ORIGINAL ARTICLE
Cycle control with triphasic norgestimate and ethinyl estradiol, a new oral contraceptive agent KATHRYNM. ANDOLSEK,M.D., M.P.H.
From t h e Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina
Acta Obstet Gynecol
Scand 1992; Vol 71, Suppl 156: 22-26
1:ffective cycle control was demonstrated based on two multicenter, 2-year studies of the ti-iphasic oral contraceptive (OC) agent containing the new progestin norgestimate. The estrogen in this OC is ethinyl estradiol. These open-label Phase 111 studies were conducted in the United States by 33 investigators at 33 sites who treated a total of 1,783 subjects, healthy women 17 to 38 years of age with menstrual cycle characteristics considered to be within the normal range. The norgestimate/ethinyl estradiol preparation was taken for up to 24 cycles. Follow-up information was collected 3 to 4 months post-treatment. Bleeding pattern analyses were based o n 27,970 valid cycles. Normal cyclic bleeding patterns were experienced by most of the women during the study; only minimal and statistically and clinically insignificant variations in menstrual flow, dysmenorrhea, and premenstrual tension occurred. There was a low incidence of failed withdrawal bleeding in single cycles ( t l . O X after cycle 6). There were no cases of amenorrhea, defined as two consecutive cycles of missed withdrawal flow. The incidence of breakthrough bleeding or spotting was highest during the initial treatment cycles and diminished with continued use of the formulation. The mean incidence of breakthrough hleeding was 2.36% in cycles 13 to 24. Apart from somewhat higher initial percentages among women new to oral contraception, the pattern of midcycle bleeding or spotting was similar to that of all women studied. Effective long-term cycle control was demonstrated in women who used this OC agent. Key
NwdT:
Norgestimate, cycle control
Introduction The choice of progestin is increasingly becoming recognized as important to the selection of oral contraceptive (OC) agents. The progestin influences health consequences, such as lipid metabolism, and can also affect patient compliance. Progestins have been linked with side effects that are most frequently responsible for a woman’s decision to stop taking an OC. Progestational selectivity is an important aspect o f the pharmacologic profile of the new contraceptive progestin norgestimate (NGM). N G M has a high binding affinity for progestin receptors and a low binding affinity for androgen receptors. It binds to uterine progestin receptors t o the same extent that progesterone does. However, its affinity for Aclu Ohsrer Gynecol Scand Suppl 156 (IYY2)
androgen receptors is even weaker than that of progesterone (1,2). NGM has little if any affinity for the androgenicity marker, sex hormone binding globulin (SHBG), a serum protein that binds androgens, rendering them inactive (3). In women using NGM in a combination OC containing ethinyl estradiol ( E E ) , elevated serum levels of SHBG indicated a low potential for androgenicity (4-6).Related studies show that NGM/EE influences serum lipids in a beneficial pattern, elevating serum levels of high-density lipoprotein (HDL), while lowering the ratio of lowdensity lipoproteins to H D L (4-6). I n triphasic NGM/EE, a new OC formulation. the amount of EE remains constant (35 pg) and the amount of NGM increases sequentially over a 21day period (Table I). The two studies described in
Cycle control Table 1. Triphasic norgestimate/ethinyl estradiol regimen‘ Cycle days 1-7 8-14 15-21
Norgcstimate
Ethinyl cstradiol
(M)
(Yg)
180
35 35 35
215 250
*Ortho Tri-C‘
[email protected]@
this paper were conducted from June 1984 through June 1988 at clinic and private settings throughout the United States. This report focuses on cycle control, which has been demonstrated to be a key determinant in the acceptability of OC agents among women and a factor in patient compliance.
Study design Two multicentered, open-label, noncomparative Phase 111 studies were conducted through 24 cycles of treatment with follow-up information collected 3 to 4 months post-treatment. Thirty-three investigators were each scheduled to enroll and treat approximately 50 subjects. A total of 1,783 women were enrolled and took the study drug. Although a few investigators enrolled more than 50 women, the enrollment was fairly evenly distributed across the study sites. The study was carefully monitored, with routine checks at 6- to 12-week intervals to verify the accuracy and completeness of the medical records data and their transcription to standardized case report forms. StuLly popkition The subjects were sexually active, nonpregnant, healthy women, 17 to 38 years of age, who had regular menstrual cycles and no evidence of infertility. The women had no signs of cervical dysplasia o n a Papanicolaou smear taken before they began the study drug. Postpartum and postabortal subjects were admitted following their first subsequent spontaneous menses. Subjects who had used an intrauterine device were required to have at least one normal menstrual cycle following its removal before they were accepted into the study. All means of contraception other than the test preparation were discontinued during the study. The exclusion criteria included any medical contraindications to treatment with steroid hormones; history of deep vein thrombophlebitis or thromboembolism; current cervical dyplasia; and known coronary artery o r cerebrovascular disease. A history of disorders possibly related to estrogen use was
23
also a reason for exclusion, as was use of an investigational drug or device within 30 days of admission to the study. Both “fresh” and “switchover” subjects were included in this study. Fresh subjects were defined as women who had not used hormonal contraceptive agents for at least 3 months before the start of the study drug. Switchover subjects were women who had used such agents during that 3-month period but had discontinued them before the start of the study drug. All women were counseled extensively and gave informed consent after the risks, bcnefits, and requirements of the study were explained to them.
Contraceptive regimen The two menstrual cycles preceding use of the study drug acted as control cycles, following which the women used the triphasic NGM/EE regimen for up to 24 months.
Cycle control Two types of cycle control data were collected: cycle characteristics and bleeding information. Cycle characteristics include amount of flow and severity of dysmenorrhea and premenstrual tension. Women used a daily diary card to record their use of the test preparation and the occurrence of bleeding and spotting. Bleeding was defined as any vaginal blood Table 11. Population characteristics at baseline: age. cthnicity, smoking, body weight
N Age (yr)
17 18-20
21-25 2630 31-35 3638 Total Mean Standard dcviation
Ethnicity
Smoking
Body weight
7
I
301 768
SO7 I82 13 1,783 24.X 4.31
(%, 0.1 16.9 43.1 28.4 10.2 1.3 i 063
White Black Oriental Other Total
1,600 131 5 1.783
YO. 1 7.3 0.3 2.3 100.0
Yes NO
52x 1.255
7o.J
Total
1.783
100.0
Ih 135.x 24.96 80/310
61.72 11.34 36/141
Mean Standard deviation Minimum/maximum
5
29.6
k!4
24
K. M . Andoisek
Table I l l . Population characteristics at baseline: contraceptive status, pregnancy, and menstrual histories N Contraceptive status
Previouh pregnancies
Yo
period, were not 'Onsidered valid and were excluded from the bleeding analysis. Bleeding variables
Postpartum Direct switch Indirect switch Fresh Not known Total
59 1,098 145 450 31 1,783
3.3 61.6 8.1 25.2 1.7 100.0
Breakthrough bleeding was distinguished from the withdrawal flow expected to occur during the pillfree interval. The parameters were defined as follows:
None One o r more Total
615 L I 168 1,783
34.5
100.0
454 996 167 165
25.5 55.9 9.4 9.3
ing the pill taking interval that is neither early withdrawal flow nor withdrawal flow continuing from the previous pill cycle. 2. Amenorrhea: in the absence of pregnancy, two consecutive cycles without bleeding or spotting.
Amount of flow Light Average Heavy Vdfiabk Not known Total Breakthrough bleeding Never Sometimes Often Total
65.5
1
1,783
100.0
1,237 517 2Y 1,76
69.4 29.0 1.6 10fi
Direct switch: not postpartum. and time since last OC used is 5 1 1 days. Indirect switch: not postpartum, and time since last OC used is > 11 days and 5 8 3 days.
flow requiring protection. Spotting was defined as any such bleeding that did not. Summaries of bleeding variables were based on the number of valid bleeding cycles, whereas summaries of cycle characteristics were based on data from all subjects. Cycles in which the pill-taking period was significantly shortened o r lengthened, or merged with another
1. Breakthrough bleeding o r spotting: bleeding dur-
Results Baseline characteristics of the women are presented in Tables I1 and 111. A total of 1,783 women used the triphasic NGM/EE preparation; 1,450 used it for 6 cycles, 1,208 for 12 cycles, and 749 for 24 cycles. The total number of on-treatment cycles was 28,527. The bleeding pattern summary analyzed data describing 27,970 valid cycles. Normal cyclic bleeding patterns were exhibited by most of the study participants. The duration of menses varied from 5.58 days in cycle 1 to 5.07 days during cycles 13 through 24. Only minimal and clinically insignificant changes in the amount of flow and in the severity of dysmenorrhea and premenstrual tension occurred during the study. The average duration of menses decreased from 5.58 days in cycle 1 to 5.07 days during cycles 13 through 24. The amount of flow tended to normalize over the course of the study with an increase in the percentage of subjects reporting average flow and decreases
Table I V . Amount of flow Number of subjects ( O h ) Cycle Control 1 3
3 3 5 6 12
IH 24
None 2 25 25 14 19 15 8 8 6 6
(0.1) (1.4) (1.5) (0.9) (1.3) (1.0) (0.6) (0.7) (0.6) (0.8)
Light 600 558 416 404 340 346 339 285 240 167
NA = not available Actu Obsrer Gynecol Scand Suppl156 (1992)
(33.7) (31.3) (24.5) (25.1) (22.6) (23.4) (23.4) (23.6) (24.2) (22.3)
Average 1,039 1,052 1,072 1,060 1,034 988 980 820 699 537
(58.3) (59.0) (63.2) (65.9) (68.7) (66.9) (67.6) (67.9) (70.5) (71.7)
Heavy 142 (8.0) 143 (8.0) 177 (10.4) 129 (8.0) 94 (6.2) 109 (7.4) 118 (8.1) 92 (7.6) 44 (4.4) 35 (4.7)
Total subjects
NA 0 5 5 2 18 18 5 3 2 4
(0.0) (0.3) (0.3) (0.1) (1.2) (1.2) (0.3) (0.2) (0.2) (0.5)
1,783 1,783 1,695 1,609 1,505 1,476 1,450 1.208 99 1 749
Cycle control
Table V. Absence of withdrawal flow Cycle
Cyclesltotal no.(%)*
1 2 3 4 5
2811,720 1511,629 2411,536 1611.476 811,449 1411,398 5617,492 67110,952
6
7- 12 13-24
25
bleeding remained at