Optimum dosage of an oral contraceptive A report from the study of seven combinations of norgestimate and ethinyl estradiol JOHN S. LAWSON, M.S.* S. EUGENE YULIANO, M.D.* SAMUEL A. PASQUALE, M.D. JENNIFER J. OSTERMAN, B.A. Raritan, New Jerse,v
A statistically designed study was carried out to determine an optimum combination of norgestimate and ethinyl estradiol as an oral contraceptive, based on efficacy, safety, and side-effect patterns. A total of 1,991 patients were studied for more than two years while they were receiving various dosage combinations of these steroids. There were seven dosage combinations studied as part of a statistically orthogonal experimental design, augmented by three combinations near the center. The data arising from these studies were used to fit approximate functions relating the amount of norgestimate and ethinyi estradioi to the rate of spotting and breakthrough bieeding, gastrointestinai disturbance, and pregnancies. These functions, in turn, helped to identify an optimum dosage (0.125 mg. of norgestimate plus 0.035 mg. of ethinyl estradiol) in the entire range of combinations studied. (AM. J. 0BSTET. GYNECOL. 134:315, 1979.)
THE MOST WIDELY USED oral contraceptives are combination products that consist of a synthetic estrogen and progestin. These drugs are extremely effective and possess a relatively high degree of safety. However, through the years there have been continued efforts to seek effective lower-dose forms of these drugs. In the late 1960's, researchers Inman and Vessey' in Great Britain, Sartwell and associates 2 in the United States, and others reported an association between the use of oral contraceptives and an increase in the risk of certain types of thromboembolic diseases. Later, Inman and associates 3 reported a positive correlation between the risk of these diseases and the dose of estrogen in an oral contraceptive. It has also been reported that certain side effects commonly attributed to the use of oral contraceptives (i.e., nausea, headache, nervousness) are From the Division of Scientific Information and the Department of Medical Research, Oriho Pharmaceutical Corporation. Received for publication March 7, 1978. Revised june 16, 1978. Accepted june 20, 1978. Reprint requests: JohnS. Lawson, FMC Corporation, U.S. Hwy. No.1, Princeton, New .Jersey 08540. 0002-9378/79/110315+06$00.60/0
©
1979 The C. V. Mosby Co.
related to the amount of estrogen in the contraceptive. In April, 1970, both the United States Food and Drug Administration 4 and the Medical Committee of the International Planned Parenthood Association·; issued statements recommending the use of oral contraceptives containing the lowest effective levels of estrogen whenever possible. Since 1970, there have been reports in the literature demonstrating the efficacy and side-effect patterns of oral contraceptives with dosages lower than those of previously marketed products. Bye and Elstein 6 and others 7 • 8 have shown that combination contraceptives containing less than 0.05 mg. of ethinyl estradiol (EE) are effective in preventing pregnancies. One disadvantage to reducing the dosage of estrogen in oral contraceptives is the fact, reported independent!~ in several articles, 7- 9 that annoying intermenstrual bleeding, such as spotting or breakthrough bleeding (BTB), increases. Spotting and BTB rates are influenced not only by the amount of estrogen in an oral contraceptive but also by the ratio of the amounts of estrogen and progestin. 10 This makes the selection of an appropriate dosage for a low-dose oral contraceptive difficult. There have been reports in the literature 7 • 9 of clini315
316
Lawson et al.
Table I. Dosage regimens of norgestin1ate and EE Regimen A
B
C.P, R (;
H ()
"[
Progestin (norgestirnate) (mg.)
(EE) (mg.)
Estrogen
0.250 0.250 0.125 0.060 (l.060 0.090 0.125
0.020 0.050 0.035 0.020 0.050 0.030 0.025
Table II. Number of patients completing each cycle Regimen
Cycle
2 :1
4 5 6 7 R 9 lO
II
12 l:l
14 15 lfi
17 18 19 20 21 22 23
A
B
C,P,R
H
G
()
T
100 98 94 89 80 79 76 75
117 116 I 14 113 109
1398 1304 977 552 529
105
SIS
505 478 460 294 !55 132
97 94 90 83 78 73 71 65 56 29 2
195 191 !8R 183 181 177 174 168 162
197 182 174 113 90 34
102 100 93 90 81 49 20
97 95 90 86 81 80 77 75 71 67 60 32
73 68 63 37 2
l
77 74
70 69 66 64 64 6:1 48 23 2
cal studi~:s com paring seYeral regimens of lower-dose combination oral contraceptives for purposes of selecting an optimum combination and/or determining the relationship of bleeding patterns/ efficacy to the dosage of the product. Because bleeding patterns arc affected not only by the dosage of estrogen and progestin but also by the ratio of the two components, and since an optimum combination of two steroids may not be one of the regimens selected for a study, extremely sensitive study designs (i.e., selection of study regimens) and efficient methods of data analysis are needed fort hese types of studies. Application of statistical response surface methods" seems appropriate in this situation. Response surface methods are a collection of mathernatical and statistical procedures useful in studies where a response (numerical measure of the outcome of an experiment) is influenced by other independent \'ariables that can be controlled. The procedures cOil·· sist of experimental designs (i.e .. methods for selectin~
lcJr experiments). regression techniqtic·s !i.e .. nH·ilullh of fitting an approximate lunction;d rdatmn;.hip he· tween the response measurenwnt and the indepett mg. ol norgestirnate and O.OcFi mg. of EF. thus lllaking the choice of an optitual dosagc easier
REFERENCES
I. Inman, W. H. N., and VesseY, J\.1. P.: Investigation oi deaths from pulmonarv. coronary and cerebral thrombosis and embolism in women of childbearing age. Rr. :VIed.J.2: l93,196H. 2. Sartwell. P. E .. :VIasi, A. T., Arthes. F. (;., et. al.: Thromboemboiism and orai contraceptives: An epidemiological case-control study, Am. J. Epidemiol. 90: 365, 1969. :~. Inman, W. H., Vessey, M. P., Weserholm, B .. and Engelund. A.: Thromboembolic disease and the steroidal content of oral contraceptives: A report to the committee on safety of drugs. Br. Med. J. 2: 203, 1970. 4. Current Drug Information, Food and Drug Administration. April 24, 1970. 5. Kleinman, R. L: Comments on Steroidal Contraception: A Report of the Meeting of the International Planned Parenthood Federation Central Medical Committee and hs Ad\'isors, To Dis.
dmne/ethinyl estradiol. Contraception 12: ·495, ]q7~>. Allen. H. H.: Clinical assessment nf a low-dose oestrogen low-dose progestogen combined oral contracepti1e. Curr. Med. Res. Opin. 2: 101, 197+. Preston, S. \'.: :\ report of a collaborative dme respons" dinicai study using decreasing doses of combination or,ll contraceptives, Contraception. 6: 17, 1972. Nelson, J. H.: Selecting the optimum oral contraceptin·. J Reprod. Med. 11: 1~5. 197~. Myers, R. H.: Response Surface :Vlethodologv, Bostou. 1971, Allyn and Bacon. Cutler, S. J., and Ederer, F.: :Vlaximum utilintttiJ!l ui tht' lite table method in analyzing survival. .J. Chronic Dio.. 8: 699, 1958. Grizzle, J. E., Starmer, C. F.. and Koch. C.(.. : Analv;i' ol categorical data bv linear models. Biometrics 23: B7 1969. Koch, G. G., Johnson,\\'. P .. and Tollev. H. D.: A line~n· models approach to the anahsis of survival and extent of disease m multidimensional contingenn table~ . .J. Am. Stat. Assoc. 67: 783, 1972. Berkson, J: Maximum likelihood and minimum x' e
A statistically designed study was carried out to determine an optimum combination of norgestimate and ethinyl estradiol as an oral contraceptive, based on efficacy, safety, and side-effect patterns. A total of 1,991 patients were studied for more than two years while they were receiving various dosage combinations of these steroids. There were seven dosage combinations studied as part of a statistically orthogonal experimental design, augmented by three combinations near the center. The data arising from these studies were used to fit approximate functions relating the amount of norgestimate and ethinyi estradioi to the rate of spotting and breakthrough bieeding, gastrointestinai disturbance, and pregnancies. These functions, in turn, helped to identify an optimum dosage (0.125 mg. of norgestimate plus 0.035 mg. of ethinyl estradiol) in the entire range of combinations studied. (AM. J. 0BSTET. GYNECOL. 134:315, 1979.)
THE MOST WIDELY USED oral contraceptives are combination products that consist of a synthetic estrogen and progestin. These drugs are extremely effective and possess a relatively high degree of safety. However, through the years there have been continued efforts to seek effective lower-dose forms of these drugs. In the late 1960's, researchers Inman and Vessey' in Great Britain, Sartwell and associates 2 in the United States, and others reported an association between the use of oral contraceptives and an increase in the risk of certain types of thromboembolic diseases. Later, Inman and associates 3 reported a positive correlation between the risk of these diseases and the dose of estrogen in an oral contraceptive. It has also been reported that certain side effects commonly attributed to the use of oral contraceptives (i.e., nausea, headache, nervousness) are From the Division of Scientific Information and the Department of Medical Research, Oriho Pharmaceutical Corporation. Received for publication March 7, 1978. Revised june 16, 1978. Accepted june 20, 1978. Reprint requests: JohnS. Lawson, FMC Corporation, U.S. Hwy. No.1, Princeton, New .Jersey 08540. 0002-9378/79/110315+06$00.60/0
©
1979 The C. V. Mosby Co.
related to the amount of estrogen in the contraceptive. In April, 1970, both the United States Food and Drug Administration 4 and the Medical Committee of the International Planned Parenthood Association·; issued statements recommending the use of oral contraceptives containing the lowest effective levels of estrogen whenever possible. Since 1970, there have been reports in the literature demonstrating the efficacy and side-effect patterns of oral contraceptives with dosages lower than those of previously marketed products. Bye and Elstein 6 and others 7 • 8 have shown that combination contraceptives containing less than 0.05 mg. of ethinyl estradiol (EE) are effective in preventing pregnancies. One disadvantage to reducing the dosage of estrogen in oral contraceptives is the fact, reported independent!~ in several articles, 7- 9 that annoying intermenstrual bleeding, such as spotting or breakthrough bleeding (BTB), increases. Spotting and BTB rates are influenced not only by the amount of estrogen in an oral contraceptive but also by the ratio of the amounts of estrogen and progestin. 10 This makes the selection of an appropriate dosage for a low-dose oral contraceptive difficult. There have been reports in the literature 7 • 9 of clini315
316
Lawson et al.
Table I. Dosage regimens of norgestin1ate and EE Regimen A
B
C.P, R (;
H ()
"[
Progestin (norgestirnate) (mg.)
(EE) (mg.)
Estrogen
0.250 0.250 0.125 0.060 (l.060 0.090 0.125
0.020 0.050 0.035 0.020 0.050 0.030 0.025
Table II. Number of patients completing each cycle Regimen
Cycle
2 :1
4 5 6 7 R 9 lO
II
12 l:l
14 15 lfi
17 18 19 20 21 22 23
A
B
C,P,R
H
G
()
T
100 98 94 89 80 79 76 75
117 116 I 14 113 109
1398 1304 977 552 529
105
SIS
505 478 460 294 !55 132
97 94 90 83 78 73 71 65 56 29 2
195 191 !8R 183 181 177 174 168 162
197 182 174 113 90 34
102 100 93 90 81 49 20
97 95 90 86 81 80 77 75 71 67 60 32
73 68 63 37 2
l
77 74
70 69 66 64 64 6:1 48 23 2
cal studi~:s com paring seYeral regimens of lower-dose combination oral contraceptives for purposes of selecting an optimum combination and/or determining the relationship of bleeding patterns/ efficacy to the dosage of the product. Because bleeding patterns arc affected not only by the dosage of estrogen and progestin but also by the ratio of the two components, and since an optimum combination of two steroids may not be one of the regimens selected for a study, extremely sensitive study designs (i.e., selection of study regimens) and efficient methods of data analysis are needed fort hese types of studies. Application of statistical response surface methods" seems appropriate in this situation. Response surface methods are a collection of mathernatical and statistical procedures useful in studies where a response (numerical measure of the outcome of an experiment) is influenced by other independent \'ariables that can be controlled. The procedures cOil·· sist of experimental designs (i.e .. methods for selectin~
lcJr experiments). regression techniqtic·s !i.e .. nH·ilullh of fitting an approximate lunction;d rdatmn;.hip he· tween the response measurenwnt and the indepett mg. ol norgestirnate and O.OcFi mg. of EF. thus lllaking the choice of an optitual dosagc easier
REFERENCES
I. Inman, W. H. N., and VesseY, J\.1. P.: Investigation oi deaths from pulmonarv. coronary and cerebral thrombosis and embolism in women of childbearing age. Rr. :VIed.J.2: l93,196H. 2. Sartwell. P. E .. :VIasi, A. T., Arthes. F. (;., et. al.: Thromboemboiism and orai contraceptives: An epidemiological case-control study, Am. J. Epidemiol. 90: 365, 1969. :~. Inman, W. H., Vessey, M. P., Weserholm, B .. and Engelund. A.: Thromboembolic disease and the steroidal content of oral contraceptives: A report to the committee on safety of drugs. Br. Med. J. 2: 203, 1970. 4. Current Drug Information, Food and Drug Administration. April 24, 1970. 5. Kleinman, R. L: Comments on Steroidal Contraception: A Report of the Meeting of the International Planned Parenthood Federation Central Medical Committee and hs Ad\'isors, To Dis.
dmne/ethinyl estradiol. Contraception 12: ·495, ]q7~>. Allen. H. H.: Clinical assessment nf a low-dose oestrogen low-dose progestogen combined oral contracepti1e. Curr. Med. Res. Opin. 2: 101, 197+. Preston, S. \'.: :\ report of a collaborative dme respons" dinicai study using decreasing doses of combination or,ll contraceptives, Contraception. 6: 17, 1972. Nelson, J. H.: Selecting the optimum oral contraceptin·. J Reprod. Med. 11: 1~5. 197~. Myers, R. H.: Response Surface :Vlethodologv, Bostou. 1971, Allyn and Bacon. Cutler, S. J., and Ederer, F.: :Vlaximum utilintttiJ!l ui tht' lite table method in analyzing survival. .J. Chronic Dio.. 8: 699, 1958. Grizzle, J. E., Starmer, C. F.. and Koch. C.(.. : Analv;i' ol categorical data bv linear models. Biometrics 23: B7 1969. Koch, G. G., Johnson,\\'. P .. and Tollev. H. D.: A line~n· models approach to the anahsis of survival and extent of disease m multidimensional contingenn table~ . .J. Am. Stat. Assoc. 67: 783, 1972. Berkson, J: Maximum likelihood and minimum x' e
