dose. After repeated administration of this contraceptive patch, there is no accumulation of blood concentration in the rabbit body.

Ethinyl estradiol and levonorgestrel in a transdermal contraceptive delivery system.

INTRODUCTION: The new transdermal contraceptive delivery system (TCDS) developed by Agile Therapeutics containing ethinyl estradiol and levonorgestrel (EE/LNG) is a reversible contraceptive method that maintains stable serum levels of both estrogen and progestin, and has efficacy similar to that of combination oral contraceptives (COC). AREAS COVERED: We provided information of this new TCDS compared with the only TCDS available on the market that contains EE and norelgestromin, and has a higher EE exposure than a COC with 35 µg of EE potentially increasing the risk of venous thromboembolism. The article will summarize finding from clinical studies Phase I, II and III of EE/LNG TCDS. EXPERT OPINION: The development of the lower dose EE/LNG TCDS has demonstrated less EE exposure. The serum levels of EE and LNG were stable and comparable between various application sites and daily life conditions. Moreover, the EE/LNG TCDS showed comparable efficacy among obese and non-obese users. However, the Pearl index of this EE/LNG TCDS is questionable and the problem of compliance is a potential confounder of the results. The current Phase III efficacy study will contribute to a further evaluation of compliance and efficacy and will be completed in 2016.

Pharmacy claims data versus patient self-report to measure contraceptive method continuation.

OBJECTIVE: To compare self-reported 12-month continuation of oral contraceptive pills (OCPs), patch, and ring versus continuation by pharmacy claims data. STUDY DESIGN: Women in the Contraceptive CHOICE Project who chose OCPs, the patch, or the ring as their initial method were included. Continuation was assessed by periodic telephone survey and by obtaining prescription claims data. Continuation was defined as no gap of more than 30 days. Kaplan-Meier survival functions were used to estimate continuation rates and cumulative unintended pregnancy rates. Kappa statistic assessed the level of agreement between self-report and claims data. RESULTS: We analyzed 1510 women who initiated use by 3 months and provided information on discontinuation. Of OCP users, 59% continued their method at 12 months by self-report versus 38% by pharmacy claims. Patch and ring users had self-reported/pharmacy continuation of 45%/28% and 57%/37%, respectively. Kappa coefficients and their 95% confidence intervals between the two measurements were 0.46 (0.40, 0.52), 0.54 (0.39, 0.68), and 0.54 (0.47, 0.61) for OCP, patch, and ring, respectively. Among women who self-reported continuation, unintended pregnancy rates were 0.4% in those who continued by pharmacy claims versus 4.9% in those who discontinued according to claims data. CONCLUSION: Contraceptive continuation rates differ by self-report versus pharmacy claims with women overestimating their continuation by self-report. IMPLICATIONS: This article directly compares contraception continuation rates by self-report and by pharmacy claims data. The study suggests that previously reported continuation rates from survey data overestimate specific method use.

Transdermal contraception and the renin-angiotensin-aldosterone system in premenopausal women.

The oral contraceptive pill (OCP) activates the renin-angiotensin-aldosterone system (RAAS) through first-pass hepatic metabolism. Although usually benign, RAAS activation may have detrimental effects on renal and hemodynamic function in some women. Since combined hormonal contraception with the transdermal patch (EVRA) does not undergo first-pass hepatic metabolism, we hypothesized that the RAAS response would be different from that of OCP subjects. Thirty-five nonsmoking, premenopausal women (15 control subjects, 10 OCP subjects, and 10 contraceptive patch subjects) without evidence of cardiovascular disease, renal disease, or diabetes were studied. Baseline angiotensinogen, renin, angiotensin II, aldosterone, and plasma renin activity were assessed along with hormonal and hemodynamic responses to simulated orthostatic stress using incremental lower body negative pressure (LBNP; -15, -25, and -40 mmHg). Baseline levels of angiotensinogen, angiotensin II, and plasma renin activity were significantly higher in OCP subjects compared with normotensive control and contraceptive patch subjects (P < 0.05), whereas aldosterone was significantly higher in OCP versus control subjects only (P < 0.05). Plasma renin levels were significantly lower at baseline in contraceptive patch subjects compared with normotensive control and OCP subjects (P < 0.05). In response to LBNP, increases in renin, angiotensin II, and aldosterone were attenuated in contraceptive patch subjects in conjunction with an exaggerated decline in mean arterial pressure (P < 0.05 vs. control and OCP subjects). The contraceptive patch in healthy premenopausal women is associated with an impaired ability to maintain blood pressure in response to LBNP, possibly due to insensitivity of the endogenous RAAS. Further evaluation may be beneficial in women with kidney disease.

Self-reported and verified compliance in a phase 3 clinical trial of a novel low-dose contraceptive patch and pill.

OBJECTIVE: Pregnancy rates in US contraceptive clinical trials are increasing due to decreased treatment compliance. This study compared compliance with a new low-dose levonorgestrel (LNG) and ethinyl estradiol (EE) contraceptive patch (CP, Twirla™) with that of a low-dose combination oral contraceptive (COC) in a demographically diverse population. STUDY DESIGN: This analysis was part of an open-label, parallel-group, multicenter phase 3 study that randomized healthy sexually active women (17-40years) to 13cycles of LNG/EE CP or 6cycles of COC, then 7cycles of LNG/EE CP. We defined self-reported compliance as cycles that, according to diaries, show 21days of patch wear without missed days or any patch worn >7days or 21days of pill-taking without missed pill days. We verified compliance by detectable plasma presence of LNG and EE at cycles 2, 6, and 13. RESULTS: Of the intention-to-treat population with diary information (N=1328, mean age 26.4years, 46% minorities, 33% obese), 10.0% of the CP (n=998) versus 21.2% of the COC group (n=330) self-reported noncompliance after 6cycles (p<.001). Laboratory assessments verified 10-14% of participants in both groups as noncompliant. Self-reported perfect use did not vary between obese [body mass index (BMI) ≥30kg/m(2)] versus nonobese (BMI <30kg/m(2)) participants in both groups or when stratified by age, education, or race/ethnicity in the CP group. CONCLUSIONS: Self-reported compliance was significantly greater in the CP than COC group and did not vary by obesity status. Discrepancies between self-reported and verified compliance question reliability of patient diaries. IMPLICATIONS STATEMENT: This paper, based on an analysis of a phase 3 trial, shows that compliance was significantly greater with a new weekly transdermal CP than with a once-daily COC in obese as well as nonobese participants. Discrepancies between self-reported compliance and laboratory-verified compliance raise questions regarding the reliability of patient diaries.

Pharmacokinetics and adhesion of a transdermal patch containing ethinyl estradiol and gestodene under conditions of heat, humidity, and exercise: A single-center, open-label, randomized, crossover study.

In this open-label, randomized study, 36 women (18-45 years) applied an ethinyl estradiol/gestodene contraceptive patch once-weekly for 3 weeks followed by a 1-week, patch-free interval, in 3 treatment periods. The primary objective was to evaluate the pharmacokinetics of ethinyl estradiol and gestodene under conditions of heat, humidity, and exercise. The secondary objective was to evaluate patch adhesion under the same conditions. Weeks 1 and 2 of each period comprised "standardized normal activity" (SNA); in week 3, SNA continued or women used a sauna, whirlpool, swimming pool, or performed an exercise combination. Thirty-one women completed the study; 23 yielded evaluable pharmacokinetic data. Analyses were exploratory and conducted using an analysis of variance. Area under the concentration-time curve from 0 to 168 hours (AUC0-168 ) for gestodene and ethinyl estradiol during sauna, swimming, and whirlpool was equivalent to previous SNA recordings. For exercise combination, the gestodene AUC0-168 was 12% lower compared with SNA, albeit not considered clinically relevant. Two women lost a total of 3 patches during sporting activities; other detachments during this week were not correlated with sporting activity. Overall, hormone delivery using the ethinyl estradiol/gestodene patch under conditions of heat, humidity, and exercise corresponded to delivery under normal conditions.

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.

A comparison of bleeding patterns and cycle control using two transdermal contraceptive systems: a multicenter, open-label, randomized study.

OBJECTIVE(S): To investigate the bleeding pattern and cycle control parameters of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a patch containing 0.6 mg EE and 6 mg norelgestromin (NGMN). STUDY DESIGN: In this phase III, open-label, randomized, parallel-group trial, healthy women aged 18-35 years (smokers aged 18-30 years) received either the EE/GSD patch (n=200) or the EE/NGMN patch (n=198). Treatment consisted of one patch per week for 3 weeks followed by a 7-day, patch-free interval for seven cycles. Bleeding control was assessed in two 90-day reference periods. RESULTS: In reference period 1, mean number of bleeding/spotting days was comparable across treatment groups (p>0.05). However, in reference period 2, there were fewer bleeding/spotting days in the EE/GSD patch group (15.7 versus 18.4; p<0.0001). Mean number of bleeding/spotting episodes was comparable across groups for both reference periods, but bleeding/spotting episodes were shorter for the EE/GSD patch than the EE/NGMN patch during reference period 1 (5.13 days versus 5.53 days, respectively; p<0.05) and reference period 2 (5.07 versus 5.66; p=0.0001). Both treatment groups showed a similar frequency of withdrawal bleeding episodes; however, across all seven cycles, the length of these episodes was consistently shorter with the EE/GSD patch (p<0.01). There were no notable treatment differences in intracyclic bleeding. CONCLUSION(S): Bleeding pattern and cycle control achieved with the EE/GSD patch was similar to that of the EE/NGMN patch. IMPLICATIONS STATEMENT: The paper presents data on the bleeding pattern and cycle control parameters of an investigational transdermal contraceptive patch containing EE and GSD compared with an approved contraceptive patch containing EE and NGMN. This descriptive study found that bleeding patterns associated with the EE/GSD patch were similar to those of an EE/NGMN patch providing higher EE exposure.