Elsevier

Contraception

Volume 101, Issue 4, April 2020, Pages 276-282
Contraception

Original Research Article
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☆,☆☆

https://doi.org/10.1016/j.contraception.2019.12.012Get rights and content

Abstract

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.

Introduction

A transdermal contraceptive patch containing estrogen and progestin is effective and convenient, and thus its use is associated with improved compliance when compared with oral contraceptives [1], [2], [3]. The norelgestromin (NGMN) and ethinyl estradiol (EE) transdermal contraceptive patch (NGMN-EE patch), containing 6 mg NGMN and 600 µg EE [4], is currently available in 60 countries worldwide. The 20 cm2 patch, used once weekly for 3 consecutive weeks followed by a patch-free week, has average daily release rates of ~203 µg/day for NGMN and ~33.9 µg/day for EE [4]. The steady-state concentrations (Css) for NGMN (~0.8 ng/mL) and EE (~50 pg/mL) were achieved by 48 h after single application and maintained throughout the recommended wear period of 7 days [5], [6]. Further, contraceptive efficacy of the NGMN-EE patch has been demonstrated in phase 2 and 3 studies with an overall Pearl Index of 1.24 (95% CI, 0.9–2.33) [7], [8].

The NGMN-EE patch consists of 3 layers, a contact adhesive/drug-containing layer, a colored protective backing layer, and a disposable polyester film (release liner) that protects the contact layer and is removed prior to application. The adhesive/drug layer of the patch contains several excipients (e.g., crospovidone, lauryl lactate, and polyisobutylene [PIB]/polybutene) that facilitate drug delivery and skin adhesion. The adhesive component in the currently marketed NGMN-EE patch comprises a high molecular weight PIB, which has been discontinued by the manufacturer, and hence an equivalent alternative has to be identified. The newly sourced high molecular weight PIB is expected to have similar drug delivery and adhesion properties and may serve as an alternate adhesive component.

The present study aimed to establish the bioequivalence of a transdermal contraceptive patch containing the newly sourced adhesive component (test patch) and the currently marketed patch (reference patch). Additionally, the adhesion properties, irritation potential, and safety and tolerability of the test and the reference patch were compared.

Section snippets

Participants

Healthy women aged 18–45 years, with body mass index (BMI) ≥18 and ≤30 kg/m2, and body weight ≤100 kg were enrolled in this study. Participants were included if they were normotensive (systolic/diastolic blood pressure 90–140 mm Hg/≤90 mm Hg); had normal sinus rhythm with heart rate (HR) ≥45 and ≤100 beats per minute; QT interval corrected for HR according to Fridericia’s formula (QTcF) ≤470 ms; QRS interval ≤120 ms; PR interval ≤220 ms; 12-lead electrocardiogram consistent with normal cardiac

Disposition and baseline demographics

Overall, 70 women were enrolled and randomized to one of the four treatment sequences (Fig. 1). Of 70 participants, 63 (90%) completed both treatment periods and seven (10%) withdrew (Fig. 1). Mean (SD) age, body weight, and BMI were 31.5 (7.87) years, 66.1 (8.6) kg, and 24.0 (2.86), respectively; 62 (88.6%) of the participants were White. Immunological laboratory analyses (for HIV, hepatitis B virus surface antigen, and hepatitis C virus antibody) were negative for all participants.

Pharmacokinetic results

The PK

Discussion

The present study evaluated the bioequivalence of a contraceptive patch containing the newly sourced adhesive component compared with the currently marketed NGMN-EE patch. For both active components, EE and NGMN, the mean plasma concentration–time profiles and exposures, as measured by Css and AUCs after a single 7-day application of the test patch, was bioequivalent to that of the currently marketed patch. The intra-subject CV for PK parameters was estimated using the formula: CV2 = exp(SD2

Authors’ contributions

DAP (Study Responsible Clinical Pharmacologist) and SV (Study Responsible Physician): participated in study design, protocol development, and data analysis and interpretation. SV: responsible for study medical/safety monitoring. JA and JN (Lead Statisticians): contributed to study design, protocol development, statistical analyses and data interpretation. FR (Principle Investigator): responsible for the study conduct and safety of participants. JM: provided background expertise, contributed to

Acknowledgments

Authors thank the staff at the Clinical Pharmacology Unit (Janssen Research & Development, Merksem, Belgium) for their efforts during study conduct, Dr. Yang Lu (Frontage Laboratories, PA) for bioanalytical services, Lan Lan and Dr. Joanna Magielse (SGS Life Sciences) for pharmacokinetic data analysis, Bishakha Majumder and Hitendra Pandey (Tata Consultancy Services Ltd., Mumbai, India) for biostatistics and programming services, and Drs. Jyothi Ramanathan (SIRO Clinpharm Pvt Ltd., Hyderabad,

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Funding: This work was supported by Janssen Research & Development, LLC.

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Declaration of conflicts of interest: All authors are employees of Janssen Research and Development.

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