Norelgestromin Research Articles

Development of Norelgestromin Dissolving Bilayer Microarray Patches for Sustained Release of Hormonal Contraceptive.

Microarray patches (MAPs) offer a noninvasive and patient-friendly drug delivery method, suitable for self-administration, which is especially promising for low- and middle-income country settings. This study focuses on the development of dissolving bilayer MAPs loaded with norelgestromin (NGMN) as a first step towards developing a future potential drug delivery system for sustained hormonal contraception. The fabricated MAPs were designed with the appropriate needle lengths to penetrate the stratum corneum, while remaining minimally stimulating to dermal nociceptors. Ex vivo assessments showed that the MAPs delivered an average of 176 ± 60.9 μg of NGMN per MAP into excised neonatal porcine skin, representing 15.3 ± 5.3% of the loaded drug. In vivo pharmacokinetic analysis in Sprague Dawley rats demonstrated a Tmax of 4 h and a Cmax of 67.4 ± 20.1 ng/mL for the MAP-treated group, compared to a Tmax of 1 h and a Cmax of 700 ± 138 ng/mL for the intramuscular (IM) injection group, with a relative bioavailability of approximately 10% for the MAPs. The MAP-treated rats maintained plasma levels sufficient for therapeutic effects for up to 7 days after a single application. These results indicate the potential of NGMN-loaded dissolving bilayer MAPs, with further development focused on extending the release duration and improving bioavailability for prolonged contraceptive effects.

Use of serum evaluation of contraceptive and ovarian hormones to assess reduced risk of pregnancy among women presenting for emergency contraception in a multicenter clinical trial

ObjectiveTo evaluate ovulation risk among women enrolling in an emergency contraception (EC) study by measuring contraceptive steroids and ovarian hormones. Study DesignWe used standard chemoluminescent assays to evaluate endogenous hormones [estradiol (E2), progesterone (P4), FSH, LH] and liquid chromatography-tandem triple quadrupole mass spectrometry (LC-MS/MS) to simultaneously analyze concentrations of ethinylestradiol (EE), dienogest (DNG), norelgestromin (NGMN), norethindrone (NET), gestodene (GSD), levonorgestrel (LNG), etonogestrel (ENG), segesterone acetate (NES), medroxyprogesterone acetate (MPA), and drospirenone (DRSP), in serum samples obtained at the time of enrollment in a recent study comparing oral ulipristal acetate and LNG EC in women with weight ≥ 80kg reporting no recent use of hormonal contraception. ResultsWe enrolled 532 and obtained a valid baseline blood sample from 520 women. Of these, 117 (22.5%) had detectable concentrations of a progestin [MPA (n=58, 11.2%), LNG (50, 9.6%), ENG (11, 2.1%), NET (5, 0.96%), NGMN (3, 0.06%), or DRSP (1, 0.02%)]. LNG was co-detected in all three participants with samples containing NGMN. Multiple progestins were detected in 8 other women: ENG/MPA (1); ENG/LNG (2); MPA/LNG (5). Samples from 55 (10.6%) had concentrations of one or more progestin considered above the minimum level for contraceptive [MPA ≥ 0.1ng/mL, n = 19; NGMN/LNG ≥ 0.2ng/mL, n = 31; ENG ≥ 0.09 ng/mL, n = 8; NET ≥ 0.35 ng/mL, n = 4]. We detected concentrations of serum P4 ≥ 3ng/mL, indicative of luteal phase (post-ovulation) status, in an additional 194 (37.3%) samples. ConclusionsMore than one third of enrolled in our clinical trial of oral emergency contraception had evidence of prior ovulation at the time of enrollment. Additionally, about 23% had evidence of recent use of hormonal contraception recent use of hormonal contraception. This results would have decreased the expected risk of pregnancy in the study. ImplicationsMany participants in a recent clinical trial of oral emergency contraception did not appear to be at risk for pregnancy or would not have benefited from intervention due to cycle timing. Investigators should consider the effects of these findings on expected pregnancy rates when determining sample size in future EC clinical trials, particularly when using non-inferiority designs or historical controls.Keywords

Effects of rimegepant 75 mg daily on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate in healthy female participants.

To assess the effect of single and multiple doses of rimegepant 75 mg dose on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol (EE)/norgestimate (NGM) in healthy females of childbearing potential or non-menopausal females with tubal ligation. Females of childbearing age experience the highest prevalence of migraine and frequently inquire about the concomitant use of anti-migraine medications and contraceptives. Rimegepant, a calcitonin gene-related peptide receptor antagonist, demonstrated efficacy and safety for treating an acute migraine attack and preventing migraine. This open-label, single-center, phase 1, drug-drug interaction study explored the effects of rimegepant 75 mg daily dose on the pharmacokinetics of an oral contraceptive containing EE/NGM 0.035 mg/0.25 mg in healthy females of childbearing potential or non-menopausal females with tubal ligation. During cycles 1 and 2, participants received EE/NGM once daily for 21 days followed by placebo tablets with inactive ingredients for 7 days. Rimegepant was administered during only cycle 2 for 8 days, from days 12 through 19. The primary endpoint was the effect of single and multiple doses of rimegepant on the pharmacokinetics of EE and norelgestromin (NGMN), an active metabolite of NGM, at steady state, including area under the concentration-time curve for 1 dosing interval (AUC0-τ,ss ) and maximum observed concentration (Css[max] ). The study enrolled 25 participants, with pharmacokinetic data assessed for 20 participants. A single 75 mg dose of rimegepant co-administered with EE/NGM increased exposures of EE and NGMN by ≤16% (geometric mean ratio [GMR], 1.03; 90% confidence interval [CI], 1.01-1.06; and GMR, 1.16; 90% CI, 1.13-1.20, respectively). After 8 days of co-administering EE/NGM with rimegepant, EE pharmacokinetic parameters, AUC0-τ,ss and Css(max) , increased by 20% (GMR, 1.20; 90% CI, 1.16-1.25) and 34% (GMR, 1.34; 90% CI, 1.23-1.46), respectively, and NGMN pharmacokinetic parameters increased by 46% (GMR, 1.46; 90% CI, 1.39-1.52) and 40% (GMR, 1.40; 90% CI, 1.30-1.51), respectively. The study identified modest elevations in overall EE and NGMN exposures after multiple doses of rimegepant, but these elevations are unlikely to be clinically relevant in healthy females with migraine.

Randomized, double-blind, two-way crossover bioequivalence and adhesion study, in healthy women, of a transdermal contraceptive patch with a newly sourced adhesive component at the end of shelf life vs. the EVRA patch at the beginning of shelf life.

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 to 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.

The effect of multiple doses of ubrogepant on the pharmacokinetics of an oral contraceptive in healthy women: Results of an open-label, single-center, two-period, fixed-sequence study

Background: Ubrogepant is a novel, oral calcitonin gene–related peptide receptor antagonist for acute treatment of migraine. This study evaluated potential drug–drug interactions between ubrogepant and an oral contraceptive containing ethinyl estradiol (EE) and norgestimate (NGM). Methods: This open-label, single-center, two-period, fixed-sequence study enrolled healthy, postmenopausal or oophorectomized, adult women. In period 1, participants received a single oral dose of EE 0.035 mg/NGM 0.25 mg (EE-NGM) followed by a 7-day washout. In period 2, participants received oral ubrogepant 50 mg daily on days 1–14; single-dose EE-NGM was coadministered with ubrogepant on day 10. Pharmacokinetic parameters for plasma EE and norelgestromin (NGMN) were compared with and without ubrogepant. Results: Twenty-two participants aged 46–66 years were enrolled; 21 completed the study. Geometric mean ratios and 90% confidence intervals for the comparison of EE-NGM + ubrogepant to EE-NGM alone were contained within 0.80 and 1.25 for area under the plasma drug concentration–time curve (AUC) from time zero to infinity (AUC0–∞; 0.96 [0.91, 1.01]) and C max (0.91 [0.82, 1.004]) of NGMN and AUC0–∞ (0.97 [0.93, 1.01]) of EE, but not C max of EE (0.74 [0.69, 0.79]). Median t max of EE was delayed following EE-NGM + ubrogepant (3.0 h) versus EE-NGM alone (median of 1.5 h), whereas median t max of NGMN was unchanged (1.5 h). Geometric mean apparent terminal half-life ( t ½) was similar with and without ubrogepant for EE (23 vs. 21 h) and NGMN (36 h both conditions). All ubrogepant-related adverse events were mild or moderate. Conclusion: Ubrogepant did not demonstrate potential for clinically meaningful drug–drug interactions with an EE-NGM oral contraceptive. Trial registration: Not applicable (phase 1 trial)

The pharmacokinetics of 12-week continuous contraceptive patch use

ObjectivesWe sought to assess the change in serum ethinyl estradiol (EE2) and norelgestromin (NGMN) levels over 12 weeks of continuous contraceptive patch use. Study designWe 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. ResultsTwenty-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. ConclusionWhile 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.

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 0.55mg ethinyl estradiol (EE) and 2.1mg gestodene (GSD) compared with a patch containing 0.6mg EE and 6mg norelgestromin (NGMN). Study designIn 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. ResultsIn 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 statementThe 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.

Mathematical modeling of the release of active ingredients from a contraceptive patch: ortho evra(®) as a case study.

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.

Effect of raltegravir on estradiol and norgestimate plasma pharmacokinetics following oral contraceptive administration in healthy women

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)]. 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. 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 (AUC(0-24 h) ) and 1.06 (0.98-1.14) for the maximum concentration of drug in the plasma (C(max) ); 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 AUC(0-24 h) and 1.29 (1.23-1.37) for C(max) . There were no discontinuations due to a study drug-related adverse experience, nor any serious clinical or laboratory adverse experience. 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.

Effect of Laropiprant, a PGD2 Receptor 1 Antagonist, on Estradiol and Norgestimate Pharmacokinetics After Oral Contraceptive Administration in Women

Laropiprant is a prostaglandin D2 receptor 1 antagonist that is being developed in combination with niacin for the treatment of dyslipidemia. This randomized clinical study evaluated the effect of laropiprant on the pharmacokinetics of ethinyl estradiol (EE) and norelgestromin (NGMN), the principal circulating metabolite of norgestimate, in healthy women receiving 3 or more months of an oral contraceptive (Ortho Tri-Cyclen; Ortho-McNeil Pharmaceutical, Raritan, NJ), which contains EE and norgestimate. Twenty-one female subjects with normal menstrual cycles received the oral contraceptive on Days 1 to 21 during two consecutive contraceptive cycles. Subjects received double-blind 40 mg/day laropiprant or placebo on Days 1 to 21 of each contraceptive cycle. Plasma samples were collected predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose on Day 21 to measure area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24hr) and maximum concentration observed in plasma (Cmax) of EE and NGMN. Comparability would be declared if the 90% confidence intervals for the geometric mean ratio of AUC0-24hr and Cmax in the absence and presence of laropiprant were within predefined bounds (0.80-1.25). The estimated geometric mean ratios (90% confidence intervals) of EE and NGMN, respectively, were 1.08 (1.04-1.13) and 0.97 (0.94-0.99) for AUC0-24hr and 1.16 (1.06-1.27) and 1.00 (0.94-1.06) for Cmax. The 90% confidence intervals for the geometric mean ratio of EE Cmax minimally exceeded the prespecified bounds; the other relevant pharmacokinetic parameters fell within the predefined bounds. Coadministration of 40 mg laropiprant with the oral contraceptive did not lead to clinically meaningful alterations in the pharmacokinetics of EE or NGMN.

Comparison of bleeding/spotting profiles between an extended regimen and a cyclic regimen of transdermal norelgestromin/ethinyl estradiol during the first 56 days of treatment

Introduction: A subanalysis of a clinical trial comparing an extended regimen with a cyclic regimen of transdermal norelgestromin (NGMN)/ethinyl estradiol (EE) was conducted to assess differences in bleeding/spotting profiles between regimens during the first 56 days (two cycles) of treatment. Materials and Methods: Healthy regularly menstruating women (N=239) were randomized 2:1 to receive an extended regimen (n=158, weekly patch applications for 12 weeks/one patch-free week/three weekly applications) or a cyclic regimen (n=81, four consecutive cycles of three weekly patch applications/one patch-free week) of NGMN/EE. Subjects recorded bleeding data daily. Results for the intent-to-treat population are presented. Results: During the first 56 days of treatment, women receiving the extended regimen versus those receiving the cyclic regimen, respectively, had significantly fewer median bleeding days (1 vs. 9; p<.001), bleeding episodes (0.5 vs. 2; p<.001), bleeding/spotting days (6 vs. 10; p=.009) and bleeding/spotting episodes (1 vs. 2; p<.001) and a higher incidence of amenorrhea (28% vs. 1%; p<.001). Median time to first bleeding with the extended regimen versus the cyclic regimen was 54 versus 25 days, respectively (p<.001). Discussion: This is one of the largest trials to date to assess an extended regimen of a hormonal contraceptive approved for cyclic use. During the first 56 days of treatment, the extended regimen had significantly fewer median bleeding/spotting days compared with the cyclic regimen and effectively delayed menses. Conclusion: Extended-regimen transdermal NGMN/EE delays menses and reduces bleeding during the first 56 days of treatment compared with the cyclic regimen, a profile that may be preferred by women who seek flexibility with their contraceptive method.

Serum Ethinyl Estradiol Levels with the Ring, Patch, and Pill

Exposure to ethinyl estradiol varies with the contraceptive regimen employed, but which contraceptive is the least estrogenic? In this open-label trial, Dutch investigators compared serum EE levels during use of three estrogen-progestin contraceptive methods: the vaginal ring (15 μg EE/120 μg etonogestrel daily), the transdermal patch (20 μg EE/150 μg norelgestromin daily), and an oral contraceptive (OC; 30 …

Serum distribution of the major metabolites of norgestimate in relation to its pharmacological properties

Norelgestromin (NGMN) and levonorgestrel (LNG) are the main active metabolites of norgestimate (NGM), but their relative contributions to the pharmacological effects of NGM are unclear. We have therefore determined the serum distribution of these NGM metabolites and assessed their steady-state concentrations in women following ≥3 cycles of oral contraceptive (OC) use. The administration of 250 μg NGM/35 μg ethinyl estradiol (EE) resulted in significantly higher sex hormone-binding globulin (SHBG) levels (p = 0.002), and 30% lower serum non-protein-bound (NPB) levels of testosterone, when compared to treatment with 150 μg LNG/30 μg EE. We also confirmed that NGMN does not bind to SHBG, and found that 97.2% of this metabolite is bound to albumin while only 2.8% is in the NPB fraction. In contrast, most of the LNG was bound to SHBG (92.5% and 87.2% after NGM/EE and LNG/EE treatment, respectively), and the NPB fraction of LNG (0.7%) during NGM/EE treatment was lower (p < 0.001) than during LNG/EE treatment (1.4%). Combining these serum distributions with the C max and AUC 0–24h data obtained after NGM/EE treatment gave NPB and albumin-bound values of NGMN that were much greater than the corresponding LNG values. Furthermore, the C max and AUC 0–24h values for NPB LNG during NGM/EE treatment were estimated to be lower than during LNG/EE treatment. Since LNG is primarily bound by SHBG, its access to target tissues is restricted. Moreover, because SHBG does not bind NGMN, it appears to be quantitatively the more important NGM metabolite available to target tissues, and probably accounts for a substantial proportion of the progestogenic activity of NGM/EE OCs. However, it is also possible that simultaneous exposure of NGMN and LNG after treatment with NGM/EE may provide clinical benefits not seen with LNG/EE combinations.

Norelgestromin as selective estrogen enzyme modulator in human breast cancer cell lines: Effect on sulfatase activity in comparison to medroxyprogesterone acetate

Human breast cancer tissue contains enzymes (estrone sulfatase, 17β-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of estradiol (E 2) formation. In this tissue, E 2 can be synthesized by two main pathways: (1) sulfatase—transforms estrogen sulfates into bioactive E 2, and the (2) aromatase—converts androgens into estrogens. Quantitative assessment of E 2 formation in human breast tumors indicates that metabolism of estrone sulfate (E 1S) via the sulfatase pathway produces 100–500 times more E 2 than androgen aromatization. In the present study, we demonstrated in T-47D and MCF-7 human breast cancer cells that norelgestromin (NGMN) (a metabolite of norgestimate) is a potent inhibitory agent of the estrone sulfatase activity. After 24 h incubation of physiological concentrations of E 1S (5×10 −9 mol/l) the inhibitory effect of NGMN at concentrations of 5×10 −9, 5×10 −7 and 5×10 −5 mol/l was 43±7, 74±4 and 97±2%, respectively, in T-47D cells; 25±4, 57±5 and 96±2% respectively, in MCF-7 cells. Comparative studies using medroxyprogesterone acetate (MPA) showed that this progestin also has an inhibitory effect on sulfatase activity, but significantly less intense than that of NGMN. The inhibition for MPA at concentrations of 5×10 −9, 5×10 −7 and 5×10 −5 mol/l was 31±5, 47±3 and 61±3%, respectively, for T-47D cells; 6±3, 20±3 and 63±4%, respectively, for MCF-7 cells. In conclusion, the present data show that NGMN is a very potent inhibitory agent for sulfatase activity in the hormone-dependent breast cancer cells, resulting in decreased tissue concentration of E 2. The clinical significance of this finding remains to be elucidated.

Birth Control: One Patch at a Time

These authors conducted a noncomparative, open-label, manufacturer-supported study to evaluate patient compliance with and the safety, efficacy, and cycle control of weekly transdermal contraceptive patches. The patches release ethinyl estradiol (the estrogen used in all low-dosage oral contraceptives [OCs]) and norelgestromin (the active metabolite of norgestimate, a progestin used in OCs). More than 1600 volunteers aged 18 to 45 from 73 clinics …

Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants

This open-label, randomized study evaluated the pharmacokinetics of norelgestromin (NGMN) and ethinyl estradiol (EE) following the application of a contraceptive patch (1/week) for three cycles (3 weeks/cycle). Healthy women (n = 24) wore a 20-cm 2 patch (ORTHO EVRA/EVRA) on either their abdomen or buttock during blood sampling weeks and on any of four approved sites at other times. Serum was analyzed for NGMN and EE from samples taken during Week 1 of Cycle 1 and Weeks 1–3 of Cycle 3. Steady-state conditions were achieved during the three-cycle study. The patch delivered NGMN and EE at steady-state concentrations within their reference ranges throughout three cycles of treatment; reference ranges are based on studies with ORTHO-CYCLEN/Cilest. Steady-state serum concentrations and area under the curve from 0 to 168 h increased only slightly from Cycle 1, Week 1 to Cycle 3, Week 3 for NGMN and EE, indicating minimal accumulation. Treatment was well tolerated, and patch adhesion was excellent.

Transdermal contraception.

This review summarizes the clinical studies involving the once-weekly Ortho Evra/Evra contraceptive patch. The patch delivers norelgestromin (NGMN), 150 microg, and ethinyl estradiol (EE), 20 microg, daily to the systemic circulation. The contraceptive patch provided ovulation suppression and cycle control similar to that of oral norgestimate 250 microg/EE 35 microg, significantly decreased mean maximum follicular diameter following a 3-day intentional delayed dosing phase when compared with oral levonorgestrel (LNG) 50/75/125 microg/EE 30/40/30 micorg and oral LNG 100 microg/EE 20 microg, and was as effective as oral LNG 50/75/125 microg/EE 30/40/30 microg and oral desogestrel 150 microg/EE 20 microg in altering cervical mucus composition (i.e., creating a scanty, viscous consistency). The contraceptive patch provided efficacy, cycle control, and safety comparable to that seen with oral LNG 50/75/125 microg/EE 30/40/30 microg, but women were able to correctly follow the weekly dosing regimen significantly more often than the daily oral contraceptive dosing regimen. Less than 2% of patches were replaced because of complete detachment in these trials. The patch was not associated with phototoxicity or photoallergy. The contraceptive patch, the only noninvasive, weekly birth control method that a woman can self-administer, will be a valuable addition to current contraceptive options.