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Current Medical Research and Opinion
Vol. 3, No. 2, 1975
Clinical trial of a low dose combined oral contraceptive (COvranette’)
B.Chir. and
G . L. FOSS,M.A., M.D.,
K. Fotherby, Ph.D., F.R.I.C. Male Subfertility and Endocrine Clinics, Bristol, and Royal Postgraduate Medical School, London, England
C u r . med. Res. Opin., (1975), 3,72.
Received: 6th January 1975
Summary A combination of 150 pg. d-norgestrel with 30 pg. ethinyl oestradiol was administered to I20 womenfor a total of 767 cycles. No pregnancies occurred and cycle control was good, 99% of the cycles being within the range of 28f3 days. Breakthrough bleeding occurred in 7.2% of the cycles, spotting in 8.9% and amenorrhoea in 0.8%. Sideeffects were minimal. Key words: Norgestrel- ethinyl oestradiol - contraceptives, oral
Introduction The use of oral contraceptives containing a mixture of a synthetic oestrogen and a synthetic progestogen is reported to be associated with the occurrence of a number of side-effects, although considerable doubt exists about the significance of many of these rep0rts.~,6However, it is clear that the use of combined oral contraceptives is associated with a significantly increased incidence of some serious side-effects, for example, venous thromboembolism3and that the incidence of such side-effectsmay be related to the dose of oestrogen in the oral contraceptive. In 1970, it was recommended by the Committee on Safety of Drugs7 that the dose of oestrogen should not exceed 50 pg. in any formulation used as an oral contraceptive. The use of low doses of progestogens administered daily indicated that the oestrogen was not essential for the anti-fertility effect, but in the absence of oestrogen there was increased incidence of irregular bleeding. In a trial of formulations containing various amounts of norethisterone and ethinyl oestradiol, Preston9 showed that the dose of ethinyl oestradiol could be reduced to 20 to 30 pg. per day without loss of anti-fertility effect or an increased incidence of irregular menstruation. The success as a hormonal contraceptive of the combination of 500 pg. dlnorgestrel (corresponding to 250 pg. d-norgestrel, the biologically active form) and 50 pg. ethinyl oestradiol (‘Ovran’)? led to an investigation of the amount by which the dose of notgestrel or ethinyl oestradiol could be reduced without decreasing the efficacy of the preparation. Use of the combination of 500 pg. dl-norgestrel and 30 pg. ethinyl oestradiol was associated with good cycle control and no pregnancies,2,4 but clinical experience showed that the ratio of d-norgestrel to ethinyl ?trade mark, Wyeth
72
G. L. Foss and K. Fotherby
Curr Med Res Opin Downloaded from informahealthcare.com by Queen's University on 01/04/15 For personal use only.
oestradiol was unbalanced by comparison with the 5:l ratio in ‘Ovran’. Accordingly, trials were started using 150 pg. d-norgestrel with 30 pg. ethinyl oestradiol (‘Ovranette’)t and the results are reported in this communication. While these trials were in progress, publications appeared of trials of this formulation in Americanlo and Canadian’ women.
Methods The 120 women included in the trial ranged in age from 17 to 43 years and were not suffering from any condition which contra-indicated the use of hormonal contraceptives. Most of them had been included in previous trials. All women received a clinical examination and the details of the examination together with blood pressure, weight, gynaecological findings, pre-treatment menstrual and coital status were recorded on printed enrolment forms. Any symptoms experienced in a pretreatment cycle were also recorded. The patients were supplied with cycle record forms and a 4-months’ supply of tablets containing 150 pg. d-norgestrel and 30 pg. ethinyl oestradiol, in packs of 21 tablets. They were instructed to start tablet-taking from the fifth day of their next cycle, to take the tablets for 21 days and to leave 7 clear days without tablets before starting the next course. A record was kept of cycle number, date of tablet-taking, menstrual loss, days of intermenstrual spotting and bleeding, menstruation, occasions of coitus and occurrence of any side-effects. At every 3-monthly visit to the clinic the subjects’ weight and blood pressure were recorded and at 6-monthly visits they were also examined again clinically.
Results A total of 767 cycles were completed by 120 women; the number of women completing each cycle is shown in Figure 1. No pregnancies occurred during the trial. Cycle control Length. Cycle control was acceptable and 99 % of the cycles were within the range of 28&3 days. Cycle lengths were not markedly different from those observed with the combination of 250 pg. d-norgestrel and 30 pg. ethinyl oestIadiol, (Figure 2). Bleedingpattern. The mean duration of menstrual bleeding was 4.3f0.8 days. Menstrual loss was reported to be normal in 66 % of cycles, increased in 7.2 %, and decreased in 26.8%. Intermenstrual bleeding occurred in 7.2% of cycles and spotting in 8.9 %. Seventy-four women reported no intermenstrual bleeding or spotting. Untoward effects No significant changes in weight occurred; for women completing 7 to 9 cycles of treatment, 19% recorded a weight increase of 3 kg. or more and the same ?trade mark, Wyeth 73
Clinical trial of a low dose combined oral contraceptive (‘Ovranette’)
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Figure 1. Number of cycles completed in trial by women taking 150 pg. d-norgestrel and 30 pg. ethinyl oestradiol
Cqclc number
proportion recorded a decrease of 3 kg. or more. No significant change was seen in the blood pressure measurements. Few side-effects were recorded, but whether any of them were related to tablet-taking cannot be assessed. The incidence of reported side-effects was not very different in this trial from that recorded for subjects taking 250 pg. d-norgestrel and 30 pg. ethinyl oestradiol, (Table I). TabIe I. Side-effectsreported for two formulations of d-norgestrel and ethinyl oestradiol. (Values represent ”/o of cycles in which side-effect was reported) Side-effect
Formulation 150 pg. d-norgestrel +30 pg. ethinyl oestradiol
Breast discomfort Headache Nausea Depression Discharge
74
2.3 3.8 2.2 1.8 1.o
250 pg. d-norgestrel +30 pg. ethinyl oestradiol
0.9
4.4 0.8 4.2 1.o
(3.
L. Foss and K. Fotherby
Figure 2. Comparison of menstrual cycle lengths in women ushg 150 pg. d-norgestrel and 30 pg. ethinyl oestradiol (‘Ovranette’) with those using 250 pg. d-norgestrel and 30 pg. ethinyl oestradiol (‘Ovran’ 30)
Curr Med Res Opin Downloaded from informahealthcare.com by Queen's University on 01/04/15 For personal use only.
150 pg. d-norgestrelf 30 pg. ethinyl oestradiol
-I 55
45
-8
40 -
b
30-
M
250 pg. d-norgestrel+ 30 pg. ethinyl oestradiol Women 184 Cycles I938
.... .::::::: .... ....
.... .... .... .... .... .... .... .... .... .... .... .... .... .... ..,. .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... ......... ........ ......... ............ ............. ............ ............. ............ ............. ............ ............. ............ ............. ............ ............. ............ ............. ............
35-
ffi
+ .-
.... .... :::::::: .... .... :::::::: .... .... .... .... .... .... .... .... .... .... ..,. .... .... .... .... .... .... .... .... .... .... .... .... .... .... ..... .... ..... .... .... ..... ....
. . . . I
Women 120 Cycles 767
2520 -
v....
15 -
105-
............. ............ ............. ............ ............. ............ ............. ............ ............. ............ .............
Discussion The cycle control in this trial was similar to that found by Woutersz’oand Allen,’ but was not as good as that reported for the formulations with a larger progestogen dose, (Table TI). Table II. Cycle control with various combinations of norgestrel and ethhyl oestradiol Combination
150d/30* (Present paper) 150d/301 150d/3010 250d/30**4 25Od/3O2 250d/50***8
No. women
No. cycles
% of cycles with Breakthrough bleeding
Spotting
Amenorrhoea
Cycle length (days) Mean*SD
Length of menstruation (days) Mean fS D
120
767
7.2
8.9
0.8
28.3k3.3
4.3 10.8
99 238 I84 623 5169
754 1076 1938 5062 49683
5.0
5.0 8.1
2.7 2.0 1.8 2.2 0.7
28.6k4.6 28.4 1 0 . 2 29.0 28.0f3 28.0
4.0k0.9 4.4h0.04 4.2 4.3 4-5
7.0 -8.25.2 1.6
8.8 2.3
*ISOd/30= 150 pg. d-norgestrel with 30 pg. ethinyl oestradiol (‘Ovranette’) **250d/30= 250 pg. d-norgestrel (present as 500 pg. dl-norgestrel) with 30 pg. ethinyl oestradiol (‘Ovran’-30) ***250d/50=250 Irg. d-norgestrel (present as 500 pg. dl-norgestrel) with 50 pg. ethinyl oestradiol (‘Ovran’)
75
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Clinical trial of a low dose combined oral contraceptive (‘Ovranette’)
It is apparent, however, that the 5 :1 ratio of d-norgestrel to ethinyl oestradiol in the preparation (‘Ovranette’) used in this trial provides good contraceptive protection and good cycle control even though the dose of the two components (150d/30)was reduced by 40 % compared with the original combination (equivalent of 250d/50, ‘Ovran’). The potential risk of serious side-effects is also presumably decreased. For patients who had changed from a 250/30 to a 150/30 combination, the increase in vaginal secretions due to the relative increase in oestrogen content made intercourse more comfortable. This 150/30 combination also appeared to be associated with an increase in libido and many patients had withdrawn from the 250/30 trial due to loss of libido. Acknowledgements We wish to thank John Wyeth and Brother Ltd., Taplow for the supply of ‘Ovranette’tablets and Miss Anne Kingston, their Information Officer, for the statistical analyses.
References 1. Allen, H. H., (1974). Clinical assessment of a low-dose oestrogen, low-dose progestogen combined oral contraceptive. Curr. med. Res. Opin., 2, 101. 2. Bye, P. G. T., and Elstein, M., (1973). Clinical assessment of a low-oestrogen combined oral contraceptive. Brit. med. J., 2, 389. 3. Doll, R., and Vessey, M. P., (1970). Evaluation of rare adverse effects of systemic contraceptives. Brit. Med. Bull., 26, 33. 4. Foss, G. L., and Fotherby, K., (1973). Low-oestrogen combined oral contraceptive. Acta Europ. Fertilitatis, 4, 57. 5. Goldzieher, J. W., Moses, L. E., Averkin, E., Scheel, C., and Taber, B. Z., (1971). A placebocontrolled double-blind crossover investigation of the side effects attributed to oral contraceptives. Fertil. Sieril., 22, 609. 6. Goldzieher, J. W., Moses, L. E., Averkin, E., Scheel, C., andTaber, B. Z., (1971). Nervousness and depression attributed to oral contraceptives : a double-blind placebo-controlled study. Amer. J . Obstet. Gynecol., 111,1013. 7. Inman, W. H. W., Vessey, M. P., Westerholm,B.,and Engelund, A., (1970). Thromboembolic disease and the steroidal content of oral contraceptives. Brit. med. J.,2,203. 8. Laurie, R. E., and Lewis, E. T., (1968). Fertility control with Ovral. A clinical review. J. Reprod. Fert., Suppl. 5,95. 9. Preston, S. N., (1972). A report of a collaborative dose-response clinical study using decreasing doses combination oral contraceptives. Contraception, 6, 17. 10. Woutersz, T. B., (1974). A new low-oestrogen, low-progestogen combined oral contraceptive. Curr. med. Res. Opin., 2,95.
76
Current Medical Research and Opinion
Vol. 3, No. 2, 1975
Clinical trial of a low dose combined oral contraceptive (COvranette’)
B.Chir. and
G . L. FOSS,M.A., M.D.,
K. Fotherby, Ph.D., F.R.I.C. Male Subfertility and Endocrine Clinics, Bristol, and Royal Postgraduate Medical School, London, England
C u r . med. Res. Opin., (1975), 3,72.
Received: 6th January 1975
Summary A combination of 150 pg. d-norgestrel with 30 pg. ethinyl oestradiol was administered to I20 womenfor a total of 767 cycles. No pregnancies occurred and cycle control was good, 99% of the cycles being within the range of 28f3 days. Breakthrough bleeding occurred in 7.2% of the cycles, spotting in 8.9% and amenorrhoea in 0.8%. Sideeffects were minimal. Key words: Norgestrel- ethinyl oestradiol - contraceptives, oral
Introduction The use of oral contraceptives containing a mixture of a synthetic oestrogen and a synthetic progestogen is reported to be associated with the occurrence of a number of side-effects, although considerable doubt exists about the significance of many of these rep0rts.~,6However, it is clear that the use of combined oral contraceptives is associated with a significantly increased incidence of some serious side-effects, for example, venous thromboembolism3and that the incidence of such side-effectsmay be related to the dose of oestrogen in the oral contraceptive. In 1970, it was recommended by the Committee on Safety of Drugs7 that the dose of oestrogen should not exceed 50 pg. in any formulation used as an oral contraceptive. The use of low doses of progestogens administered daily indicated that the oestrogen was not essential for the anti-fertility effect, but in the absence of oestrogen there was increased incidence of irregular bleeding. In a trial of formulations containing various amounts of norethisterone and ethinyl oestradiol, Preston9 showed that the dose of ethinyl oestradiol could be reduced to 20 to 30 pg. per day without loss of anti-fertility effect or an increased incidence of irregular menstruation. The success as a hormonal contraceptive of the combination of 500 pg. dlnorgestrel (corresponding to 250 pg. d-norgestrel, the biologically active form) and 50 pg. ethinyl oestradiol (‘Ovran’)? led to an investigation of the amount by which the dose of notgestrel or ethinyl oestradiol could be reduced without decreasing the efficacy of the preparation. Use of the combination of 500 pg. dl-norgestrel and 30 pg. ethinyl oestradiol was associated with good cycle control and no pregnancies,2,4 but clinical experience showed that the ratio of d-norgestrel to ethinyl ?trade mark, Wyeth
72
G. L. Foss and K. Fotherby
Curr Med Res Opin Downloaded from informahealthcare.com by Queen's University on 01/04/15 For personal use only.
oestradiol was unbalanced by comparison with the 5:l ratio in ‘Ovran’. Accordingly, trials were started using 150 pg. d-norgestrel with 30 pg. ethinyl oestradiol (‘Ovranette’)t and the results are reported in this communication. While these trials were in progress, publications appeared of trials of this formulation in Americanlo and Canadian’ women.
Methods The 120 women included in the trial ranged in age from 17 to 43 years and were not suffering from any condition which contra-indicated the use of hormonal contraceptives. Most of them had been included in previous trials. All women received a clinical examination and the details of the examination together with blood pressure, weight, gynaecological findings, pre-treatment menstrual and coital status were recorded on printed enrolment forms. Any symptoms experienced in a pretreatment cycle were also recorded. The patients were supplied with cycle record forms and a 4-months’ supply of tablets containing 150 pg. d-norgestrel and 30 pg. ethinyl oestradiol, in packs of 21 tablets. They were instructed to start tablet-taking from the fifth day of their next cycle, to take the tablets for 21 days and to leave 7 clear days without tablets before starting the next course. A record was kept of cycle number, date of tablet-taking, menstrual loss, days of intermenstrual spotting and bleeding, menstruation, occasions of coitus and occurrence of any side-effects. At every 3-monthly visit to the clinic the subjects’ weight and blood pressure were recorded and at 6-monthly visits they were also examined again clinically.
Results A total of 767 cycles were completed by 120 women; the number of women completing each cycle is shown in Figure 1. No pregnancies occurred during the trial. Cycle control Length. Cycle control was acceptable and 99 % of the cycles were within the range of 28&3 days. Cycle lengths were not markedly different from those observed with the combination of 250 pg. d-norgestrel and 30 pg. ethinyl oestIadiol, (Figure 2). Bleedingpattern. The mean duration of menstrual bleeding was 4.3f0.8 days. Menstrual loss was reported to be normal in 66 % of cycles, increased in 7.2 %, and decreased in 26.8%. Intermenstrual bleeding occurred in 7.2% of cycles and spotting in 8.9 %. Seventy-four women reported no intermenstrual bleeding or spotting. Untoward effects No significant changes in weight occurred; for women completing 7 to 9 cycles of treatment, 19% recorded a weight increase of 3 kg. or more and the same ?trade mark, Wyeth 73
Clinical trial of a low dose combined oral contraceptive (‘Ovranette’)
Curr Med Res Opin Downloaded from informahealthcare.com by Queen's University on 01/04/15 For personal use only.
Figure 1. Number of cycles completed in trial by women taking 150 pg. d-norgestrel and 30 pg. ethinyl oestradiol
Cqclc number
proportion recorded a decrease of 3 kg. or more. No significant change was seen in the blood pressure measurements. Few side-effects were recorded, but whether any of them were related to tablet-taking cannot be assessed. The incidence of reported side-effects was not very different in this trial from that recorded for subjects taking 250 pg. d-norgestrel and 30 pg. ethinyl oestradiol, (Table I). TabIe I. Side-effectsreported for two formulations of d-norgestrel and ethinyl oestradiol. (Values represent ”/o of cycles in which side-effect was reported) Side-effect
Formulation 150 pg. d-norgestrel +30 pg. ethinyl oestradiol
Breast discomfort Headache Nausea Depression Discharge
74
2.3 3.8 2.2 1.8 1.o
250 pg. d-norgestrel +30 pg. ethinyl oestradiol
0.9
4.4 0.8 4.2 1.o
(3.
L. Foss and K. Fotherby
Figure 2. Comparison of menstrual cycle lengths in women ushg 150 pg. d-norgestrel and 30 pg. ethinyl oestradiol (‘Ovranette’) with those using 250 pg. d-norgestrel and 30 pg. ethinyl oestradiol (‘Ovran’ 30)
Curr Med Res Opin Downloaded from informahealthcare.com by Queen's University on 01/04/15 For personal use only.
150 pg. d-norgestrelf 30 pg. ethinyl oestradiol
-I 55
45
-8
40 -
b
30-
M
250 pg. d-norgestrel+ 30 pg. ethinyl oestradiol Women 184 Cycles I938
.... .::::::: .... ....
.... .... .... .... .... .... .... .... .... .... .... .... .... .... ..,. .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... ......... ........ ......... ............ ............. ............ ............. ............ ............. ............ ............. ............ ............. ............ ............. ............ ............. ............
35-
ffi
+ .-
.... .... :::::::: .... .... :::::::: .... .... .... .... .... .... .... .... .... .... ..,. .... .... .... .... .... .... .... .... .... .... .... .... .... .... ..... .... ..... .... .... ..... ....
. . . . I
Women 120 Cycles 767
2520 -
v....
15 -
105-
............. ............ ............. ............ ............. ............ ............. ............ ............. ............ .............
Discussion The cycle control in this trial was similar to that found by Woutersz’oand Allen,’ but was not as good as that reported for the formulations with a larger progestogen dose, (Table TI). Table II. Cycle control with various combinations of norgestrel and ethhyl oestradiol Combination
150d/30* (Present paper) 150d/301 150d/3010 250d/30**4 25Od/3O2 250d/50***8
No. women
No. cycles
% of cycles with Breakthrough bleeding
Spotting
Amenorrhoea
Cycle length (days) Mean*SD
Length of menstruation (days) Mean fS D
120
767
7.2
8.9
0.8
28.3k3.3
4.3 10.8
99 238 I84 623 5169
754 1076 1938 5062 49683
5.0
5.0 8.1
2.7 2.0 1.8 2.2 0.7
28.6k4.6 28.4 1 0 . 2 29.0 28.0f3 28.0
4.0k0.9 4.4h0.04 4.2 4.3 4-5
7.0 -8.25.2 1.6
8.8 2.3
*ISOd/30= 150 pg. d-norgestrel with 30 pg. ethinyl oestradiol (‘Ovranette’) **250d/30= 250 pg. d-norgestrel (present as 500 pg. dl-norgestrel) with 30 pg. ethinyl oestradiol (‘Ovran’-30) ***250d/50=250 Irg. d-norgestrel (present as 500 pg. dl-norgestrel) with 50 pg. ethinyl oestradiol (‘Ovran’)
75
Curr Med Res Opin Downloaded from informahealthcare.com by Queen's University on 01/04/15 For personal use only.
Clinical trial of a low dose combined oral contraceptive (‘Ovranette’)
It is apparent, however, that the 5 :1 ratio of d-norgestrel to ethinyl oestradiol in the preparation (‘Ovranette’) used in this trial provides good contraceptive protection and good cycle control even though the dose of the two components (150d/30)was reduced by 40 % compared with the original combination (equivalent of 250d/50, ‘Ovran’). The potential risk of serious side-effects is also presumably decreased. For patients who had changed from a 250/30 to a 150/30 combination, the increase in vaginal secretions due to the relative increase in oestrogen content made intercourse more comfortable. This 150/30 combination also appeared to be associated with an increase in libido and many patients had withdrawn from the 250/30 trial due to loss of libido. Acknowledgements We wish to thank John Wyeth and Brother Ltd., Taplow for the supply of ‘Ovranette’tablets and Miss Anne Kingston, their Information Officer, for the statistical analyses.
References 1. Allen, H. H., (1974). Clinical assessment of a low-dose oestrogen, low-dose progestogen combined oral contraceptive. Curr. med. Res. Opin., 2, 101. 2. Bye, P. G. T., and Elstein, M., (1973). Clinical assessment of a low-oestrogen combined oral contraceptive. Brit. med. J., 2, 389. 3. Doll, R., and Vessey, M. P., (1970). Evaluation of rare adverse effects of systemic contraceptives. Brit. Med. Bull., 26, 33. 4. Foss, G. L., and Fotherby, K., (1973). Low-oestrogen combined oral contraceptive. Acta Europ. Fertilitatis, 4, 57. 5. Goldzieher, J. W., Moses, L. E., Averkin, E., Scheel, C., and Taber, B. Z., (1971). A placebocontrolled double-blind crossover investigation of the side effects attributed to oral contraceptives. Fertil. Sieril., 22, 609. 6. Goldzieher, J. W., Moses, L. E., Averkin, E., Scheel, C., andTaber, B. Z., (1971). Nervousness and depression attributed to oral contraceptives : a double-blind placebo-controlled study. Amer. J . Obstet. Gynecol., 111,1013. 7. Inman, W. H. W., Vessey, M. P., Westerholm,B.,and Engelund, A., (1970). Thromboembolic disease and the steroidal content of oral contraceptives. Brit. med. J.,2,203. 8. Laurie, R. E., and Lewis, E. T., (1968). Fertility control with Ovral. A clinical review. J. Reprod. Fert., Suppl. 5,95. 9. Preston, S. N., (1972). A report of a collaborative dose-response clinical study using decreasing doses combination oral contraceptives. Contraception, 6, 17. 10. Woutersz, T. B., (1974). A new low-oestrogen, low-progestogen combined oral contraceptive. Curr. med. Res. Opin., 2,95.
76
