Volume 166 Number 6, Part 2
plasma insulin and acute-phase response. Arteriosclerosis 1989;9:362-7. 21. Reaven G. Banting Lecture 1988: role of insulin resistance in human disease. Diabetes 1988;37:1595-607. 22. Ducimetiere P, Eschwege E, Papoz L, Richard J, Claude J, Rosselin G. Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease in a middle-aged population. Diabetologia 1980; 19:205-10. 23. Pyorala K, Savolainen E, Kaukola S, HaapakoskiJ. Plasma insulin as coronary heart disease risk factor: relationship
Long-term oral contraceptive use
to other risk factors and predictive value during 9V, year follow-up of the Helsinki Policemen Study population. Acta Med Scand 1985;701(suppl):38-52. 24. Godsland I, Crook D, Wynn V. Coronary heart disease risk markers in users of low-dose oral contraceptives. J Reprod Med 1991;36(suppl):226-37. 25. Wynn V. Effect of duration of low-dose oral contraceptive administration on carbohydrate metabolism. AMJ OBSTET GYNECOL 1982;142:739-46. 26. Wynn V, Godsland I. Effects of oral contraceptives on carbohydrate metabolism. J Reprod Med 1986;31 :892-7.
The efficacy and tolerability of norgestimate/ ethinyl estradiol (250 l-Lg of norgestimate/35 p.g of ethinyl estradiol): Results of an open, multicenter study of 59,701 women Benno Runnebaum, MD, K. Grunwald, MD, and T. Rabe, MD Heidelberg, Germany The efficacy and tolerability of a new oral contraceptive, norgestimatelethinyl estradiol (250 f.Lg of norgestimate/35 f.Lg of ethinyl estradiol; Cilag GmbH Research, SUlzbach, Germany) were examined in an open-label study of 59,701 women who were evaluated during 342,348 menstrual cycles; 42,022 women completed the planned treatment regimen of six cycles. A use-efficacy (overall) Pearl index of 0.25 pregnancies per 100 woman-years was calculated based on 342,348 cycles. Tolerability was assessed for all women who completed six treatment cycles. Reductions in mean cycle length and duration of bleeding were noted; 32% of the women experienced reductions in the intensity of bleeding by the end of cycle 6. After six cycles of use, amenorrhea occurred in 1%, spotting in 4%, and breakthrough bleeding in 3% of the participating women. Treatment with norgestimatelethinyl estradiol had minimal effects on weight, blood pressure, pulse, lipid metabolism, and blood glucose. Adverse effects (acne, nausea, or headaches) occurred at low frequencies and in many cases, were reduced compared with pretreatment levels. The results of this large-scale open trial were comparable with results from two other multicenter trials of the same formulation. (AM J OesTET GYNECOL 1992;166:1963-8.)
Key words: Norgestimate, ethinyl estradiol, progestins, oral contraceptives In recent years, much research has focused on the development of oral contraceptives with reduced hormone content. I Both the estrogen and progestin components of oral contraceptive formulations are thought to contribute to minor adverse effects, such as nausea,
From Universitiits-Frauenklinik, Abt. fur Gyniikologische Endokrinologie und FertilitiitsstOrungen. Reprint requests: Prof Dr. med Dr. med. h.c. Benno Runnebaum, Abt. Fur Gyniikologische Endokrinologie und FertilitiitsstOrungen, Universitiits-Frauenklinik, Vossstrasse 9, D-6900 Heidelberg, Germany. 610137508
headache, and bleeding irregularities I and to more serious health problems, such as an increased risk of cardiovascular disease noted with high-dose formulations.>' Among the minor adverse effects, nausea and headache are generally linked to estrogen dose. With the introduction of oral contraceptive preparations with estrogen doses of 50 f,Lg or less, the incidence of these adverse effects has generally been reduced.' However, breakthrough bleeding (BTB) and spotting, which appear to be determined by the estrogen/progestin ratio, have been more difficult to address. 1963
1964 Runnebaum, Grunwald, and Rabe
Most of the early studies suggested that the estrogen content of oral contraceptives was related to venous but not to arterial thromboembolic disease.' This finding led to investigation of the influence of the progestin component of oral contraceptives on various risk factors for occlusive arterial disease. In general, estrogen has a favorable effect on cholesterol fractions: it is associated with a reduction in serum concentration of low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol, as well as in the high-density lipoprotein subfraction, HDL 2 • All progestins now in clinical use, however, oppose the effects of the estrogen component." Thus in recent years, one goal of oral contraceptive research has been the development of a highly selective progestin with specific and potent progestational activities and minimal or no androgenic effects." Norgestimate (NGM), a progestin with marked progestational activity and a relative lack of androgenic activity, is promising in this regard.' Orally administered NGM is rapidly absorbed, reaches peak blood levels within 30 minutes to 2 hours, and has a plasma half-life of 6 to 14 hours. In the laboratory NGM has been extensively studied. NGM and its major metabolite l7-deacetyl norgestimate contribute to the biologic response." In previous clinical trials, the efficacy and safety of NGM/ethinyl estradiol (EE) (250 ILg of NGM/35 ILg of EE; CHest, Cilag GmbH Research, Sulzbach, Germany; Ortho-Cyclen, R. W.Johnson Pharmaceutical Research Institute, Raritan, N.J.) have been established.v" The current open-label trial, which enrolled 59,701 women, for a planned treatment period of six cycles, was designed to generate additional data on the efficacy and tolerability of NGM/EE, with special emphasis on changes in bleeding and in metabolic parameters.
Methods Study design. The trial was an open-label, noncomparative study with a large patient population. The planned length of active treatment was six cycles. Patient selection. Women of childbearing age who were in good general health and had regular menstrual cycles of approximately 28 to 32 days ' duration (including 3 to 5 days of bleeding) were eligible for entry. Exclusion criteria included: (1) the presence of vascular or hematologic disorders such as acute or chronic thromboembolism, cerebrovascular illness, myocardial infarction, or sickle cell anemia; (2) the presence of reproductive disorders such as amenorrhea, a history of herpes gestationis, or severe pruritus during pregnancy; (3) suspected or current pregnancy; and (4) general medical problems such as liver or gallbladder disease, cancer, or other metabolic derangements. Data collection. Data gathered during the initial visit included age, height, and weight, as well as information
June 1992 Am J Obstet Gynecol
on smoking habits, alcohol consumption, gynecologic history (including previous contraceptive use), famil y medical history, and the use of other concurrent medications. During the study, information on the cycle (including cycle length, duration and intensity of bleeding, lack of bleeding during tablet-free interval, occurrence of spotting or BTB, dysmenorrhea, and other gynecologic findings) was recorded by each patient on her study calendar, which she brought with her to the checkup examinations after the third and sixth cycles. Clinical variables measured during office visits before treatment and after the third and sixth cycle included blood pressure, pulse, and body weight. Concomitant symptoms, such as acne, nausea, breast tension, headaches, or other, were recorded by the patient on her study calendar. Reports on adverse symptoms were elicited by a questionnaire. Laboratory variables , including serum cholesterol, serum triglyceride, and blood and urinary glucose levels, were evaluated in a subgroup of 3000 women before the study and after the third and sixth cycles. Evaluation of data. The efficacy of NGM/EE was based on the computation of the overall Pearl index'? for the entire study population and the related 95% confidence intervals, which were computed under the assumption of Poisson-distribution data." Tolerability was evaluated by tabulating data on the menstrual cycle, adverse experiences, routine physical findings, and measurements of serum cholesterol, triglyceride, blood glucose, and urinary glucose levels for patients who completed cycle 6 of treatment with NGM/EE.
Results Premature termination. During the study, 59,701 patients were enrolled by 1609 physicians. Treatment was discontinued prematurely in 6588 patients (11%). Terminations were at the physicians' request, at the patients' request, or were the result of a joint decision (Table I). Patient characteristics. Among the 59,701 women who received NGM/EE, mean (:t standard deviation) age was 24.0 :t 6.7 years, mean height was 166.4 :t 6.3 em, mean weight was 61.2 :t 9.0 kg, and mean Broca index was 103.0%:t 23.3 % (Broca index = bod~ weight/0.9 X [heightIlOOD. The mean (:t standard deviation) age at menarche was 12.9 :t 1.3 years. Before they received NGM/EE, 88 % of the women had a regular menstrual cycle (i.e., range, 24 to 32 days). Among women with regular cycles, the mean (:t standard deviation) duration of the cycle was 28.0 :t 2.2 days, and the mean duration of bleeding was 4.9 :t 1.3 days. The intensity of the bleeding was designated as normal by 74% of the women, light by 13%, and heavy by 14%. Of the study subjects , 14% reported inter-
Volume 166 Number 6, Part 2
Efficacy and tolerability of NGM/EE
1965
Table I. Persons responsible for decisions to withdraw from treatment, by cycle Cycle
Physician
1
2
87 91
3
397
4
104
5 6 Totals
49 208 936
Patient
Both
Unkn own
300
59 62 258
54
428 1909
709 294 791 4431
menstrual bleeding (9% spotting and 5% BTB ), and 35% reported dysmenorrhea before treatment. At the time of enrollment into the study, 32% of the patients had already given birth; of these women, 88% had one or two children. Miscarriages and abortions had been experienced by 11% of the patients; of these women, 96 % had had one or two such experiences. When questioned about their use of contraceptives , 54% had not used contracep tives previously, and 46 % had used oral contraceptives. Triphasic formulations were the most common preparations used. Patients were directly switched over to the new oral cont raceptive without a washout period . Gynecologic or other concomitant illnesses were documented among 4.1 % (247 3) of the 59,701 patients. The most frequently reported disorders were gynecologic, reported by 1285 pat ients, and metabolic or endocrine , repo rt ed by 718 patients. Infections of the cervix were the most frequentl y reported gynecologic disorder (17%), followed by tho se of the breast (8%). Disorders of the th yroid gland were reported by 669 patients. Of the subj ects enrolled, 1490 patients received concomitant therapy; thyroid medications were the most frequently used (by 923 patients). The high number of patients taking thyroid medications can be explained by the fact that iod ine supplements are required in some parts of German y and were evidently considered th yroid medication. Efficacy. Efficacy was evalua ted over 342,348 cycles. Pregnancies occurred in 71 women during the treatment period . Thus the use-efficacy Pearl index was 0.25 pregnancies per 100 woman- years; the 95% con fidence interval was 0.19 to 0.31. Tolerability. In all measures of tolerability, only the 42 ,022 patients who completed six cycles of NGM/EE were included. Clinical variables. NGM/EE resulted in no significant changes in bod y weight, blood pressure, or pulse rate after six cycles of treatment. Mean bod y weight increased 0.6 % over initial values. Mean systolic and diastolic blood pressures incre ased 0.5 % and 1.3%, respectively, and mean pul se rate decreased 0.7% over the initial values. Menstrual cycles. NGM/EE resulted in excellent cycle control, as demonstrated by the low incidence of BTB,
64 22 123 588
70 193 154 40 122 633
Totals (%)
516 635 2757 1031 405
(7.8) (9.6) (41.8) (15.6) (6.1)
1244 (18.9) 6588 (100)
intermenstrual spotting, and amenorrhea . The percentage of patients reporting BTB decreased from 4.5% before therapy to 3% after six cycles of NGM/EE treatment. Ninety-four percent of the patients reported no BTB either before the study or during cycle 6 of therapy. In 3% of the patients BTB was no longer present compared with before therapy. Only 2% reported a first episode of BTB, and I % reported BTB before therapy and in cycle 6. Similarly, th e percentage of patients experiencing intermenstrual spotting decreased from 9% before the study to 4% after six cycles of NGM/EE treatment. Eighty-eight percent of subjects reported no spotting either before entry or during cycle 6 of therapy. Of the remaining 12%, 8% reported discontinuation of spotting after six cycles of NGM /EE, 3% who had not experienced spotting before they entered the study reported it during cycle 6, and 1% reported spotting both before th erap y and in cycle 6. Amenorrhea (no bleeding in a given cycle) occurred in onl y 1.4% of the women during cycle 6. The length of cycle 6 was unaffected by NGM/EE in 62% of the patients, whereas it was shortened in 27% and lengthened in 11% compared with baseline values. The duration of bleeding in cycle 6 decreased or remained th e same in 91 % of patients (53% and 38%, respectively) and incr eased in onl y 9% of patients. Also, the severity of bleeding remained unchanged or was amelior ated in most patients in treatment cycle 6. Whereas 96 % of patients exp erienced no change (64%) or a decrease in severity (32%), onl y 4% reported an incr ease compa red with baseline values. NGM /EE demonstrated no adverse effe ct on the reproductive tr act during this study. Gynecologic disease was identified in 0.5% of the women at the beginning of the study and in 0.4 % at the end of cycle 6. Laboratory values. Total seru m cholesterol, triglyceride, and blood glucose levels were evaluated in 7% of the study population before the study and after the sixth cycle of NGM /EE tr eatment. Cholesterol and triglyceride levels were assessed enz ymaticall y. The number of patients with serum cholesterol, trigl yceride, and blood gluco se levels within normal limits at entry remained virtually unchanged during treatment. Of the 2197 patients who entered the study with total choles-
1966 Runnebaum, Grunwald, and Rabe
J u ne 199::'
Am
J O bstet (;y neco l
2200 Serum cholesterol 2.000
D
:s 5 2 mmol/L
1.800
lIIII[]
> 52 mmoli L
1600 1 -100 sn
C
2.071 1 200 2.187
~
~
Q.
1000 800 190
600 756
400 200 0 Pretreatme nt
Cycle 6
5.2 mmo l/L
Fig. 1. Numbers of patients with seru m cholester ol levels :55.2 and > 5.2 mmol /L before and aft er six cycles of tre atm ent.
terol levels in th e low or normal range «5.2 mm ol/L), 95 % still had low or normal levels aft er six cycles of NGM I [E , and 5% had increased levels ( Fig. I ). Of 756 pati ents who entered th e study with elevated choleste rol levels (~5 . 2 mmol /L ), 75% had levels remaining above 5.2 mmol/L, and the remaining 25 % had norma l or low cholesterol levels «5.2 mmol /L) after six cycles of NGM/ EE. Similar patterns were observed for serum tri glyceride levels ( Fig. 2). Of the 207 5 patients who entered the stu dy with low 0\' normal trigl ycerid e levels « 1.7 mmoIlL), 96 % still had low or normal levels after six cycles of NG M I EE. On th e other hand , of the 500 patients who entered th e stu d y with high trig lyceride levels (~l. 7 mmol/ L), 72% still had high levels, and 28% had normal levels o f triglyce rides afte r six cycles of NGM /EE . Blood glucose levels appeared to be normalized by NGM/EE treatment (Fi g. 3). Of the 2738 patients entering the study with low or normal fast ing serum glu cose levels « 6.4 mmol/ L), 98% still had normal levels after six cycles of NGM I EE. Similarly, of 139 pat ient s with initi ally high blood glucose levels ( ~ 6.4 mmoIlL), 48% had normal levels at the end of th e stu dy. Adverse effects. The presence of acne, nau sea , headaches, and breast tension (tightness in the breasts) was reponed by each patient o n her study calendar. The
effect of NGM I EE on th ese side effects was evaluated by comparing the percentage of pat ients experiencing these symptoms at the pretherapy office visit with th e percentage r ecording them after six cycles of treatment. Informat ion obtained from the person al histories of 41 ,208 patients indic ated th at 35,556 (70% ) never had acne eithe r at any time before the NGM /EE study or during it. The incidence of acn e was reduced fro m 12% d uring the pretherapy cycle to 9% a fter the six cycles of treatment. At th e end of th e sixth cycle of treatment, 8% of patients descr ibed their acne as persisting since before therap y, whereas 5% rep oned th at it was no longer present. O nly I % of th e pa tients who did not report acne before the study exper ienced it during th e sixth cycle. The incide nce of headache also decreased during the study. Headache, which occurred in 13% of women before N GM / EE therapy, was reported by on ly 5% of subjects after six cycles of treatment. Headaches experienced before the study improved in 9% of women, and onl y 2% of subjects reported worsening of their headaches durin g cycle 6 of the study. Nausea de creased from a pretreatment incidence of 6% to 4% during the sixth cycle of treatment. Although 5% of subjects reponed th at nausea was no longer present , 1% reponed it as un changed, and 1% experienced nausea for th e first tim e during the sixth cycle.
Efficacy and tolerability of NGM/EE
Volume 166 Number 6, Part 2
2,000 Serum triglycerides
D Iillllll
1.600
1.200
2.075
s 1.7 mmo l/L > 1.7 mmol/L
1,982
'"
C
'!:.'
iii
11.
800
400
OL.---.JL-_ _-l.._ _--.JIU..l.Ill..::.:::...lllll.
Pretreatment ~
Cycle 6
1.7 mmol/L
-llJl1llllll.ll1Jl.IL_ _-Il.llll.ll1Jl1lll..L-_ _
Pretreatment
Cycle 6
> 1.7 mmol/L
Fig. 2. Number of patients with serum triglyceride levels 51. 7 and> I. 7 mmoll L before and after six cycles of treatment.
F
ling
D
rum rue 6
mrnot L
mmol L
2
2738
67
2 ()
Pr r
trn nt
4 rnrnot
L
C I 6
Pr
r
i rn n t
64 mmolll
Fig. 3. Number of patients with fasting serum glucose levels 56.4 and after six cycles of treatment.
~6.4
mmollL before and
1967
1968 Runnebaum, Grunwald, and Rabe
Breast tension (tightness in the breasts) was reported by 12% of subjects before they entered the study. At the end of the study, 4% of subjects no longer reported this side effect. However, 9% of patients reported breast tension as a new side effect after six cycles of NGM/EE.
Comment
The results of the present study, in which 59,701 women received NGM/EE for up to six cycles, for a total of 342,438 menstrual cycles, support those of previously reported multicenter trials, as reviewed by Corson" and Becker. 9 The use-efficacy Pearl index of 0.25 reported in the current study is similar to the Pearl index of 0 in a 12-month European multicenter open study of 147 women'? and 0.64 in a 24-month U.S. comparative study of 1473 women (compared with a Pearl index of 0.62 for norgestrel)." The adverse effects observed in the current study are also similar to those noted in earlier trials . In the 12month open clinical trial (Cilag International Medical Documentation, Medoc-Report NRG 08238, 1989), only 16 adverse effects were reported by 11 patients. In that study NGM/EE had no effect on mean body weight or blood pressure. The mean duration and intensity of menstrual flow decreased during therapy. As expected, BTB and spotting are elevated (3% and 13% of patients, respectively) during the first cycle but returned to baseline levels by cycle 3 /4, and amenorrhea never occurred." Other studies confirm the safety and efficacy of NGM/EE. A small study (Cilag International Medical Documentation, Medoc-Report NRG 05301 , 1985) (19 patients) conducted in Germany demonstrated that NGM/EE resulted in no relevant alterations in the coagulation system after the six cycles of treatment. Another study (Cilag International Medical Documentation, Medoc-Report NRG 05288, 1985) (21 subjects; six cycles) demonstrated that NGM/EE had very low androgenic activit y, as determined by high levels of sex hormone-binding globulin and low levels of free testosterone. In the same study levels of follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, and prolactin confirmed the contraceptive efficacy of NGM /EE. Furthermore, no clinically significant changes in fasting blood glucose or basal insulin levels were reported during this six-cycle study. Serum cholesterol and triglyceride levels, which were reduced in cycle 3, returned to baseline levels in cycle 6. Low-density lipoprotein cholesterol levels decreased in both cycles 3 and 6, high-density lipoprotein cho lesterollevels increased during NGM/EE treatment. In the current study, reductions in cycle length and duration of bleeding of 4% and 16%, respectively, were noted; 32% of the women experienced reductions in the intensity of bleeding. Similarly, spotting and BTB
June 1992 Am J Obstet Gynecol
decreased over time, with 97 % of women reporting an absence of irregular bleeding by the end of cycle 6. Weight, blood pressure, and pulse were minimally affected. The percentage of women who experienced acne, nausea, or headache at the end of six cycles of treatment was lower than the percentage with these symptoms before treatment with NGM/EE. In general, for patients entering the study with normal levels of total serum cholesterol, serum triglycerides, and blood glucose, these levels were still within the normal range after six cycles of NGM/EE treatment. Of those patients entering the study with high cholesterol and serum triglyceride values, 25% and 28%, respectively, had normal levels after six cycles of NGM/EE treatment. In 50% of patients entering the study with high blood glucose levels, these levels were normal after six cycles of NGM/EE. Thus NGM/EE had minimal effects on total serum cholesterol, serum triglyceride, and blood glucos e levels. These data are consistent with the more rigorous evaluations of these metabolic effects obtained in earlier trials." 9 To date all evidence indicates that NGM /EE is an effective oral contraceptive with a favorable profile for safety and patient tolerance, characterized by neutral or beneficial effects on metabolic functions and a low frequency of minor adverse effects. REFERENCES I. Lawson ]S, Yuliano SE, Pasquale SA, Osterman J. Opti-
2.
3.
4.
5. 6. 7. 8.
9. 10. II.
mum dosage of an oral contraceptive-a report from the study of seven combinations of norgestimate and ethinyl estradiol. AMJ OBSTET GYNECOL 1979;134:315-20. Inman WHN, Vessey MP. Investigation of deaths from pulmonary, coronary and cerebral thrombosis and embolism in women of childbearing age . Br Med J 1968;2:193 . Sartwell PE, Masi AT, Arthes FG, Greene GR, Smith HE . Thromboembolism and oral contraceptives: an epidemiological case-control study. Am] EpidemioI1969;90 :36580. Inman WH , Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives: a report to the committee on the safety of drugs. Br Med] 1970;2:203. Bouiger LE, Boman G, Eklund G. Westerholm B. Oral contraceptives and thromboembolic disease: effects of lowering oestrogen content. Lancet 1980; 1:1097-1101. Corson SL. Efficacy and clinical profile of a new oral contraceptive containing norgestimate- U.S. clinical trials. Acta Obstet Gynecol Scand 1990; 152(suppl):25-3 I. Phillips A. The selectivity of a new progestin . Acta Obstet Gynecol Scand 1990; 152(suppl):21-24. McGuireJL, Phillips A, Hahn D-W, Tolman EL, Flor S, Kafrissen ME. Pharmacologic and pharmacokinetic characteristics of norgestimate and its metabolites. AM J OBSTET GYNECOL 1990;163:2127-31. Becker H. Supportive European data on a new oral contraceptive containing norgcstimate. Acta Obstet Gynecol Scand 1990;152(suppl):33-9 . Pearl R. Con traception and fertility in 2000 women. Hum Bioi 1932;4:363. Sachs L. Angewandte Statistik. Berlin: Springer-Verlag, 5. Auflage, 1978.
plasma insulin and acute-phase response. Arteriosclerosis 1989;9:362-7. 21. Reaven G. Banting Lecture 1988: role of insulin resistance in human disease. Diabetes 1988;37:1595-607. 22. Ducimetiere P, Eschwege E, Papoz L, Richard J, Claude J, Rosselin G. Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease in a middle-aged population. Diabetologia 1980; 19:205-10. 23. Pyorala K, Savolainen E, Kaukola S, HaapakoskiJ. Plasma insulin as coronary heart disease risk factor: relationship
Long-term oral contraceptive use
to other risk factors and predictive value during 9V, year follow-up of the Helsinki Policemen Study population. Acta Med Scand 1985;701(suppl):38-52. 24. Godsland I, Crook D, Wynn V. Coronary heart disease risk markers in users of low-dose oral contraceptives. J Reprod Med 1991;36(suppl):226-37. 25. Wynn V. Effect of duration of low-dose oral contraceptive administration on carbohydrate metabolism. AMJ OBSTET GYNECOL 1982;142:739-46. 26. Wynn V, Godsland I. Effects of oral contraceptives on carbohydrate metabolism. J Reprod Med 1986;31 :892-7.
The efficacy and tolerability of norgestimate/ ethinyl estradiol (250 l-Lg of norgestimate/35 p.g of ethinyl estradiol): Results of an open, multicenter study of 59,701 women Benno Runnebaum, MD, K. Grunwald, MD, and T. Rabe, MD Heidelberg, Germany The efficacy and tolerability of a new oral contraceptive, norgestimatelethinyl estradiol (250 f.Lg of norgestimate/35 f.Lg of ethinyl estradiol; Cilag GmbH Research, SUlzbach, Germany) were examined in an open-label study of 59,701 women who were evaluated during 342,348 menstrual cycles; 42,022 women completed the planned treatment regimen of six cycles. A use-efficacy (overall) Pearl index of 0.25 pregnancies per 100 woman-years was calculated based on 342,348 cycles. Tolerability was assessed for all women who completed six treatment cycles. Reductions in mean cycle length and duration of bleeding were noted; 32% of the women experienced reductions in the intensity of bleeding by the end of cycle 6. After six cycles of use, amenorrhea occurred in 1%, spotting in 4%, and breakthrough bleeding in 3% of the participating women. Treatment with norgestimatelethinyl estradiol had minimal effects on weight, blood pressure, pulse, lipid metabolism, and blood glucose. Adverse effects (acne, nausea, or headaches) occurred at low frequencies and in many cases, were reduced compared with pretreatment levels. The results of this large-scale open trial were comparable with results from two other multicenter trials of the same formulation. (AM J OesTET GYNECOL 1992;166:1963-8.)
Key words: Norgestimate, ethinyl estradiol, progestins, oral contraceptives In recent years, much research has focused on the development of oral contraceptives with reduced hormone content. I Both the estrogen and progestin components of oral contraceptive formulations are thought to contribute to minor adverse effects, such as nausea,
From Universitiits-Frauenklinik, Abt. fur Gyniikologische Endokrinologie und FertilitiitsstOrungen. Reprint requests: Prof Dr. med Dr. med. h.c. Benno Runnebaum, Abt. Fur Gyniikologische Endokrinologie und FertilitiitsstOrungen, Universitiits-Frauenklinik, Vossstrasse 9, D-6900 Heidelberg, Germany. 610137508
headache, and bleeding irregularities I and to more serious health problems, such as an increased risk of cardiovascular disease noted with high-dose formulations.>' Among the minor adverse effects, nausea and headache are generally linked to estrogen dose. With the introduction of oral contraceptive preparations with estrogen doses of 50 f,Lg or less, the incidence of these adverse effects has generally been reduced.' However, breakthrough bleeding (BTB) and spotting, which appear to be determined by the estrogen/progestin ratio, have been more difficult to address. 1963
1964 Runnebaum, Grunwald, and Rabe
Most of the early studies suggested that the estrogen content of oral contraceptives was related to venous but not to arterial thromboembolic disease.' This finding led to investigation of the influence of the progestin component of oral contraceptives on various risk factors for occlusive arterial disease. In general, estrogen has a favorable effect on cholesterol fractions: it is associated with a reduction in serum concentration of low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol, as well as in the high-density lipoprotein subfraction, HDL 2 • All progestins now in clinical use, however, oppose the effects of the estrogen component." Thus in recent years, one goal of oral contraceptive research has been the development of a highly selective progestin with specific and potent progestational activities and minimal or no androgenic effects." Norgestimate (NGM), a progestin with marked progestational activity and a relative lack of androgenic activity, is promising in this regard.' Orally administered NGM is rapidly absorbed, reaches peak blood levels within 30 minutes to 2 hours, and has a plasma half-life of 6 to 14 hours. In the laboratory NGM has been extensively studied. NGM and its major metabolite l7-deacetyl norgestimate contribute to the biologic response." In previous clinical trials, the efficacy and safety of NGM/ethinyl estradiol (EE) (250 ILg of NGM/35 ILg of EE; CHest, Cilag GmbH Research, Sulzbach, Germany; Ortho-Cyclen, R. W.Johnson Pharmaceutical Research Institute, Raritan, N.J.) have been established.v" The current open-label trial, which enrolled 59,701 women, for a planned treatment period of six cycles, was designed to generate additional data on the efficacy and tolerability of NGM/EE, with special emphasis on changes in bleeding and in metabolic parameters.
Methods Study design. The trial was an open-label, noncomparative study with a large patient population. The planned length of active treatment was six cycles. Patient selection. Women of childbearing age who were in good general health and had regular menstrual cycles of approximately 28 to 32 days ' duration (including 3 to 5 days of bleeding) were eligible for entry. Exclusion criteria included: (1) the presence of vascular or hematologic disorders such as acute or chronic thromboembolism, cerebrovascular illness, myocardial infarction, or sickle cell anemia; (2) the presence of reproductive disorders such as amenorrhea, a history of herpes gestationis, or severe pruritus during pregnancy; (3) suspected or current pregnancy; and (4) general medical problems such as liver or gallbladder disease, cancer, or other metabolic derangements. Data collection. Data gathered during the initial visit included age, height, and weight, as well as information
June 1992 Am J Obstet Gynecol
on smoking habits, alcohol consumption, gynecologic history (including previous contraceptive use), famil y medical history, and the use of other concurrent medications. During the study, information on the cycle (including cycle length, duration and intensity of bleeding, lack of bleeding during tablet-free interval, occurrence of spotting or BTB, dysmenorrhea, and other gynecologic findings) was recorded by each patient on her study calendar, which she brought with her to the checkup examinations after the third and sixth cycles. Clinical variables measured during office visits before treatment and after the third and sixth cycle included blood pressure, pulse, and body weight. Concomitant symptoms, such as acne, nausea, breast tension, headaches, or other, were recorded by the patient on her study calendar. Reports on adverse symptoms were elicited by a questionnaire. Laboratory variables , including serum cholesterol, serum triglyceride, and blood and urinary glucose levels, were evaluated in a subgroup of 3000 women before the study and after the third and sixth cycles. Evaluation of data. The efficacy of NGM/EE was based on the computation of the overall Pearl index'? for the entire study population and the related 95% confidence intervals, which were computed under the assumption of Poisson-distribution data." Tolerability was evaluated by tabulating data on the menstrual cycle, adverse experiences, routine physical findings, and measurements of serum cholesterol, triglyceride, blood glucose, and urinary glucose levels for patients who completed cycle 6 of treatment with NGM/EE.
Results Premature termination. During the study, 59,701 patients were enrolled by 1609 physicians. Treatment was discontinued prematurely in 6588 patients (11%). Terminations were at the physicians' request, at the patients' request, or were the result of a joint decision (Table I). Patient characteristics. Among the 59,701 women who received NGM/EE, mean (:t standard deviation) age was 24.0 :t 6.7 years, mean height was 166.4 :t 6.3 em, mean weight was 61.2 :t 9.0 kg, and mean Broca index was 103.0%:t 23.3 % (Broca index = bod~ weight/0.9 X [heightIlOOD. The mean (:t standard deviation) age at menarche was 12.9 :t 1.3 years. Before they received NGM/EE, 88 % of the women had a regular menstrual cycle (i.e., range, 24 to 32 days). Among women with regular cycles, the mean (:t standard deviation) duration of the cycle was 28.0 :t 2.2 days, and the mean duration of bleeding was 4.9 :t 1.3 days. The intensity of the bleeding was designated as normal by 74% of the women, light by 13%, and heavy by 14%. Of the study subjects , 14% reported inter-
Volume 166 Number 6, Part 2
Efficacy and tolerability of NGM/EE
1965
Table I. Persons responsible for decisions to withdraw from treatment, by cycle Cycle
Physician
1
2
87 91
3
397
4
104
5 6 Totals
49 208 936
Patient
Both
Unkn own
300
59 62 258
54
428 1909
709 294 791 4431
menstrual bleeding (9% spotting and 5% BTB ), and 35% reported dysmenorrhea before treatment. At the time of enrollment into the study, 32% of the patients had already given birth; of these women, 88% had one or two children. Miscarriages and abortions had been experienced by 11% of the patients; of these women, 96 % had had one or two such experiences. When questioned about their use of contraceptives , 54% had not used contracep tives previously, and 46 % had used oral contraceptives. Triphasic formulations were the most common preparations used. Patients were directly switched over to the new oral cont raceptive without a washout period . Gynecologic or other concomitant illnesses were documented among 4.1 % (247 3) of the 59,701 patients. The most frequently reported disorders were gynecologic, reported by 1285 pat ients, and metabolic or endocrine , repo rt ed by 718 patients. Infections of the cervix were the most frequentl y reported gynecologic disorder (17%), followed by tho se of the breast (8%). Disorders of the th yroid gland were reported by 669 patients. Of the subj ects enrolled, 1490 patients received concomitant therapy; thyroid medications were the most frequently used (by 923 patients). The high number of patients taking thyroid medications can be explained by the fact that iod ine supplements are required in some parts of German y and were evidently considered th yroid medication. Efficacy. Efficacy was evalua ted over 342,348 cycles. Pregnancies occurred in 71 women during the treatment period . Thus the use-efficacy Pearl index was 0.25 pregnancies per 100 woman- years; the 95% con fidence interval was 0.19 to 0.31. Tolerability. In all measures of tolerability, only the 42 ,022 patients who completed six cycles of NGM/EE were included. Clinical variables. NGM/EE resulted in no significant changes in bod y weight, blood pressure, or pulse rate after six cycles of treatment. Mean bod y weight increased 0.6 % over initial values. Mean systolic and diastolic blood pressures incre ased 0.5 % and 1.3%, respectively, and mean pul se rate decreased 0.7% over the initial values. Menstrual cycles. NGM/EE resulted in excellent cycle control, as demonstrated by the low incidence of BTB,
64 22 123 588
70 193 154 40 122 633
Totals (%)
516 635 2757 1031 405
(7.8) (9.6) (41.8) (15.6) (6.1)
1244 (18.9) 6588 (100)
intermenstrual spotting, and amenorrhea . The percentage of patients reporting BTB decreased from 4.5% before therapy to 3% after six cycles of NGM/EE treatment. Ninety-four percent of the patients reported no BTB either before the study or during cycle 6 of therapy. In 3% of the patients BTB was no longer present compared with before therapy. Only 2% reported a first episode of BTB, and I % reported BTB before therapy and in cycle 6. Similarly, th e percentage of patients experiencing intermenstrual spotting decreased from 9% before the study to 4% after six cycles of NGM/EE treatment. Eighty-eight percent of subjects reported no spotting either before entry or during cycle 6 of therapy. Of the remaining 12%, 8% reported discontinuation of spotting after six cycles of NGM /EE, 3% who had not experienced spotting before they entered the study reported it during cycle 6, and 1% reported spotting both before th erap y and in cycle 6. Amenorrhea (no bleeding in a given cycle) occurred in onl y 1.4% of the women during cycle 6. The length of cycle 6 was unaffected by NGM/EE in 62% of the patients, whereas it was shortened in 27% and lengthened in 11% compared with baseline values. The duration of bleeding in cycle 6 decreased or remained th e same in 91 % of patients (53% and 38%, respectively) and incr eased in onl y 9% of patients. Also, the severity of bleeding remained unchanged or was amelior ated in most patients in treatment cycle 6. Whereas 96 % of patients exp erienced no change (64%) or a decrease in severity (32%), onl y 4% reported an incr ease compa red with baseline values. NGM /EE demonstrated no adverse effe ct on the reproductive tr act during this study. Gynecologic disease was identified in 0.5% of the women at the beginning of the study and in 0.4 % at the end of cycle 6. Laboratory values. Total seru m cholesterol, triglyceride, and blood glucose levels were evaluated in 7% of the study population before the study and after the sixth cycle of NGM /EE tr eatment. Cholesterol and triglyceride levels were assessed enz ymaticall y. The number of patients with serum cholesterol, trigl yceride, and blood gluco se levels within normal limits at entry remained virtually unchanged during treatment. Of the 2197 patients who entered the study with total choles-
1966 Runnebaum, Grunwald, and Rabe
J u ne 199::'
Am
J O bstet (;y neco l
2200 Serum cholesterol 2.000
D
:s 5 2 mmol/L
1.800
lIIII[]
> 52 mmoli L
1600 1 -100 sn
C
2.071 1 200 2.187
~
~
Q.
1000 800 190
600 756
400 200 0 Pretreatme nt
Cycle 6
5.2 mmo l/L
Fig. 1. Numbers of patients with seru m cholester ol levels :55.2 and > 5.2 mmol /L before and aft er six cycles of tre atm ent.
terol levels in th e low or normal range «5.2 mm ol/L), 95 % still had low or normal levels aft er six cycles of NGM I [E , and 5% had increased levels ( Fig. I ). Of 756 pati ents who entered th e study with elevated choleste rol levels (~5 . 2 mmol /L ), 75% had levels remaining above 5.2 mmol/L, and the remaining 25 % had norma l or low cholesterol levels «5.2 mmol /L) after six cycles of NGM/ EE. Similar patterns were observed for serum tri glyceride levels ( Fig. 2). Of the 207 5 patients who entered the stu dy with low 0\' normal trigl ycerid e levels « 1.7 mmoIlL), 96 % still had low or normal levels after six cycles of NG M I EE. On th e other hand , of the 500 patients who entered th e stu d y with high trig lyceride levels (~l. 7 mmol/ L), 72% still had high levels, and 28% had normal levels o f triglyce rides afte r six cycles of NGM /EE . Blood glucose levels appeared to be normalized by NGM/EE treatment (Fi g. 3). Of the 2738 patients entering the study with low or normal fast ing serum glu cose levels « 6.4 mmol/ L), 98% still had normal levels after six cycles of NGM I EE. Similarly, of 139 pat ient s with initi ally high blood glucose levels ( ~ 6.4 mmoIlL), 48% had normal levels at the end of th e stu dy. Adverse effects. The presence of acne, nau sea , headaches, and breast tension (tightness in the breasts) was reponed by each patient o n her study calendar. The
effect of NGM I EE on th ese side effects was evaluated by comparing the percentage of pat ients experiencing these symptoms at the pretherapy office visit with th e percentage r ecording them after six cycles of treatment. Informat ion obtained from the person al histories of 41 ,208 patients indic ated th at 35,556 (70% ) never had acne eithe r at any time before the NGM /EE study or during it. The incidence of acn e was reduced fro m 12% d uring the pretherapy cycle to 9% a fter the six cycles of treatment. At th e end of th e sixth cycle of treatment, 8% of patients descr ibed their acne as persisting since before therap y, whereas 5% rep oned th at it was no longer present. O nly I % of th e pa tients who did not report acne before the study exper ienced it during th e sixth cycle. The incide nce of headache also decreased during the study. Headache, which occurred in 13% of women before N GM / EE therapy, was reported by on ly 5% of subjects after six cycles of treatment. Headaches experienced before the study improved in 9% of women, and onl y 2% of subjects reported worsening of their headaches durin g cycle 6 of the study. Nausea de creased from a pretreatment incidence of 6% to 4% during the sixth cycle of treatment. Although 5% of subjects reponed th at nausea was no longer present , 1% reponed it as un changed, and 1% experienced nausea for th e first tim e during the sixth cycle.
Efficacy and tolerability of NGM/EE
Volume 166 Number 6, Part 2
2,000 Serum triglycerides
D Iillllll
1.600
1.200
2.075
s 1.7 mmo l/L > 1.7 mmol/L
1,982
'"
C
'!:.'
iii
11.
800
400
OL.---.JL-_ _-l.._ _--.JIU..l.Ill..::.:::...lllll.
Pretreatment ~
Cycle 6
1.7 mmol/L
-llJl1llllll.ll1Jl.IL_ _-Il.llll.ll1Jl1lll..L-_ _
Pretreatment
Cycle 6
> 1.7 mmol/L
Fig. 2. Number of patients with serum triglyceride levels 51. 7 and> I. 7 mmoll L before and after six cycles of treatment.
F
ling
D
rum rue 6
mrnot L
mmol L
2
2738
67
2 ()
Pr r
trn nt
4 rnrnot
L
C I 6
Pr
r
i rn n t
64 mmolll
Fig. 3. Number of patients with fasting serum glucose levels 56.4 and after six cycles of treatment.
~6.4
mmollL before and
1967
1968 Runnebaum, Grunwald, and Rabe
Breast tension (tightness in the breasts) was reported by 12% of subjects before they entered the study. At the end of the study, 4% of subjects no longer reported this side effect. However, 9% of patients reported breast tension as a new side effect after six cycles of NGM/EE.
Comment
The results of the present study, in which 59,701 women received NGM/EE for up to six cycles, for a total of 342,438 menstrual cycles, support those of previously reported multicenter trials, as reviewed by Corson" and Becker. 9 The use-efficacy Pearl index of 0.25 reported in the current study is similar to the Pearl index of 0 in a 12-month European multicenter open study of 147 women'? and 0.64 in a 24-month U.S. comparative study of 1473 women (compared with a Pearl index of 0.62 for norgestrel)." The adverse effects observed in the current study are also similar to those noted in earlier trials . In the 12month open clinical trial (Cilag International Medical Documentation, Medoc-Report NRG 08238, 1989), only 16 adverse effects were reported by 11 patients. In that study NGM/EE had no effect on mean body weight or blood pressure. The mean duration and intensity of menstrual flow decreased during therapy. As expected, BTB and spotting are elevated (3% and 13% of patients, respectively) during the first cycle but returned to baseline levels by cycle 3 /4, and amenorrhea never occurred." Other studies confirm the safety and efficacy of NGM/EE. A small study (Cilag International Medical Documentation, Medoc-Report NRG 05301 , 1985) (19 patients) conducted in Germany demonstrated that NGM/EE resulted in no relevant alterations in the coagulation system after the six cycles of treatment. Another study (Cilag International Medical Documentation, Medoc-Report NRG 05288, 1985) (21 subjects; six cycles) demonstrated that NGM/EE had very low androgenic activit y, as determined by high levels of sex hormone-binding globulin and low levels of free testosterone. In the same study levels of follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, and prolactin confirmed the contraceptive efficacy of NGM /EE. Furthermore, no clinically significant changes in fasting blood glucose or basal insulin levels were reported during this six-cycle study. Serum cholesterol and triglyceride levels, which were reduced in cycle 3, returned to baseline levels in cycle 6. Low-density lipoprotein cholesterol levels decreased in both cycles 3 and 6, high-density lipoprotein cho lesterollevels increased during NGM/EE treatment. In the current study, reductions in cycle length and duration of bleeding of 4% and 16%, respectively, were noted; 32% of the women experienced reductions in the intensity of bleeding. Similarly, spotting and BTB
June 1992 Am J Obstet Gynecol
decreased over time, with 97 % of women reporting an absence of irregular bleeding by the end of cycle 6. Weight, blood pressure, and pulse were minimally affected. The percentage of women who experienced acne, nausea, or headache at the end of six cycles of treatment was lower than the percentage with these symptoms before treatment with NGM/EE. In general, for patients entering the study with normal levels of total serum cholesterol, serum triglycerides, and blood glucose, these levels were still within the normal range after six cycles of NGM/EE treatment. Of those patients entering the study with high cholesterol and serum triglyceride values, 25% and 28%, respectively, had normal levels after six cycles of NGM/EE treatment. In 50% of patients entering the study with high blood glucose levels, these levels were normal after six cycles of NGM/EE. Thus NGM/EE had minimal effects on total serum cholesterol, serum triglyceride, and blood glucos e levels. These data are consistent with the more rigorous evaluations of these metabolic effects obtained in earlier trials." 9 To date all evidence indicates that NGM /EE is an effective oral contraceptive with a favorable profile for safety and patient tolerance, characterized by neutral or beneficial effects on metabolic functions and a low frequency of minor adverse effects. REFERENCES I. Lawson ]S, Yuliano SE, Pasquale SA, Osterman J. Opti-
2.
3.
4.
5. 6. 7. 8.
9. 10. II.
mum dosage of an oral contraceptive-a report from the study of seven combinations of norgestimate and ethinyl estradiol. AMJ OBSTET GYNECOL 1979;134:315-20. Inman WHN, Vessey MP. Investigation of deaths from pulmonary, coronary and cerebral thrombosis and embolism in women of childbearing age . Br Med J 1968;2:193 . Sartwell PE, Masi AT, Arthes FG, Greene GR, Smith HE . Thromboembolism and oral contraceptives: an epidemiological case-control study. Am] EpidemioI1969;90 :36580. Inman WH , Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives: a report to the committee on the safety of drugs. Br Med] 1970;2:203. Bouiger LE, Boman G, Eklund G. Westerholm B. Oral contraceptives and thromboembolic disease: effects of lowering oestrogen content. Lancet 1980; 1:1097-1101. Corson SL. Efficacy and clinical profile of a new oral contraceptive containing norgestimate- U.S. clinical trials. Acta Obstet Gynecol Scand 1990; 152(suppl):25-3 I. Phillips A. The selectivity of a new progestin . Acta Obstet Gynecol Scand 1990; 152(suppl):21-24. McGuireJL, Phillips A, Hahn D-W, Tolman EL, Flor S, Kafrissen ME. Pharmacologic and pharmacokinetic characteristics of norgestimate and its metabolites. AM J OBSTET GYNECOL 1990;163:2127-31. Becker H. Supportive European data on a new oral contraceptive containing norgcstimate. Acta Obstet Gynecol Scand 1990;152(suppl):33-9 . Pearl R. Con traception and fertility in 2000 women. Hum Bioi 1932;4:363. Sachs L. Angewandte Statistik. Berlin: Springer-Verlag, 5. Auflage, 1978.
