ORIGINAL ARTICLE
Clinical evaluation of a new triphasic oral contraceptive: norgestimate and ethinyl estradiol ALAIN GAUTHIER, M.D.,a DAVIDUPMALIS,M.D.,b AND MARIE-PAULE DAIN, M.D.‘ From the Service de Gynecologie Sociale, Centre Hospitalier, Lille, France,” the R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey,b and CILAG, FranceC
Actu Obstet Gynecol Scand
1992; Vol 71, Suppl 156: 27-32
The safety and efficacy of the triphasic oral contraceptive agent containing norgestimate and ethinyl estradiol were evaluated in a 12-month study of 661 women. Excellent contraceptive efficacy was achieved, with two pregnancies ascribed to product failure in a total of 6,511 treatment cycles. The life-table predicted pregnancy rate was 0.57 per 100 woman-years of use. The overall and theoretical Pearl indexes were 0.5.5 and 0.37, respectively. Good cycle control was maintained in patterns similar to those noted in previous studies. The incidence of dysmenorrhea and premenstrual syndrome was sharply reduced. Side effects reported were typical of those associated with use of low-dose oral contraceptive agents. Acceptability was high compared with agents used previously by the subjects. Total cholesterol did not change but high-density lipoprotein cholesterol was significantly elevated at 3 and 12 months. There were no clinically significant changes in the parameters of hematology or blood chemistry tested. Key wordst Norgestimate, androgenicity, efficacy, lipids, hematology, cycle control
Introduction Oral contraceptive (OC) formulations have improved markedly since their inception, first in the lowering of estrogen/progestin dosages and then in the characteristics of the progestin component. The progestin norgestimate (NGM) was developed to address the need for a selective progestational agent with a low potential for noncontraceptive metabolic actions (Fig. 1). NGM is similar to natural progesterone in its strong affinity for uterine progestin receptors and its weak affinity for the androgen receptor (1). In clinical studies of the monophasic OC containing NGM and ethinyl estradiol (EE), contraception was achieved in association with favorable lipid changes and without clinically significant effects on parameters of carbohydrate metabolism or blood coagulation ( 2 4 ) . The ratio of low-density lipoprotein (LDL) to high-density lipoprotein (HDL) was decreased significantly among women taking the preparation, primarily because of significant increases in serum levels of H D L (2).
The study reported here was part of the large program undertaken to evaluate the safety and contraceptive efficacy of triphasic NGM/EE (Ortho TriCyclen@, Tri-Cilest@), a new phased-dose preparation that lowers the total dose of progestin delivered, compared with the monophasic OC, while holding the dosage of EE constant.
Methods This was a 12-month open trial in a diverse population of women who were recruited, evaluated, and followed up by 29 independent gynecologists in France.
Study population The subjects were healthy women between the ages of 18 and 40 years who were sexually active, had regular menstrual cycles, and were not pregnant. Subjects were excluded for the following reasons: Actu Obster Gyriecol S c u d SuppI 156 (1992)
28
A . Gauthier et al.
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Fig. 1. Norgestimate structure. standard contraindications to the use of hormonal contraceptive agents; impairment of liver or kidney function; and metabolic disorders such as diabetes or porphyria. Results of a Papanicolaou smear had to be class I or 11. Entry into the study was also not possible if the subject was on an amenorrheic cycle or required treatment with an agent not compatible with oral contraception (e.g., barbiturates, rifampicin. certain anticonvulsants). Informed consent was obtained from all subjects. Fresh subjects were defined as those who had not used an O C in the previous three menstrual cycles or had not had a pregnancy terminated in the 42 days before the start of study medication. Evaltiation of the subjects
Complete histories were obtained from the subjects during the second half of the reference cycle, and physical and gynecologic examinations were performed. Follow-up evaluations were conducted at the end of treatment cycles 1, 3, 6, and 12 or whenever treatment was discontinued. Laboratory tests
Blood specimens were drawn for analysis from fasting subjects at the end of the pretreatment cycle and the end of treatment cycles 3 and 12. Tests were carried out in all subjects at these points to determine hematologic values, transaminase activity, blood glucose levels, and serum concentrations of urea, uric acid, and lipids. Regimen
For fresh starts. use of triphasic NGM/EE was started on the first day of menstrual flow and continued for a total of 21 days, followed by 7 days without treatment (Fig. 2). Subjects switching from another O C regimen started on day 5 . This regimen was repeated for the 12 cycles of the study. Acla Vbsret Gyrircol S c a d Suppl156 (lY92)
Statistical analysis
The pregnancy rate was assessed by life-table analysis and the Pearl index. The life-table analysis was generated from the LIFETAB computer program based on work by Taylor and Potter (5,6). The Pearl index was calculated by multiplying the number of on-treatment pregnancies by 1.200 and dividing the product by the number of treatment cycles. Clinical laboratory parameters were analyzed for changes from baseline. For other variables, summary statistics were calculated (mean, median, maximum, minimum, and standard deviation). For the categorical variables of cycle characteristics such as blood flow and severity of dysmenorrhea, the distribution of responses was determined for the pretreatment cycle and during cycles 1, 3, 6, and 12. Breakthrough bleeding was defined as bleeding occurring during the monthly treatment period that was not early withdrawal flow or withdrawal flow continuing from the previous treatment cycle. A cycle was not included in the analysis if the pill-taking period was
Clinical evaluation of a new triphasic oral contraceptive: norgestimate and ethinyl estradiol ALAIN GAUTHIER, M.D.,a DAVIDUPMALIS,M.D.,b AND MARIE-PAULE DAIN, M.D.‘ From the Service de Gynecologie Sociale, Centre Hospitalier, Lille, France,” the R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey,b and CILAG, FranceC
Actu Obstet Gynecol Scand
1992; Vol 71, Suppl 156: 27-32
The safety and efficacy of the triphasic oral contraceptive agent containing norgestimate and ethinyl estradiol were evaluated in a 12-month study of 661 women. Excellent contraceptive efficacy was achieved, with two pregnancies ascribed to product failure in a total of 6,511 treatment cycles. The life-table predicted pregnancy rate was 0.57 per 100 woman-years of use. The overall and theoretical Pearl indexes were 0.5.5 and 0.37, respectively. Good cycle control was maintained in patterns similar to those noted in previous studies. The incidence of dysmenorrhea and premenstrual syndrome was sharply reduced. Side effects reported were typical of those associated with use of low-dose oral contraceptive agents. Acceptability was high compared with agents used previously by the subjects. Total cholesterol did not change but high-density lipoprotein cholesterol was significantly elevated at 3 and 12 months. There were no clinically significant changes in the parameters of hematology or blood chemistry tested. Key wordst Norgestimate, androgenicity, efficacy, lipids, hematology, cycle control
Introduction Oral contraceptive (OC) formulations have improved markedly since their inception, first in the lowering of estrogen/progestin dosages and then in the characteristics of the progestin component. The progestin norgestimate (NGM) was developed to address the need for a selective progestational agent with a low potential for noncontraceptive metabolic actions (Fig. 1). NGM is similar to natural progesterone in its strong affinity for uterine progestin receptors and its weak affinity for the androgen receptor (1). In clinical studies of the monophasic OC containing NGM and ethinyl estradiol (EE), contraception was achieved in association with favorable lipid changes and without clinically significant effects on parameters of carbohydrate metabolism or blood coagulation ( 2 4 ) . The ratio of low-density lipoprotein (LDL) to high-density lipoprotein (HDL) was decreased significantly among women taking the preparation, primarily because of significant increases in serum levels of H D L (2).
The study reported here was part of the large program undertaken to evaluate the safety and contraceptive efficacy of triphasic NGM/EE (Ortho TriCyclen@, Tri-Cilest@), a new phased-dose preparation that lowers the total dose of progestin delivered, compared with the monophasic OC, while holding the dosage of EE constant.
Methods This was a 12-month open trial in a diverse population of women who were recruited, evaluated, and followed up by 29 independent gynecologists in France.
Study population The subjects were healthy women between the ages of 18 and 40 years who were sexually active, had regular menstrual cycles, and were not pregnant. Subjects were excluded for the following reasons: Actu Obster Gyriecol S c u d SuppI 156 (1992)
28
A . Gauthier et al.
0
Fig. 1. Norgestimate structure. standard contraindications to the use of hormonal contraceptive agents; impairment of liver or kidney function; and metabolic disorders such as diabetes or porphyria. Results of a Papanicolaou smear had to be class I or 11. Entry into the study was also not possible if the subject was on an amenorrheic cycle or required treatment with an agent not compatible with oral contraception (e.g., barbiturates, rifampicin. certain anticonvulsants). Informed consent was obtained from all subjects. Fresh subjects were defined as those who had not used an O C in the previous three menstrual cycles or had not had a pregnancy terminated in the 42 days before the start of study medication. Evaltiation of the subjects
Complete histories were obtained from the subjects during the second half of the reference cycle, and physical and gynecologic examinations were performed. Follow-up evaluations were conducted at the end of treatment cycles 1, 3, 6, and 12 or whenever treatment was discontinued. Laboratory tests
Blood specimens were drawn for analysis from fasting subjects at the end of the pretreatment cycle and the end of treatment cycles 3 and 12. Tests were carried out in all subjects at these points to determine hematologic values, transaminase activity, blood glucose levels, and serum concentrations of urea, uric acid, and lipids. Regimen
For fresh starts. use of triphasic NGM/EE was started on the first day of menstrual flow and continued for a total of 21 days, followed by 7 days without treatment (Fig. 2). Subjects switching from another O C regimen started on day 5 . This regimen was repeated for the 12 cycles of the study. Acla Vbsret Gyrircol S c a d Suppl156 (lY92)
Statistical analysis
The pregnancy rate was assessed by life-table analysis and the Pearl index. The life-table analysis was generated from the LIFETAB computer program based on work by Taylor and Potter (5,6). The Pearl index was calculated by multiplying the number of on-treatment pregnancies by 1.200 and dividing the product by the number of treatment cycles. Clinical laboratory parameters were analyzed for changes from baseline. For other variables, summary statistics were calculated (mean, median, maximum, minimum, and standard deviation). For the categorical variables of cycle characteristics such as blood flow and severity of dysmenorrhea, the distribution of responses was determined for the pretreatment cycle and during cycles 1, 3, 6, and 12. Breakthrough bleeding was defined as bleeding occurring during the monthly treatment period that was not early withdrawal flow or withdrawal flow continuing from the previous treatment cycle. A cycle was not included in the analysis if the pill-taking period was
