Bioequivalence Study of Patches With Different Release Profiles
Condition: Female Contraception
Study type: Observational

Summary: 
      The purpose of this study was to determine the bioequivalence of a norelgestromin/ethinyl
      estradiol (NGMN/EE) transdermal contraceptive system.
    

Detailed description: 
      The primary objective was to determine the bioequivalence of a norelgestromin/ethinyl
      estradiol (NGMN/EE) transdermal contraceptive system lot with a cumulative release profile
      below the lower limit of the specifications (low spec lot) compared with a currently marketed
      lot of EVRANORELGESTROMIN/ETHINYL ESTRADIOL with a cumulative release profile well within the
      specifications limits (reference lot), after application to the buttock. This was a single
      center, randomized, double-blind, 2 way crossover study. The double-blind treatment phase
      included two 7-day treatment periods separated by a 28 day washout period. Safety was
      assessed throughout the study. The study population was comprised of healthy women aged 18 to
      45 years, inclusive, who weighed at least 110 pounds with a body mass index (BMI) between 16
      and 29.9 kg/m2, and a hematocrit of at least 36%. Eligible patient were randomly assigned to
      1 of 2 treatment sequence groups. A 20 cm2 NGMN/EE transdermal contraceptive patch (low spec
      lot [test] or EVRANORELGESTROMIN/ETHINYL ESTRADIOL [reference]) was applied to each patient
      on the buttock and worn for 7 days. Twenty-eight days after removal of the first patch (Day
      36 of Period 2), the patient crossed over to the other treatment. After each patch was
      removed, the skin was checked for redness and swelling. Blood samples were collected for
      measurement of drug concentrations during the 7-day wear periods and for 3 days after each
      patch was removed. Patients were telephoned weekly during the washout period to remind them
      to use back-up contraception. After the last blood sample collection on Day 46, or in
      instances where the patient withdrew early from the study, post treatment procedures
      including physical and gynecologic examinations, vital signs, laboratory evaluations, and a
      serum pregnancy test were performed. The following pharmacokinetic parameters were to be
      estimated for NGMN, NG, and EE after low spec lot and EVRANORELGESTROMIN/ETHINYL ESTRADIOL
      patch application: Cmax - maximum observed serum concentration after patch application; tmax
      - time of maximum serum concentration after patch application; Css - mean steady-state
      concentration for NGMN and EE after patch application calculated as the mean concentration
      between 48 and 168 hours; Cavg - average concentration for NG calculated as AUC168/168; AUC -
      the area under the serum concentration-time curve for NGMN, NG, and EE using linear
      trapezoidal summation from the data obtained after patch application from time 0 (dosing) to
      168 hours post dose (AUC168), from time 0 to 240 hours postdose (AUC240), from time 0 to
      infinity (AUCinf), and from time 0 to the last measurable concentration for EE (AUClast); and
      t½ - apparent terminal half-life, computed as (ln2/ke) where ke is the slope of the terminal
      log-linear phase of the serum concentration-time curve. Patch adhesion was assessed and
      scores summarized. Assessment of bioequivalence will be based on the use of 90% confidence
      intervals (for 2 one-sided test procedures) for the ratios of mean (low spec lot to
      EVRANORELGESTROMIN/ETHINYL ESTRADIOL ) pharmacokinetic parameters, AUC240 and Css for NGMN
      and EE. The 2 formulations will be considered bioequivalent if the 90% confidence intervals
      fall within 80% to 125% limits for both AUC240 and Css for NGMN and EE. Safety evaluations
      were based on adverse events, including erythema and application site reaction and changes in
      physical and gynecologic examinations (including breast exams), vital signs, 12-lead ECGs,
      and clinical laboratory test results from pre- to poststudy. Serum pregnancy testing and
      urine drug screening was performed. Changes from screening were summarized using descriptive
      statistics. A single low spec lot or EVRANORELGESTROMIN/ETHINYL ESTRADIOL patch (20 cm2
      transdermal contraceptive system) contains NGMN 6.0 mg and EE 0.75 mg. Each subject wore a
      patch (low spec lot or EVRANORELGESTROMIN/ETHINYL ESTRADIOL ) on the buttock for 7 days,
      according to a computer-generated randomization schedule. There was a 28-day washout period.
      Patients then crossed over to the other treatment for 7 days.
    

Time perspective: Prospective
Keywords: bioequivalence; contraception; contraceptive patch; ORTHO EVRA; norelgestromin; NGMN; ethinyl estradiol; EE