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Contraceptive efficacy and safety of a monophasic oral contraceptive containing 150 μg desogestrel and 30 μg ethinyl estradiol: United States clinical experience using a “Sunday start” approach*
FERTILITY AND STERILITY Copyright
©
Vol. 64, No.2, August 1995
Printed on acid-free paper in U. s. A.
1995 American Society for Reproductive Medicine
Contraceptive efficacy and safety of a monophasic oral contraceptive containing 150 ILg desogestrel and 30 ILg ethinyl estradiol: United States clinical experience using a "Sunday start" approach*
Morris Notelovitz, M.D., Ph.D.t Women's Medical and Diagnostic Center and The Center for Climacteric Studies, Gainesville, Florida
Objective: To report on experience in the United States with a monophasic oral contraceptive (OC) containing 150 J1g desogestrel and 30 J1g ethinyl E2 (EE). The results of a multicenter evaluation of efficacy, cycle control, and safety over 6 months of exposure using a "Sunday start" regimen is evaluated. Setting: Multicenter. Design: Open noncomparative study. Participants: Study subjects were a mean age of 25 years, and the majority were educated, nonobese, white, nulliparous, and previously had used OCs. Interventions: A total of 809 women were exposed to study medication for a total of 4,096 cycles (equivalent to 341.3 women-years of use). Results: Efficacy was excellent. One user-failure pregnancy occurred (Pearl index 0.32); there were no method-failure pregnancies. Study medication was well tolerated; 6.6% of the subjects discontinued treatment because of drug-related adverse events. The study medication exhibited no adverse effects on blood pressure, body weight, or laboratory variables. Cycle control was evaluated in 697 subjects. In a total of 3,640 cycles, the incidences of intermenstrual bleeding, breakthrough bleeding, breakthrough spotting, and absence of withdrawal bleeding were 9.8%, 1.7%,8.1%, and 1.4%, respectively, indicating appropriate cycle control. Patient acceptability was high; seven subjects (1 %) discontinued the study because of menstrual irregularity (metrorrhagia). Conclusion: The results of this study, comparable to those demonstrated in a recent European multicenter study, add further documentation to the published data on the safety, efficacy, cycle control, and acceptability of this monophasic desogestrel-containing combined OC using a "Sunday start" approach. Fertil Steril 1995;64:261-6 Key Words: Desogestrel, ethinyl estradiol, "Sunday start", progestin, cycle control
Research efforts over the past 20 years have led to the development of new progestins that minimize the side effects associated with oral contraceptive (OC) use while maintaining efficacy. This reduction in side effects is the result of enhanced selectivity of the progestins. Selectivity of a progestin refers to the ratio between the progestogenic activity and the Received September 14, 1994; revised and accepted March 9, 1995. * Supported by Organon Inc., West Orange, New Jersey. t Reprint requests: Morris Notelovitz, M.D., Ph.D., Women's Medical and Diagnostic Center and the Center of Climacteric Studies, 222 SW 36th Terrace, Suite C, Gainesville, Florida 32607 (FAX: 904-375-7901). Vol. 64, No.2, August 1995
androgenic activity. The first selective progestin, desogestrel, was discovered in 1973. This progestogen undergoes rapid and almost complete biotransformation to its 3-keto desogestrel metabolite (1, 2). This metabolite is responsible for desogestrel's pharmacologic activity and has shown relatively strong progestational activity, no estrogenic activity, and minimal intrinsic androgenicity (3). The objective of this study was to evaluate the efficacy and safety of a monophasic OC containing 150 f-Lg desogestrel and 30 f-Lg ethinyl E2 (EE, Ortho-Cept; Ortho-McNeil Pharmaceutical Corporation, Raritan, NJ; Desogen; Organon Inc., West Orange, NJ), using a "Sunday start" dosing regimen, over a 6-month period.
Notelovitz et al.
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261
MATERIALS AND METHODS
An open, multicenter, noncomparative study was conducted at nine sites across the United States. Healthy, sexually active, nonpregnant, nonlactating women 18 to 35 years of age who were willing to complete the entire study, to comply with the protocol requirements, and who gave written informed consent that was approved by each Institutional Review Board were enrolled in the study. Approximately 50% of the subjects enrolled were to be "starters" (i.e., subjects who had not used any OC in the 2 months preceding study entry); other subjects were classified as "switchers" (i.e., women who had used oral contraception immediately before the study entry). Excluded from the study were women for whom OCs were contraindicated; those who were ~20% of ideal body weight, hypertensive, or had other significant medical problems; those who had taken drugs known to interfere with OCs during the month before study enrollment; and women who had used hormonal intrauterine devices within 90 days or injected sex hormones within 12 months of the study. Women who had not had three regular menses after pregnancy or after lactation and those with a history of irregular menses (including spontaneous cycle lengths < 24 days or mt35 days), amenorrhea, or abnormal genital bleeding within 2 months before study enrollment also were excluded. During a pretreatment screening period not exceeding 21 days, fasting blood and urine samples were obtained from eligible subjects for hematologic and serum biochemical assessments, a serum ,B-hCG pregnancy test, and urinalysis. If any laboratory test was deemed pathologically significant, the subject was terminated from the study. Medical, drug use, and gynecological histories (including data on coital frequency and present means of contraception) also were obtained, and height, weight, blood pressure, and vital signs were recorded. Routine medical and gynecological examinations were performed, as well as a detailed breast examination, which noted any changes such as breast nodules or masses. A cervical Papanicolaou smear was obtained if the subject had not had one in the previous 12 months. At the start of treatment, each subject was dispensed study medication for three cycles in the form of 21-day blister strips. A "Sunday start" regimen was used in which starters took the first tablet on the Sunday after the first menstrual period beginning after the admission visit and switchers took the first tablet on the Sunday after the initiation 262
Notelovitz et al.
US clinical experience: 150
J1{5
DSa / 30
of withdrawal bleeding for the preceding nonstudy cycle. During the first cycle, subjects were instructed to use a barrier method of contraception until they had taken study medication for 7 consecutive days. Subjects also were given diaries in which to record pill taking, vaginal bleeding, concomitant medications, and any new signs and symptoms (adverse experiences). Subjects returned for clinical visits between days 15 and 21 of cycles 3 and 6. At these visits a brief medical history of the previous 3 months was elicited and vital signs were recorded, and diaries were collected and discussed with each subject. At cycle 6 (or the last visit if the patient was discontinued prematurely) all baseline examinations were repeated. A follow-up visit was scheduled for all subjects 3 months after the last visit, regardless of whether they completed the study. A subject was considered to have completed the study if she ingested study medication for six successive cycles and was re-evaluated at the cycle 6 visit. Noncompliance was defined as having missed three consecutive pills or four or more pills in anyone cycle; these patients were discontinued from the study. Contraceptive efficacy was based on the assessment of pregnancy status during the drug administration period, which began with the first pill taken and ended with the last dose. If a subject discontinued the study during the pill-free interval, the last day of drug administration was considered to be the 28th day of the cycle. Only those conceptions occurring during the drug administration period were included in the analysis. Pregnancy was confirmed by serum ,B-hCG levels. Bleeding patterns were retrieved from patient diaries and the type and number of bleeding events or their absences were analyzed as to incidence per cycle. Specific data are to be found in Results. RESULTS
A total of 809 subjects received study medication; 332 (41.0%) starters and 477 switchers (59.0%). The 809 subjects were exposed to study medication for a total of 4,096 cycles, equivalent to 341.3 womenyears of use. Subjects, who had a mean age of 24.8 ± 4.6 years (mean ± SEM) at the start of the study, were predominantly nonobese (body mass index [BMI] < 26 kg/m 2 , 90.5%; BMI > 26 kg/m 2 , 9.5%), nulliparous (79%), and white (87%). Seventy-four percent of the women had completed> 14 years of education. Approximately 90% of the subjects had used OCs at some time in the past. J1{5
EE
Fertility and Sterility
Of the 809 subjects who received study medication, 624 completed the study, including 228 starters and 396 switchers; 23% of subjects were discontinued prematurely. Overall, the most common reasons for early discontinuation were nondrug-related reasons (6.7% of all subjects), drug-related adverse events (6.6%), and reason unknown (5.7%). Compliance with the prescribed regimen was good. Across all six cycles, 72.7% of the subjects did not miss a pill, and only 3.8% missed three or more pills in a given cycle. Only 3% of subjects were discontinued because of noncompliance (i.e., missing three consecutive pills or four or more pills in any one cycle). Efficacy
A total of 10 confirmed pregnancies was reported; 5 were pretreatment, 4 were post-treatment (conception occurred after discontinuation of the study drug), and 1 pregnancy occurred during treatment. This subject was found to be pregnant at week 16 of study participation; her compliance could not be evaluated because she failed to return her diary and unused medication. Therefore, this pregnancy was classified as a user failure. The overall use effectiveness expressed as a Pearl Index was 0.32 (13 cycle method). At any scheduled visit up to cycle 6, ~90% ofthe subjects were "at risk" of pregnancy (i.e., sexually active and additional contraceptive methods seldom or never used since the last visit), based on subject reporting, and <5% were considered "no risk" (i.e., no intercourse or additional contraceptive methods used). Cycle Control Analysis
For the cycle control analysis, 697 (86.2%) of 809 subjects treated provided evaluable diary information for a total of 3,640 cycles (Fig. 1). Overall, cycle control was well maintained, and only seven subjects (1 %) discontinued the study because of menstrual irregularity (metrorrhagia). Intermenstrual bleeding, consisting mainly of breakthrough spotting (defined as any vaginal flow that did not require more than one sanitary napkin or tampon per day), occurred in 9.8% of the total cycles. As expected, the percentage of subjects who experienced intermenstrual bleeding was highest in cycle 1 and, for the most part, declined steadily with continued use. Most subjects reported only a single episode of irregular bleeding (breakthrough bleeding Vol. 64, No.2, August 1995
l
n
= 697
3
6
Cycle n = 629
n = 509
Figure 1 Incidence of intermenstrual bleeding (IMB [_]), breakthrough bleeding (BTB [0]), breakthrough spotting (BTS [I!III]), and absence of withdrawal bleeding (AWB [1Iili]). All patients treated.
or spotting) during a particular cycle, and overall there were only six reports of three or more episodes of irregular bleeding in a given cycle. Breakthrough bleeding (defined as any vaginal flow that required more than one sanitary napkin or tampon per day) occurred in 1.7% of the total cycles and was relatively consistent across all cycles. As expected, the incidence of breakthrough bleeding was consistently higher in starters compared with switchers across all cycles studied (respective ranges: 1.4% to 2.8% versus 1.1% to 1.5%). Spotting occurred overall in 8.1% of the total cycles. As shown in Figure 1, the incidence of breakthrough spotting generally decreased as the duration of use increased. Compared with switchers, starters exhibited a higher incidence of spotting (12.8% versus 7.9%) during cycle 1, but the incidence in subsequent cycles was consistently lower. Absence of withdrawal bleeding (defined as no bleeding and/or spotting episode that began during or continued into the pill-free interval) was extremely infrequent. It occurred in only 1.4% of the total cycles. Safety
The monophasic desogestrel and EE combination appeared to be well tolerated; 6.6% of the subjects discontinued treatment because of a drug-related adverse event. Moreover, no serious clinical adverse
Notelovitz et a1.
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Table 1 Mean Change from Baseline to Last Laboratory Measurement Laboratory test Biochemistry Total bilirubin (mg/dL)* (n = 708) Calcium (mg/dL)t (n = 705) Glucose (mg/dL):j: (n = 704) Total protein (g/dL)§ (n = 708) Triglycerides (mg/dL)11 (n = 709) Cholesterol (mg/dL)~ (n = 709) Lactate dehydrogenase (UIL) (n = 701) Hematology Hemoglobin (g/dL)§ (n = 698) Hematocrit (%) (n = 685) Platelets (X10 3 /IlL) (n = 697) Red blood cells (X10 6/IlL) (n = 696) White blood cells (x103/IlL) (n = 698)
Baseline mean
Last measurement mean
Mean change
SEM
0.5 8.9 85.6 7.1 94.4 176.8 131.0
0.5 8.9 85.8 7.0 115.4 183.4 133.3
-0.1 0.0 0.2 -0.1 20.9 6.6 2.3
0.008 0.01 0.457 0.015 1.56 0.876 1.01
13.0 40.3 298.3 4.5 6.7
13.3 39.0 299.4 4.4 6.5
-0.1 -1.3 1.2 -0.1 -0.2
0.030 0.145 1.75 0.011 0.06
* Conversion factor to SI units, 17.10. t Conversion factor to SI units, 0.2495. :j: Conversion factor to SI units, 0.05551.
experiences considered to be drug related were reported. The most common clinical adverse experiences reported by subjects who received study medication were dysmenorrhea, metrorrhagia, headaches, general infections of the body, and nausea. The prevalence of all of these events tended to decrease over time. One subject was discontinued from the study because of a clinically significant abnormal laboratory test value. This subject was withdrawn from treatment during cycle 2 because of symptoms consistent with hepatitis; laboratory evaluation revealed an elevated alanine aminotransferase (ALT) level (232 VI L) on day 35 of the study period. Two weeks later, ALT levels had returned to within the acceptable range. Overall, the monophasic desogestrel and EE combination produced few changes in the laboratory tests evaluated (Table 1). Small increases were seen at the last laboratory measurement, after 6 months of treatment, in the mean values for triglycerides (from 94.4 to 115.4 mg/dL [1.07 mmol/L to 1.30 mmol/L]) and cholesterol (from 176.8 to 183.4 mgl dL [2.00 to 2.07 mmol/L]) but were within the normal clinical ranges. Treatment with monophasic desogestrel and EE had no significant clinical effects on the vital signs of any of the subjects. Overall, there were no significant changes in mean body weight, and the mean BMI remained relatively unchanged from cycles 4 to 6 (Fig. 2). Five subjects discontinued the study because of weight gain, which was considered possibly related to study medication in all but one subject. Another subject discontinued the study because of 264
Notelovitz et al.
§ Conversion factor to SI units, 10.0. II Conversion factor to SI units, 0.01129. ~ Conversion factor to SI units, 0.02586.
edema considered to be treatment related and weight gain considered of unlikely relationship to treatment. Blood pressure values remained constant throughout the study (Fig. 3). Two patients presented with clinically significant blood pressure values (systolic > 140 mm Hg or an increase of > 15 mm Hg from baseline, or diastolic> 90 mm Hg and an increase of > 10 mm Hg from baseline). One of these was reported as an adverse experience but was not attributed to study medication because the subject had a history of hypertension. Of the 713 subjects for whom breast examination data were obtained at baseline and poststudy, 255 (35.8%) were found to have some degree ofnodularity (from granular to very lobular) at baseline, and 250 (35.1 %) were found at follow-up.
US clinical experience: 150 J.1fJ DSG/30 J.1fJ EE
Cycle
Figure 2 Mean BMI over time. Fertility and Sterility
!£ E E
Cycle
Figure 3 Mean blood pressure readings over time. D diastolic.
~
systolic;
DISCUSSION
The results of the US multicenter clinical experience reported here are consistent with those of earlier trials conducted worldwide (4-9) as well as the recent European multicenter study (10). In the worldwide clinical trials, no method failures were reported in a total of 42,640 subjects who were treated for 183,212 cycles (4-9). Similarly, in the recent European multicenter study, no method-failure pregnancies and only 9 user-failure pregnancies were reported in a total of 1,195 subjects who were treated for a total of 11,656 cycles of exposure, corresponding to approximately 879 women-years of use (10). Cycle control with the monophasic desogestrelcontaining combined OC has been consistently good, with high patient acceptance. The results of the present cycle control analysis, which included a total of 3,640 cycles (up to six cycles of OC usage per patient), were similar to those of the recent European multicenter study in which a total of 11,426 cycles was analyzed in patients who used study medication for up to 18 cycles (10). In both the US and European trials, absence of withdrawal bleeding was very rare, occurring in <2% of the cycles. Likewise, the incidence of intermenstrual bleeding (mainly breakthrough spotting) in the two trials was comparable, being approximately 8%. In the present study, the overall incidences of breakthrough bleeding and breakthrough spotting were low (1.7% and 8.1%, respectively), and only seven patients (1%) were withdrawn from the study because of menstrual irregularity (metrorrhagia). The high efficacy and low intermenstrual bleeding rates consistently reported with the desogestrel-conVol. 64, No.2, August 1995
l..
taining combined formulation may be accounted for, to some degree, by the steady state half-life of desogestrel. Pharmacokinetic studies have shown that the steady state half-life observed after the administration of desogestrel is 38.0 ± 20 hours (11). Although the clinical implications of this long half-life have not been established, it may have relevance with regard to noncompliant patients. Throughout its clinical use, the monophasic desogestrel-containing combined OC has demonstrated consistently high levels of safety, tolerance, and patient acceptability (4-10). In the present study, only a small percentage of the subjects discontinued treatment because of drug-related adverse events. The prevalence of the most common adverse experiences-dysmenorrhea, metrorrhagia, headaches, infection, and nausea-generally decreased over time. Additionally, no adverse effects on blood pressure, body weight, or laboratory variables were observed. Slight increases in serum total cholesterol and triglycerides have been observed in previous studies, both with the monophasic desogestrel-containing combined OCs as well as with other low dose combinations (10, 12).
Acknowledgments. This study was conducted and analyzed by CLINTRIALS, Inc. (formerly Clinical Research International), Research Triangle Park, North Carolina. The contribution of the following clinical investigators is gratefully acknowledged: Allan B. Aven, M.D. (Arlington Heights, Illinois); Neal R. Cutler, M.D. (Beverly Hills, California); Howard G. McQuarrie, M.D. (Salt Lake City, Utah); and Nona F. Niland, M.D. (Austin, Texas).
REFERENCES 1. Viinikka I, Ylikorkala A, Vihko R, Hasenack HG, Nierwenhuyse H. Metabolism of a new synthetic progestogen Org 2969 in female volunteers. The distribution and excretion of radioactivity after an oral dose ofthe labelled drug. Acta Endocrinol (Copenh) 1980;93:375-9. 2. Hasenack HG, Bosch AMG, Kaar K. Serum levels of 3-ketodesogestrel after oral administration of desogestrel and 3keto-desogestrel. Contraception 1986;33:591-6. 3. Bergink EW, van Meel F, Turpijin EW, vander Vies J. Binding of progestogens to receptor proteins in MCF-7 cells. J Steroid Biochem Mol BioI 1983; 19:1563-70. 4. Bilotta P, Favilli S. Clinical evaluation of a monophasic ethinylestradiolldesogestrel-containing oral contraceptive. Arzneimittelforschung 1988;38:932-4. 5. Benagiano G. Comparison oftwo monophasic oral contraceptives: gestodene/ethinyl estradiol versus desogestrellethinyl estradiol. Int J Fertil 1989;34 Suppl:31-9. 6. Geissler KH. Hormonelle kontrazeption mit marvelon; erfahrungen mit marvelon in der gynaekologischen praxis;
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j1g
DSG/30
j1g
EE
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multicenter-studie bei 265 gynaekologen und aeber 26000 frauen. Fortschr Med 1983;101:1060-4. 7. Halbe HW, Cunha DC, Diaz JLE. Clinical experience in Brazil with a desogestrel-containing oral contraceptive. In: Halbe HW, Rekers H, editors. Oral contraception into the 1990s: the proceedings of a symposium held at the 12th World Congress of Gynecology and Obstetrics, Rio de Janeiro, October 1988. Carnforth, United Kingdom: Parthenon, 1989:6974. 8. Rekers H. Multicenter trial of a monophasic oral contraceptive containing ethinyl estradiol and desogestrel. Acta Obstet Gynecol Scand 1988;67:171-4.
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J.Lg
DSa / 30
9. Wiseman A, Bowie J, Cogswell D, Dewsbury J, Hamilton M, Hutchinson F, et al. Marvelon: clinical experience in the U.K. Br J Fam Plann 1984; 10:39-42. 10. Walling M. A multicenter efficacy and safety study of an oral contraceptive containing 150 J.Lg desogestrel and 30 J.Lg ethinyl estradiol. Contraception 1992;46:313-26. 11. Ortho-Cept Product Monograph, Ortho Pharmaceutical Corporation, Raritan, NJ. 12. Godsland IF, Crook D, Simpson R, Proudler A, Felton C, Lees B, et al. The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med 1990;323:1375-81.
J.Lg
EE
Fertility and Sterility
©
Vol. 64, No.2, August 1995
Printed on acid-free paper in U. s. A.
1995 American Society for Reproductive Medicine
Contraceptive efficacy and safety of a monophasic oral contraceptive containing 150 ILg desogestrel and 30 ILg ethinyl estradiol: United States clinical experience using a "Sunday start" approach*
Morris Notelovitz, M.D., Ph.D.t Women's Medical and Diagnostic Center and The Center for Climacteric Studies, Gainesville, Florida
Objective: To report on experience in the United States with a monophasic oral contraceptive (OC) containing 150 J1g desogestrel and 30 J1g ethinyl E2 (EE). The results of a multicenter evaluation of efficacy, cycle control, and safety over 6 months of exposure using a "Sunday start" regimen is evaluated. Setting: Multicenter. Design: Open noncomparative study. Participants: Study subjects were a mean age of 25 years, and the majority were educated, nonobese, white, nulliparous, and previously had used OCs. Interventions: A total of 809 women were exposed to study medication for a total of 4,096 cycles (equivalent to 341.3 women-years of use). Results: Efficacy was excellent. One user-failure pregnancy occurred (Pearl index 0.32); there were no method-failure pregnancies. Study medication was well tolerated; 6.6% of the subjects discontinued treatment because of drug-related adverse events. The study medication exhibited no adverse effects on blood pressure, body weight, or laboratory variables. Cycle control was evaluated in 697 subjects. In a total of 3,640 cycles, the incidences of intermenstrual bleeding, breakthrough bleeding, breakthrough spotting, and absence of withdrawal bleeding were 9.8%, 1.7%,8.1%, and 1.4%, respectively, indicating appropriate cycle control. Patient acceptability was high; seven subjects (1 %) discontinued the study because of menstrual irregularity (metrorrhagia). Conclusion: The results of this study, comparable to those demonstrated in a recent European multicenter study, add further documentation to the published data on the safety, efficacy, cycle control, and acceptability of this monophasic desogestrel-containing combined OC using a "Sunday start" approach. Fertil Steril 1995;64:261-6 Key Words: Desogestrel, ethinyl estradiol, "Sunday start", progestin, cycle control
Research efforts over the past 20 years have led to the development of new progestins that minimize the side effects associated with oral contraceptive (OC) use while maintaining efficacy. This reduction in side effects is the result of enhanced selectivity of the progestins. Selectivity of a progestin refers to the ratio between the progestogenic activity and the Received September 14, 1994; revised and accepted March 9, 1995. * Supported by Organon Inc., West Orange, New Jersey. t Reprint requests: Morris Notelovitz, M.D., Ph.D., Women's Medical and Diagnostic Center and the Center of Climacteric Studies, 222 SW 36th Terrace, Suite C, Gainesville, Florida 32607 (FAX: 904-375-7901). Vol. 64, No.2, August 1995
androgenic activity. The first selective progestin, desogestrel, was discovered in 1973. This progestogen undergoes rapid and almost complete biotransformation to its 3-keto desogestrel metabolite (1, 2). This metabolite is responsible for desogestrel's pharmacologic activity and has shown relatively strong progestational activity, no estrogenic activity, and minimal intrinsic androgenicity (3). The objective of this study was to evaluate the efficacy and safety of a monophasic OC containing 150 f-Lg desogestrel and 30 f-Lg ethinyl E2 (EE, Ortho-Cept; Ortho-McNeil Pharmaceutical Corporation, Raritan, NJ; Desogen; Organon Inc., West Orange, NJ), using a "Sunday start" dosing regimen, over a 6-month period.
Notelovitz et al.
US clinical experience: 150 fJ.g DSG/30 fJ.g EE
261
MATERIALS AND METHODS
An open, multicenter, noncomparative study was conducted at nine sites across the United States. Healthy, sexually active, nonpregnant, nonlactating women 18 to 35 years of age who were willing to complete the entire study, to comply with the protocol requirements, and who gave written informed consent that was approved by each Institutional Review Board were enrolled in the study. Approximately 50% of the subjects enrolled were to be "starters" (i.e., subjects who had not used any OC in the 2 months preceding study entry); other subjects were classified as "switchers" (i.e., women who had used oral contraception immediately before the study entry). Excluded from the study were women for whom OCs were contraindicated; those who were ~20% of ideal body weight, hypertensive, or had other significant medical problems; those who had taken drugs known to interfere with OCs during the month before study enrollment; and women who had used hormonal intrauterine devices within 90 days or injected sex hormones within 12 months of the study. Women who had not had three regular menses after pregnancy or after lactation and those with a history of irregular menses (including spontaneous cycle lengths < 24 days or mt35 days), amenorrhea, or abnormal genital bleeding within 2 months before study enrollment also were excluded. During a pretreatment screening period not exceeding 21 days, fasting blood and urine samples were obtained from eligible subjects for hematologic and serum biochemical assessments, a serum ,B-hCG pregnancy test, and urinalysis. If any laboratory test was deemed pathologically significant, the subject was terminated from the study. Medical, drug use, and gynecological histories (including data on coital frequency and present means of contraception) also were obtained, and height, weight, blood pressure, and vital signs were recorded. Routine medical and gynecological examinations were performed, as well as a detailed breast examination, which noted any changes such as breast nodules or masses. A cervical Papanicolaou smear was obtained if the subject had not had one in the previous 12 months. At the start of treatment, each subject was dispensed study medication for three cycles in the form of 21-day blister strips. A "Sunday start" regimen was used in which starters took the first tablet on the Sunday after the first menstrual period beginning after the admission visit and switchers took the first tablet on the Sunday after the initiation 262
Notelovitz et al.
US clinical experience: 150
J1{5
DSa / 30
of withdrawal bleeding for the preceding nonstudy cycle. During the first cycle, subjects were instructed to use a barrier method of contraception until they had taken study medication for 7 consecutive days. Subjects also were given diaries in which to record pill taking, vaginal bleeding, concomitant medications, and any new signs and symptoms (adverse experiences). Subjects returned for clinical visits between days 15 and 21 of cycles 3 and 6. At these visits a brief medical history of the previous 3 months was elicited and vital signs were recorded, and diaries were collected and discussed with each subject. At cycle 6 (or the last visit if the patient was discontinued prematurely) all baseline examinations were repeated. A follow-up visit was scheduled for all subjects 3 months after the last visit, regardless of whether they completed the study. A subject was considered to have completed the study if she ingested study medication for six successive cycles and was re-evaluated at the cycle 6 visit. Noncompliance was defined as having missed three consecutive pills or four or more pills in anyone cycle; these patients were discontinued from the study. Contraceptive efficacy was based on the assessment of pregnancy status during the drug administration period, which began with the first pill taken and ended with the last dose. If a subject discontinued the study during the pill-free interval, the last day of drug administration was considered to be the 28th day of the cycle. Only those conceptions occurring during the drug administration period were included in the analysis. Pregnancy was confirmed by serum ,B-hCG levels. Bleeding patterns were retrieved from patient diaries and the type and number of bleeding events or their absences were analyzed as to incidence per cycle. Specific data are to be found in Results. RESULTS
A total of 809 subjects received study medication; 332 (41.0%) starters and 477 switchers (59.0%). The 809 subjects were exposed to study medication for a total of 4,096 cycles, equivalent to 341.3 womenyears of use. Subjects, who had a mean age of 24.8 ± 4.6 years (mean ± SEM) at the start of the study, were predominantly nonobese (body mass index [BMI] < 26 kg/m 2 , 90.5%; BMI > 26 kg/m 2 , 9.5%), nulliparous (79%), and white (87%). Seventy-four percent of the women had completed> 14 years of education. Approximately 90% of the subjects had used OCs at some time in the past. J1{5
EE
Fertility and Sterility
Of the 809 subjects who received study medication, 624 completed the study, including 228 starters and 396 switchers; 23% of subjects were discontinued prematurely. Overall, the most common reasons for early discontinuation were nondrug-related reasons (6.7% of all subjects), drug-related adverse events (6.6%), and reason unknown (5.7%). Compliance with the prescribed regimen was good. Across all six cycles, 72.7% of the subjects did not miss a pill, and only 3.8% missed three or more pills in a given cycle. Only 3% of subjects were discontinued because of noncompliance (i.e., missing three consecutive pills or four or more pills in any one cycle). Efficacy
A total of 10 confirmed pregnancies was reported; 5 were pretreatment, 4 were post-treatment (conception occurred after discontinuation of the study drug), and 1 pregnancy occurred during treatment. This subject was found to be pregnant at week 16 of study participation; her compliance could not be evaluated because she failed to return her diary and unused medication. Therefore, this pregnancy was classified as a user failure. The overall use effectiveness expressed as a Pearl Index was 0.32 (13 cycle method). At any scheduled visit up to cycle 6, ~90% ofthe subjects were "at risk" of pregnancy (i.e., sexually active and additional contraceptive methods seldom or never used since the last visit), based on subject reporting, and <5% were considered "no risk" (i.e., no intercourse or additional contraceptive methods used). Cycle Control Analysis
For the cycle control analysis, 697 (86.2%) of 809 subjects treated provided evaluable diary information for a total of 3,640 cycles (Fig. 1). Overall, cycle control was well maintained, and only seven subjects (1 %) discontinued the study because of menstrual irregularity (metrorrhagia). Intermenstrual bleeding, consisting mainly of breakthrough spotting (defined as any vaginal flow that did not require more than one sanitary napkin or tampon per day), occurred in 9.8% of the total cycles. As expected, the percentage of subjects who experienced intermenstrual bleeding was highest in cycle 1 and, for the most part, declined steadily with continued use. Most subjects reported only a single episode of irregular bleeding (breakthrough bleeding Vol. 64, No.2, August 1995
l
n
= 697
3
6
Cycle n = 629
n = 509
Figure 1 Incidence of intermenstrual bleeding (IMB [_]), breakthrough bleeding (BTB [0]), breakthrough spotting (BTS [I!III]), and absence of withdrawal bleeding (AWB [1Iili]). All patients treated.
or spotting) during a particular cycle, and overall there were only six reports of three or more episodes of irregular bleeding in a given cycle. Breakthrough bleeding (defined as any vaginal flow that required more than one sanitary napkin or tampon per day) occurred in 1.7% of the total cycles and was relatively consistent across all cycles. As expected, the incidence of breakthrough bleeding was consistently higher in starters compared with switchers across all cycles studied (respective ranges: 1.4% to 2.8% versus 1.1% to 1.5%). Spotting occurred overall in 8.1% of the total cycles. As shown in Figure 1, the incidence of breakthrough spotting generally decreased as the duration of use increased. Compared with switchers, starters exhibited a higher incidence of spotting (12.8% versus 7.9%) during cycle 1, but the incidence in subsequent cycles was consistently lower. Absence of withdrawal bleeding (defined as no bleeding and/or spotting episode that began during or continued into the pill-free interval) was extremely infrequent. It occurred in only 1.4% of the total cycles. Safety
The monophasic desogestrel and EE combination appeared to be well tolerated; 6.6% of the subjects discontinued treatment because of a drug-related adverse event. Moreover, no serious clinical adverse
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Table 1 Mean Change from Baseline to Last Laboratory Measurement Laboratory test Biochemistry Total bilirubin (mg/dL)* (n = 708) Calcium (mg/dL)t (n = 705) Glucose (mg/dL):j: (n = 704) Total protein (g/dL)§ (n = 708) Triglycerides (mg/dL)11 (n = 709) Cholesterol (mg/dL)~ (n = 709) Lactate dehydrogenase (UIL) (n = 701) Hematology Hemoglobin (g/dL)§ (n = 698) Hematocrit (%) (n = 685) Platelets (X10 3 /IlL) (n = 697) Red blood cells (X10 6/IlL) (n = 696) White blood cells (x103/IlL) (n = 698)
Baseline mean
Last measurement mean
Mean change
SEM
0.5 8.9 85.6 7.1 94.4 176.8 131.0
0.5 8.9 85.8 7.0 115.4 183.4 133.3
-0.1 0.0 0.2 -0.1 20.9 6.6 2.3
0.008 0.01 0.457 0.015 1.56 0.876 1.01
13.0 40.3 298.3 4.5 6.7
13.3 39.0 299.4 4.4 6.5
-0.1 -1.3 1.2 -0.1 -0.2
0.030 0.145 1.75 0.011 0.06
* Conversion factor to SI units, 17.10. t Conversion factor to SI units, 0.2495. :j: Conversion factor to SI units, 0.05551.
experiences considered to be drug related were reported. The most common clinical adverse experiences reported by subjects who received study medication were dysmenorrhea, metrorrhagia, headaches, general infections of the body, and nausea. The prevalence of all of these events tended to decrease over time. One subject was discontinued from the study because of a clinically significant abnormal laboratory test value. This subject was withdrawn from treatment during cycle 2 because of symptoms consistent with hepatitis; laboratory evaluation revealed an elevated alanine aminotransferase (ALT) level (232 VI L) on day 35 of the study period. Two weeks later, ALT levels had returned to within the acceptable range. Overall, the monophasic desogestrel and EE combination produced few changes in the laboratory tests evaluated (Table 1). Small increases were seen at the last laboratory measurement, after 6 months of treatment, in the mean values for triglycerides (from 94.4 to 115.4 mg/dL [1.07 mmol/L to 1.30 mmol/L]) and cholesterol (from 176.8 to 183.4 mgl dL [2.00 to 2.07 mmol/L]) but were within the normal clinical ranges. Treatment with monophasic desogestrel and EE had no significant clinical effects on the vital signs of any of the subjects. Overall, there were no significant changes in mean body weight, and the mean BMI remained relatively unchanged from cycles 4 to 6 (Fig. 2). Five subjects discontinued the study because of weight gain, which was considered possibly related to study medication in all but one subject. Another subject discontinued the study because of 264
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§ Conversion factor to SI units, 10.0. II Conversion factor to SI units, 0.01129. ~ Conversion factor to SI units, 0.02586.
edema considered to be treatment related and weight gain considered of unlikely relationship to treatment. Blood pressure values remained constant throughout the study (Fig. 3). Two patients presented with clinically significant blood pressure values (systolic > 140 mm Hg or an increase of > 15 mm Hg from baseline, or diastolic> 90 mm Hg and an increase of > 10 mm Hg from baseline). One of these was reported as an adverse experience but was not attributed to study medication because the subject had a history of hypertension. Of the 713 subjects for whom breast examination data were obtained at baseline and poststudy, 255 (35.8%) were found to have some degree ofnodularity (from granular to very lobular) at baseline, and 250 (35.1 %) were found at follow-up.
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Cycle
Figure 2 Mean BMI over time. Fertility and Sterility
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Figure 3 Mean blood pressure readings over time. D diastolic.
~
systolic;
DISCUSSION
The results of the US multicenter clinical experience reported here are consistent with those of earlier trials conducted worldwide (4-9) as well as the recent European multicenter study (10). In the worldwide clinical trials, no method failures were reported in a total of 42,640 subjects who were treated for 183,212 cycles (4-9). Similarly, in the recent European multicenter study, no method-failure pregnancies and only 9 user-failure pregnancies were reported in a total of 1,195 subjects who were treated for a total of 11,656 cycles of exposure, corresponding to approximately 879 women-years of use (10). Cycle control with the monophasic desogestrelcontaining combined OC has been consistently good, with high patient acceptance. The results of the present cycle control analysis, which included a total of 3,640 cycles (up to six cycles of OC usage per patient), were similar to those of the recent European multicenter study in which a total of 11,426 cycles was analyzed in patients who used study medication for up to 18 cycles (10). In both the US and European trials, absence of withdrawal bleeding was very rare, occurring in <2% of the cycles. Likewise, the incidence of intermenstrual bleeding (mainly breakthrough spotting) in the two trials was comparable, being approximately 8%. In the present study, the overall incidences of breakthrough bleeding and breakthrough spotting were low (1.7% and 8.1%, respectively), and only seven patients (1%) were withdrawn from the study because of menstrual irregularity (metrorrhagia). The high efficacy and low intermenstrual bleeding rates consistently reported with the desogestrel-conVol. 64, No.2, August 1995
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taining combined formulation may be accounted for, to some degree, by the steady state half-life of desogestrel. Pharmacokinetic studies have shown that the steady state half-life observed after the administration of desogestrel is 38.0 ± 20 hours (11). Although the clinical implications of this long half-life have not been established, it may have relevance with regard to noncompliant patients. Throughout its clinical use, the monophasic desogestrel-containing combined OC has demonstrated consistently high levels of safety, tolerance, and patient acceptability (4-10). In the present study, only a small percentage of the subjects discontinued treatment because of drug-related adverse events. The prevalence of the most common adverse experiences-dysmenorrhea, metrorrhagia, headaches, infection, and nausea-generally decreased over time. Additionally, no adverse effects on blood pressure, body weight, or laboratory variables were observed. Slight increases in serum total cholesterol and triglycerides have been observed in previous studies, both with the monophasic desogestrel-containing combined OCs as well as with other low dose combinations (10, 12).
Acknowledgments. This study was conducted and analyzed by CLINTRIALS, Inc. (formerly Clinical Research International), Research Triangle Park, North Carolina. The contribution of the following clinical investigators is gratefully acknowledged: Allan B. Aven, M.D. (Arlington Heights, Illinois); Neal R. Cutler, M.D. (Beverly Hills, California); Howard G. McQuarrie, M.D. (Salt Lake City, Utah); and Nona F. Niland, M.D. (Austin, Texas).
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