Comparison of a novel norgestimate/ethinyl estradiol oral contraceptive (Ortho Tri-Cyclen Lo) with the oral contraceptive Loestrin Fe 1/20

doi:10.1016/S0010-7824(01)00214-1

Contraception

Volume 63, Issue 6, June 2001, Pages 289-295

https://doi.org/10.1016/S0010-7824(01)00214-1 Get rights and content

Abstract

This multicenter study compared the contraceptive efficacy, cycle control, and safety of a new triphasic norgestimate (180/215/250 μg)/ethinyl estradiol 25 μg regimen (Ortho Tri-Cyclen Lo) (n = 1,723) with that of norethindrone acetate 1 mg/ethinyl estradiol 20 μg (Loestrin Fe 1/20) (n = 1,171). Healthy women were treated for up to 13 cycles. Demographics were similar between regimens. Contraceptive efficacy was comparable for Ortho Tri-Cyclen Lo and Loestrin Fe 1/20. The overall and method failure probabilities of pregnancy through 13 cycles were 1.9% and 1.5%, respectively, with Ortho Tri-Cyclen Lo and 2.6% and 2.4%, respectively, with Loestrin Fe 1/20. Breakthrough bleeding and spotting was reported by a significantly lower percentage of participants in the Ortho Tri-Cyclen Lo group compared with the Loestrin Fe 1/20 group. At representative Cycles 1, 3, 6, 9, and 13, breakthrough bleeding and spotting rates were 16.3, 11.5, 10.3, 7.9, and 7.7%, respectively, in the Ortho Tri-Cyclen Lo group and 34.9, 22.9, 22.2, 15.9, and 13.1%, respectively, in the Loestrin Fe 1/20 group. Compliance and safety data were similar for the two regimens.

Introduction

Combination hormonal oral contraceptives are highly effective, convenient, and offer an excellent safety profile [1]. Throughout more than four decades of oral contraceptive development, various attempts have been made to further improve their tolerability and safety profiles while maintaining effective contraceptive efficacy. Estrogen and progestin doses have been lowered, newer progestins with lower androgenicity have been introduced, and multiphasic regimens have been employed.

Norgestimate (NGM) is a well-tolerated progestin used in the oral contraceptives Ortho-Cyclen and Ortho Tri-Cyclen^. NGM is a low androgenic progestin [2], [3], [4], [5], [6] that potently inhibits ovulation and maintains a thin endometrium [2], [3]. NGM does not negate the beneficial effect of estrogen on lipid profile [4], [5], [6] and has little or no effect on carbohydrate metabolism [5], [6] or coagulation factors [7].

A regimen using triphasic dosing of NGM and a constant dose of ethinyl estradiol (EE) has recently been developed by The R. W. Johnson Pharmaceutical Research Institute (Ortho Tri-Cyclen Lo). Ortho Tri-Cyclen Lo contains NGM in the same dose and triphasic regimen (180/215/250 μg) as Ortho Tri-Cyclen, but with a reduced daily dose of EE, 25 μg instead of 35 μg. This study compares the contraceptive efficacy, cycle control, and safety of Ortho Tri-Cyclen Lo and two NGM/EE-containing cyclophasic regimens with that of the oral contraceptive Loestrin Fe 1/20 [norethindrone acetate (NETA) 1 mg/EE 20 μg]. Loestrin Fe 1/20 was chosen as the comparator because when the study was initiated, it was the only oral contraceptive available in the US with an EE dose of less than 30 μg. This was considered important in evaluating product performance because cycle control is known to vary with EE dose.

Section snippets

Study design

This was a randomized, parallel-group, multicenter (100 US, 10 Canada) study of three blinded regimens of NGM/EE-containing oral contraceptives and an open-label control regimen of Loestrin Fe 1/20. Participants were randomized in a 3:3:3:2 ratio in blocks of size 11: 9 participants were assigned (three each) to the NGM/EE groups (Ortho Tri-Cyclen Lo, Cyclophasic-25, or Cyclophasic-20) for every two participants assigned to Loestrin Fe 1/20. Ortho Tri-Cyclen Lo treatment was NGM 180 μg/EE 25 μg

Demographics and disposition

The demographic and baseline characteristics of the Ortho Tri-Cyclen Lo and Loestrin Fe 1/20 groups were comparable (Table 1). In the Ortho Tri-Cyclen Lo group, 1,236 participants were enrolled for 6 cycles and 487 for 13 cycles; of the participants enrolled for 6 cycles, 978 (79.1%) completed the study, and of the participants enrolled for 13 cycles, 283 (58.1%) completed the study. In the Loestrin Fe 1/20 group, 853 participants were enrolled for 6 cycles and 318 for 13 cycles; of the

Discussion

The present study compared contraceptive efficacy, cycle control, compliance, and safety of a new NGM/EE-containing triphasic regimen, Ortho Tri-Cyclen Lo, with that of a low-dose oral contraceptive, Loestrin Fe 1/20, in a large population of healthy, sexually active women. Ortho Tri-Cyclen Lo provided contraceptive efficacy that was comparable to Loestrin Fe 1/20 and cycle control that was superior to Loestrin Fe 1/20. Compliance and tolerability were similar for both groups. The confidence

Acknowledgements

Principal investigators: J Adelglass, JM Baker, S Barbier, VD Bodden Jr., R Boroditsky, BT Bowling, SC Bowman, PL Bressman, RT Burkman, DV Coonrod, JM Cooper, RS Corwin, D Dattani, FP de Oliveira, R Dittrich, S Dunn, MS Fan, AB Fiorillo, FM Fisk, JB Frank, RH Friedman, DL Gearhart, AT Gelfand, M Gelfand, SF Gordon, L Gratkins, E Guilbert, RL Handy, MS Hanson, W Harper, MA Heuer, RL Holley, RW Honsinger, L Hopkins, M Jurado, N Kassman, B Kerzner, E Kirschman, WD Koltun, LD Komer, BR Kurtz, TE

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When bleeding patterns of participants in the study were reassessed using the new criteria recommended by the RHDAC (26) and Mishell et al. (25), significantly lower proportions of patients experienced unscheduled bleeding/spotting during cycles 1–6 with the NGM/EE 25 μg regimen than with the NETA/EE 20 μg regimen (P<.001 at each cycle) (Table 2). These results are compared with the original trial results reported by Hampton et al. (27) in Figure 1. The difference in incidence of unscheduled bleeding/spotting per cycle between the two regimens ranged from nearly 9% to more than 13.5% during the first six cycles of use.
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Analysis of bleeding data for cycles 1–6 from a randomized, multicenter trial.
221 North American centers.
Healthy, sexually active women (18–45 years old).
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Cycle control evaluated from patients' daily diaries.
For cycles 1–6, there was a statistically significant lower incidence of unscheduled bleeding/spotting with NGM/EE 25 μg (range 21.0%–34.4%) than with NETA/EE 20 μg (range 33.0%–46.6%). Of the women who had unscheduled bleeding/spotting, the mean number of days per cycle of bleeding/spotting was comparable. A statistically significant higher incidence of scheduled bleeding was seen with NGM/EE 25 μg (95.2%–97.5%) than with NETA/EE 20 μg (78.5%–84.2%).
The NGM/EE 25 μg has a lower incidence and comparable length of unscheduled bleeding and a higher incidence of scheduled bleeding than NETA/EE 20 μg in this post hoc analysis.
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With the increasing use of low-dose OCs among women of different body weights or BMIs, evaluation of their contraceptive efficacy for women of higher body weight or BMI is important. A large-scale Phase III trial [11] evaluated the efficacy of 180/215/250 mcg of NGM/25 mcg of EE and a monophasic OC containing 1 mg of norethindrone acetate (NETA)/20 mcg of EE.2 The NGM/EE and NETA/EE formulations were comparably efficacious and safe, with the NGM/EE formulation providing better cycle control [11].
This analysis investigated the association of oral contraceptive efficacy with body weight and body mass index (BMI) for hypothesis-generating purposes.
Data were from a randomized, parallel-group trial of 180/215/250 mcg of norgestimate (NGM)/25 mcg of ethinyl estradiol (EE) (given to 1671 women) and 1 mg of norethindrone acetate (NETA)/20 mcg of EE (given to 1139 women). Pregnancies were evaluated across BMI deciles and by BMI and body weight dichotomies. A Pearl index was calculated for each treatment group. The relative risk (RR) of pregnancy was calculated with a Cox proportional hazards model.
The Pearl index for women who received NGM/EE was 2.36 [95% confidence interval (CI)=1.33–3.40]; for those who received NETA/EE, the Pearl index was 3.29 (95% CI=1.81–4.77). Consistent, weak positive associations between weight and pregnancy risk were found. Overall, for women with a BMI ≥25 kg/m² (compared with women with a BMI <25 kg/m²), the RR of pregnancy was 1.84 (95% CI=0.98–3.45); that for women who received NGM/EE was 1.39 (95% CI=0.57–3.40), whereas that for women who received NETA/EE was 2.49 (95% CI=1.01–6.13). For women with a body weight ≥70 kg (compared with women with a body weight <70 kg), the RR was 1.25 (95% CI=0.63–2.46); that for women who received NGM/EE was 1.41 (95% CI=0.56–3.54), whereas that for women who received NETA/EE was 1.12 (95% CI=0.40–3.12).
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This retrospective analysis evaluated the association of age and weight with cycle control in women using either of two formulations of low-estrogen-dose oral contraceptives.
Data for this secondary analysis were derived from a randomized multicenter trial assessing the efficacy and safety of norgestimate (NGM) 180/215/250 mcg/ethinyl estradiol (EE) 25 mcg (n=1506) and norethindrone acetate 1 mg/EE 20 mcg (n=1057). In this retrospective analysis, the incidence of breakthrough bleeding/spotting (BTB/S) was evaluated in women stratified by age (18–24, 25–34 and >34 years) and weight (≤123, 124–155 and >155 lb).
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Low-dose hormone therapy in the perimenopause
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Women in group A experienced a significant reduction in number of hot flushes while no significant variation was observed in group B. The incidence of cyclic bleeding was 86% in group A and 76% in group B, the mean duration was significantly lower in group A than in group B.
LD-HT may control both irregular bleeding and hot flushes in perimenopausal women.
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2007, Contraception
Initially approved for use in the United States nearly 50 years ago, oral hormonal contraceptives containing both estrogen and progestin have undergone steady improvements in safety and convenience. Concurrent with improvements in safety associated with decreasing doses of both steroids, there has been an increased incidence of unscheduled bleeding and spotting. There exist no standards regarding data collection techniques and methods, and reporting and analysis of bleeding and spotting events during combined hormonal contraceptive (CHC) trials. For the regulatory review of hormonal contraceptives, data regarding the incidence of bleeding and spotting events are not included in either of the traditional categories of efficacy and safety. Standardization of methods for collecting and analyzing data about cycle control in all clinical trials of CHCs is long overdue. Until such standards are developed and implemented, clinicians need to familiarize themselves with the techniques used in each study in order to provide correct information to their patients about the frequency of bleeding and spotting associated with different formulations and delivery systems.

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Original research articleComparison of a novel norgestimate/ethinyl estradiol oral contraceptive (Ortho Tri-Cyclen Lo) with the oral contraceptive Loestrin Fe 1/20

Abstract

Introduction

Section snippets

Study design

Demographics and disposition

Discussion

Acknowledgements

Contraception

Contraception

Contraception

Baillieres Best Pract Res Clin Obstet Gynaecol

The pillcombined oral contraceptives

Progestational and androgenic receptor binding affinities and in vivo activities of norgestimate and other progestins

Contraception

Original research article
Comparison of a novel norgestimate/ethinyl estradiol oral contraceptive (Ortho Tri-Cyclen Lo) with the oral contraceptive Loestrin Fe 1/20