Acta Obstet Gynecol Scand Suppl 152 : 33 - 39, 1990
SUPPORTIVE EUROPEAN DATA ON A NEW ORAL CONTRACEPTIVE CONTAINING NORGESTIMATE Harald Becker From Cilag GMBH, West Germany
Abstract. Several European studies have been conducted t o confirm the efficacy, tolerability, and safety of a new oral contraceptive (OC) combining 250 pg norgestimate w i t h 35 pg ethinyl estradiol (Ortho-Cyclen or Cilest). In a 12-month multicenter German study of 147 women, treatment w i t h this formulation resulted in no pregnancies, a low incidence of side effects, and excellent cycle control. The drug had no effect on estrogen-mediated fibrin formation nor on the activity of coagulation inhibiting or promoting factors. Similarly, the documented l o w androgenicity of the highly selective progestational agent norgestimate results in a more positive metabolic profile. Glucose, insulin, and hemoglobin A,, concentrations measured before and after glucose loading were not adversely affected by treatment w i t h the norgestimatecontaining OC, and all changes were reversible on its discontinuation. In addition, lipid metabolism was positively influenced by the drug. Low-density lipoprotein cholesterol, a known risk factor for cardiovascular disease, was reduced while the cardioprotective lipid fraction, high-density lipoprotein cholesterol, was increased. Clinical trials t o determine the OC's effects on coagulation, endocrine function, and carbohydrate and lipid metabolism are reviewed. Also discussed are several studies demonstrating the formulation's unique endometrial effects, which may possibly be related t o its low androgenic activity and consequent low incidence of breakthrough bleeding and amenorrhea.
While the great majority of data on the new oral contraceptive (OC) combining 250 pg norgestimate (NGM) with 35 pg ethinyl estradiol (EE), have been generated from clinical trials in the United States, results of several European studies further support the drug's efficacy and safety. Among them is a German multicenter trial of 147 women, whose results showed NGM/EE (Cilest, in the U.S. Ortho-Cyclen) to be highly efficacious and extremely well-tolerated. Addi-
I4O
r
tional Phase I1 European studies have also been conducted primarily to assess the drug in terms of its estrogen-mediated effects on coagulation and its progestational influence on carbohydrate and lipid metabolism. In every case, the European data have supported the highly favorable findings of the U.S. experience. Preclinical study results suggesting a uniquely mild endometrial response with the progestin component
T
O?O
Fig. 1. Antithrombin I11 levels in coagulation study. Normal values range from 8 5 % to 130?'0.
Pre-cycIe (n=19)
Cycle 1 (n=18)
Cycle 3 (n=l6)
Cycle 6 (n=12)
Acra Obsret Gynecol Scand Suppl152
34
H. Becker
T
T
Pre-cycle
Cycle 1
Cycle 3
Cycle 6
(n=19)
(n=18)
(n=l6)
(n=12)
norgestimate have been confirmed by specialized microscopy studies performed in the U S . and abroad. The more natural and less atrophizing effect of NGM/EE on the endometrium may have important clinical implications with regard to excellent cycle control and minimal failure of withdrawal bleeding. All of these studies are described below.
EFFICACY AND TOLERABI LlTY OF NG M/EE: Europe a n MuItice n t er Tr ia I A 12-rnonth, multicenter, open clinical trial* was conducted in 147 healthy young women to assess efficacy, incidence of side effects, and bleeding patterns using the new NGM/EE combination OC. Inclusion criteria for entry into the study were good general health, regular menstrual cycles (28-32 days), reproductive age, and willingness to take oral contraceptives. No concomitant use of back-up contraception was permitted. Excluded from admission were women with a history of amenorrhea, acute thromboembolism, cardiovascular disease, sickle-cell anemia, impairment of liver function, genital herpes or severe pruritus, sex hormone-dependent tumors, breast or gynecologic carcinomas, undiagnosed vaginal bleeding, known or suspected pregnancy, and idiopathic jaundice during prior pregnancies. At baseline, patients underwent a thorough medical history-taking and physical exam. They were then followed for a control cycle and at the end of cycles 3, 6, 9, and 12 on-drug. The trial was originally designed
* Cilag Medical Documentation; Medoc-Report Acta Obster Gynecol Scand Suppl 152
08238.
Fig. 2. Fibrinogen levels in coagulation study. Normal values range from 1.8 to 4.5 g/L.
to last for six consecutive 28-day cycles, but was extended for an additional six treatment cycles. Efficacy was established by pregnancy rate. Tolerability was assessed according to side effects, including weight gain and blood pressure, as well as bleeding patterns.
RESULTS Subjects ranged in age from 15 to 37 years (mean: 23 years), with a mean age at menarche of 12.6 years. During the control cycle, menstruation was predominantly regular (131 women), and dysmenorrhea occurred in roughly one third of patients (52 women). Of the 147 subjects enrolled in this study, only 78 (53%) had practiced some form of contraception, primarily oral contraception (43 women). Of these 147 patients, 109 completed 12 months of treatment. The remaining 38 participants left the study prematurely due to medical or personal reasons (14 women), or as a result of administrative problems caused by extending the study on short notice (24 women). In the latter instance, the women interrupted treatment, thereby becoming ineligible for the second part of the study. Medical reasons were cited by five women as the reason for leaving, including breakthrough bleeding (two), leg pain, migraine, and seborrhea (one each). During 1,521 cycles of treatment, there were no pregnancies, thus confirming the drug’s excellent contraceptive efficacy. Very few adverse reactions were reported in follow-up evaluations. Only 16 side effects were noted in 11 patients, 14 of these in the first three treatment cycles. Treatment with NGM/EE had no ef-
European data
fect on mean body weight or systolic or diastolic blood pressure. Mean cycle length ranged from 27 to 28 days during treatment and, in individual patients, became more uniform in length during the course of the study. The mean duration of menstrual flow decreased from 4.5 days in the first treatment cycle to about 3.7 days in the sixth and subsequent cycles. The intensity of menstrual flow, classified as slight, normal, and heavy, improved during therapy with a normal flow reported in 56% of women at the control cycle and 75% of women at cycle 12. In addition, while 29% of women had heavy menstrual flow during the control cycle, no woman reported heavy flow while taking NGM/EE during cycles 4 and 7 through 12. The incidence of breakthrough bleeding or spotting was, as expected, slightly elevated during treatment cycle 1 (3% and 13% of patients, respectively), but returned to baseline by cycle 3/4. Amenorrhea never occurred during treatment. This 12-month European clinical trial supports U.S. studies (1) showing the NGM/EE combination to be an effective and well-tolerated OC. The high contraceptive efficacy, low rate of drop-outs, the small number of adverse drug reactions, and the very low incidence of breakthrough bleeding and spotting have resulted in high acceptance of the formulation by both patients and physicians since its introduction in Germany (November 1986) and Switzerland (February 1987).
SAFETY PROFILE OF NGM/EE: Phase II Trials Coagulation. A Phase I1 clinical trial* was conducted by Anger in Germany to determine the effects of 35 pg estradiol plus 250 pg norgestimate (Ortho-Cyclen or Cilest) on the coagulation system. Nineteen healthy young women who had not used OCs for the previous three months were evaluated for one control cycle and six on-drug cycles. Fasting blood samples were taken between days 18 and 21 of the control cycle and during cycles 1, 3, and 6 on-therapy for fibrinopeptide A, fibrin monomers, antithrombin 111, protein C, fibrinogen, factor VII, and factor VIII complex. The concentration of fibrinopeptide A, perhaps the
*
Cilag Medical Documentation; Medoc-Report NRG
05301.
** Cilag Medical Documentation; Medoc-Report NRG 05288.
35
7
6 5 4
ng/dL
3
2
T
I
1
i !
0 3
FoIIow-UD cycle 2
Fig. 3. SHBG rose with treatment. Data are from endocrine function study. (*p
SUPPORTIVE EUROPEAN DATA ON A NEW ORAL CONTRACEPTIVE CONTAINING NORGESTIMATE Harald Becker From Cilag GMBH, West Germany
Abstract. Several European studies have been conducted t o confirm the efficacy, tolerability, and safety of a new oral contraceptive (OC) combining 250 pg norgestimate w i t h 35 pg ethinyl estradiol (Ortho-Cyclen or Cilest). In a 12-month multicenter German study of 147 women, treatment w i t h this formulation resulted in no pregnancies, a low incidence of side effects, and excellent cycle control. The drug had no effect on estrogen-mediated fibrin formation nor on the activity of coagulation inhibiting or promoting factors. Similarly, the documented l o w androgenicity of the highly selective progestational agent norgestimate results in a more positive metabolic profile. Glucose, insulin, and hemoglobin A,, concentrations measured before and after glucose loading were not adversely affected by treatment w i t h the norgestimatecontaining OC, and all changes were reversible on its discontinuation. In addition, lipid metabolism was positively influenced by the drug. Low-density lipoprotein cholesterol, a known risk factor for cardiovascular disease, was reduced while the cardioprotective lipid fraction, high-density lipoprotein cholesterol, was increased. Clinical trials t o determine the OC's effects on coagulation, endocrine function, and carbohydrate and lipid metabolism are reviewed. Also discussed are several studies demonstrating the formulation's unique endometrial effects, which may possibly be related t o its low androgenic activity and consequent low incidence of breakthrough bleeding and amenorrhea.
While the great majority of data on the new oral contraceptive (OC) combining 250 pg norgestimate (NGM) with 35 pg ethinyl estradiol (EE), have been generated from clinical trials in the United States, results of several European studies further support the drug's efficacy and safety. Among them is a German multicenter trial of 147 women, whose results showed NGM/EE (Cilest, in the U.S. Ortho-Cyclen) to be highly efficacious and extremely well-tolerated. Addi-
I4O
r
tional Phase I1 European studies have also been conducted primarily to assess the drug in terms of its estrogen-mediated effects on coagulation and its progestational influence on carbohydrate and lipid metabolism. In every case, the European data have supported the highly favorable findings of the U.S. experience. Preclinical study results suggesting a uniquely mild endometrial response with the progestin component
T
O?O
Fig. 1. Antithrombin I11 levels in coagulation study. Normal values range from 8 5 % to 130?'0.
Pre-cycIe (n=19)
Cycle 1 (n=18)
Cycle 3 (n=l6)
Cycle 6 (n=12)
Acra Obsret Gynecol Scand Suppl152
34
H. Becker
T
T
Pre-cycle
Cycle 1
Cycle 3
Cycle 6
(n=19)
(n=18)
(n=l6)
(n=12)
norgestimate have been confirmed by specialized microscopy studies performed in the U S . and abroad. The more natural and less atrophizing effect of NGM/EE on the endometrium may have important clinical implications with regard to excellent cycle control and minimal failure of withdrawal bleeding. All of these studies are described below.
EFFICACY AND TOLERABI LlTY OF NG M/EE: Europe a n MuItice n t er Tr ia I A 12-rnonth, multicenter, open clinical trial* was conducted in 147 healthy young women to assess efficacy, incidence of side effects, and bleeding patterns using the new NGM/EE combination OC. Inclusion criteria for entry into the study were good general health, regular menstrual cycles (28-32 days), reproductive age, and willingness to take oral contraceptives. No concomitant use of back-up contraception was permitted. Excluded from admission were women with a history of amenorrhea, acute thromboembolism, cardiovascular disease, sickle-cell anemia, impairment of liver function, genital herpes or severe pruritus, sex hormone-dependent tumors, breast or gynecologic carcinomas, undiagnosed vaginal bleeding, known or suspected pregnancy, and idiopathic jaundice during prior pregnancies. At baseline, patients underwent a thorough medical history-taking and physical exam. They were then followed for a control cycle and at the end of cycles 3, 6, 9, and 12 on-drug. The trial was originally designed
* Cilag Medical Documentation; Medoc-Report Acta Obster Gynecol Scand Suppl 152
08238.
Fig. 2. Fibrinogen levels in coagulation study. Normal values range from 1.8 to 4.5 g/L.
to last for six consecutive 28-day cycles, but was extended for an additional six treatment cycles. Efficacy was established by pregnancy rate. Tolerability was assessed according to side effects, including weight gain and blood pressure, as well as bleeding patterns.
RESULTS Subjects ranged in age from 15 to 37 years (mean: 23 years), with a mean age at menarche of 12.6 years. During the control cycle, menstruation was predominantly regular (131 women), and dysmenorrhea occurred in roughly one third of patients (52 women). Of the 147 subjects enrolled in this study, only 78 (53%) had practiced some form of contraception, primarily oral contraception (43 women). Of these 147 patients, 109 completed 12 months of treatment. The remaining 38 participants left the study prematurely due to medical or personal reasons (14 women), or as a result of administrative problems caused by extending the study on short notice (24 women). In the latter instance, the women interrupted treatment, thereby becoming ineligible for the second part of the study. Medical reasons were cited by five women as the reason for leaving, including breakthrough bleeding (two), leg pain, migraine, and seborrhea (one each). During 1,521 cycles of treatment, there were no pregnancies, thus confirming the drug’s excellent contraceptive efficacy. Very few adverse reactions were reported in follow-up evaluations. Only 16 side effects were noted in 11 patients, 14 of these in the first three treatment cycles. Treatment with NGM/EE had no ef-
European data
fect on mean body weight or systolic or diastolic blood pressure. Mean cycle length ranged from 27 to 28 days during treatment and, in individual patients, became more uniform in length during the course of the study. The mean duration of menstrual flow decreased from 4.5 days in the first treatment cycle to about 3.7 days in the sixth and subsequent cycles. The intensity of menstrual flow, classified as slight, normal, and heavy, improved during therapy with a normal flow reported in 56% of women at the control cycle and 75% of women at cycle 12. In addition, while 29% of women had heavy menstrual flow during the control cycle, no woman reported heavy flow while taking NGM/EE during cycles 4 and 7 through 12. The incidence of breakthrough bleeding or spotting was, as expected, slightly elevated during treatment cycle 1 (3% and 13% of patients, respectively), but returned to baseline by cycle 3/4. Amenorrhea never occurred during treatment. This 12-month European clinical trial supports U.S. studies (1) showing the NGM/EE combination to be an effective and well-tolerated OC. The high contraceptive efficacy, low rate of drop-outs, the small number of adverse drug reactions, and the very low incidence of breakthrough bleeding and spotting have resulted in high acceptance of the formulation by both patients and physicians since its introduction in Germany (November 1986) and Switzerland (February 1987).
SAFETY PROFILE OF NGM/EE: Phase II Trials Coagulation. A Phase I1 clinical trial* was conducted by Anger in Germany to determine the effects of 35 pg estradiol plus 250 pg norgestimate (Ortho-Cyclen or Cilest) on the coagulation system. Nineteen healthy young women who had not used OCs for the previous three months were evaluated for one control cycle and six on-drug cycles. Fasting blood samples were taken between days 18 and 21 of the control cycle and during cycles 1, 3, and 6 on-therapy for fibrinopeptide A, fibrin monomers, antithrombin 111, protein C, fibrinogen, factor VII, and factor VIII complex. The concentration of fibrinopeptide A, perhaps the
*
Cilag Medical Documentation; Medoc-Report NRG
05301.
** Cilag Medical Documentation; Medoc-Report NRG 05288.
35
7
6 5 4
ng/dL
3
2
T
I
1
i !
0 3
FoIIow-UD cycle 2
Fig. 3. SHBG rose with treatment. Data are from endocrine function study. (*p
