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Current Medical Research and Opinion
Vol. 5, No. 8, 1978
Clinical experience with a low dose oral contraceptive containing norethisterone and ethinyl oestradiol
E. M. Morigi, M.D., Ph.D.,
Curr. Med. Res. Opin., (1978), 5, 655.
Received: 1st June 1978
and
S. A. Pasquale, M.D. Oriho Pharmaceutical Coup., Rariian, New Jersey, U.S.A.
Summary The results are presented of a clinical investigation of an oral contraceptive containing 0.5 mg norethisterone and 0.035 mg ethinyl oestradiol. The medication was administered orally as a 21-day cyclic regimen in 1,168 women. Duration of use wasfrom I to 53 cycles with an overall total of 16,345 cycles. When the preparation was taken as directed, no pregnancies occurred. Three women conceived during the course of this study; however, these subjects missed 3, 2, and I prescribed tablets, respectively, and their pregnancies are thus judged due to patient failure. The overall pregnancy rate was 0.22 per 100 woman years of use calculated as a Pearl Index. Intermenstrual bleeding (spotting andlor breakthrough bleeding) was noted primariljj in the earlj cycles, soon tapering of to a lower and stable level. The overall cumulative cyclic incidence of amenorrhoea was I .O%. Key words: Norethisterone - ethinyl oestradiol - contraceptives, oral
Introduction Combination oral contraceptive pills were approved for general human use in 1961. Since that time, all approved products have borne a generic resemblance in that each has contained a synthetic progestin in combination with an oestrogen. While there is little question that oral contraceptives represent a major contribution to public health, there has also been a move toward lower oestrogen formulations in order to minimize side-effects. Earlier work by Vessey9.10 and Inman4 in the U.K. and Sartwell’ in the United States suggested a possible association between the use of oral contraceptives and the occurrence of thromboembolic disease. More recent retrospective studies’ and, more importantly, a large prospective English study6 have reported an increased risk of the occurrence of thromboembolic side-effectswith usage of ‘the pill’. Furthermore, data from the above-cited continuing investigation by the Royal College of General Practitioners showed a 28 % lower incidence of deep vein thrombosis for subjects using oral contraceptives containing 50 mcg oestrogen as compared with those using combinations with a higher oestrogen content. These studies suggested that a lower oestrogen level in the pill was associated with a lower incidence of thromboembolic disorders while at the same time maintaining effective contraception. Thus, by the late 1960s, pills containing 50 mcg oestrogen were in common use, and in 1973 655
Curr Med Res Opin Downloaded from informahealthcare.com by Tufts University on 12/10/14 For personal use only.
Clinical experience with a low dose oral contraceptive containing norethisterone and ethinyl oestradiol
products containing even less than 50 mcg oestrogen were first introduced into the market. These products have been reported to be associated, however, with an increased frequency of irregular menstrual episodes and amenorrhoea, and in some cases with lower efficacy. In order to lower progestin/oestrogen levels while maintaining efficacy and patient acceptance, five combinations of norethisterone, an essentially non-oestrogenic progestin,*,e and ethinyl oestradiol, a commonly utilized oestrogen, have been investigated. All five combinations were studied by several researchers employing a special factorial technique. The various dosage combinations were tested for efficacy and for incidences of the following : pregnancy, spotting, breakthrough bleeding, and amenorrhoea. Ultimately, factorial analysis of these variables led to the conclusion that the formulation of 0.5 mg norethisterone and 0.035 mg ethinyl oestradiol (‘Modicon’t, ‘Ovysmen’*) represented the lowest effective dose of oestrogen while displaying minimal side-effects. Clinical studies were conducted on this preparation in the United States (including Puerto Rico) and Canada in clinic and private patients, and in Mexico in a clinic population. Results were reported earlier5 for 14 studies on clinic populations in the United States and Canada. Data were presented on 613 subjects who had experienced an aggregate of 8,738 cycles of use. The purpose of the present paper is to provide further data covering the work of 33 investigators in the locations and in the types 0f populations cited above. Experience is now available for 1,168 subjects who had an aggregate of 16,345 cycles of use.
Material and methods A total of 1,168 sexually active women were accepted into the study. The average age of the 1,152 subjects for whom age was recorded was 25.6 years with a range of from 13 to 54 years. Subjects between the ages of 19 and 36 represented 84.7 % of the total (Table I). Table I. Age distribution of patients in study ~
~~
Age range (yrs) 13 to 21 22 to 30 31 to 39 40 to 48 49 to 54 Not stated Total
No. patients
~
~~~
%total
330 583 213 23 3 16
28.3 49.9 18.2 2.0 0.3 1.3
1168
100.0
The average age of reported menarche was 12.9 years. (This statistic was not reported for 1 subject). Menarche occurred between the ages of 11 and 15 years in 92.1 %. Of all enrolled patients, 87.1 % had areported gravidaof oneor more; 12.9 % ttrade mark, Ortho Pharmaceutical Corp. U S A . *trade mark, Ortho Pharmaceutical Ltd., U.K.
656
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E. M. Morigi and S. A. Pasquale
were nulligravidae. Mean gravida per patient was 2.8, the mean number of deliveries was 2.4, and the mean number of abortions was 0.4. Concerning previous oral contraceptive use, 454 patients (38.9 %) reported “none previously used” and 714 (61.1 %) reported having previously taken an oral contraceptive. Selection of patients was determined by the following criteria: good general health, absence of pregnancy, reproductive age, regular menstrual periods, regular coitus and absence of history or evidence of disorders regarded as a contra-indication to sex steroid therapy, including significant past or present illness, any chronic disease, thrombophlebitis/pulmonary embolism or cerebrovascular disorders. Complete histories and results of physical examinations, with special emphasis on breast and pelvic areas, were recorded for each patient prior to admittance to the study. Routine laboratory analysis and ophthalmological examinations were performed in randomly selected patients. Full physical examinations were carried out at least annually, and patients were seen at least once every 3 months. The preparation was administered orally as a 21-day cyclic regimen, 3 weeks on medication followed by 1 week off. Each tablet contained 0.5 mg norethisterone, together with 0.035 mg ethinyl oestradiol. Tablets were packed in the manufacturer’s traditional tablet dispenser. Each patient was instructed to begin medication on Day 5 of her menstrual period and to take 1 tablet each day for 21 days, then stop for 7 full days. She was instructed to resume the next cycle of tablets on the 8th day, whether or not she was still experiencing withdrawal bleeding. Each patient was provided with a calendar, on which she was instructed to record tablet-taking days as well as bleeding episodes. These cards were reviewed at each return visit.
Results Eficacy A total of 1,168 women participated in the study and were followed through an aggregate of 16,345cycles with a range of 1 to 53 cycles for an average of 14.0 cycles per patient. No pregnancies occurred when the medication was taken as directed. There were thus no method failures. Three patients did report unplanned pregnancies while on therapy. However, these subjects did not take the medication according to the recommended method and their pregnancies are thus considered patient failures. One patient missed 3 consecutive pills, 1 missed 2 pills (Cycle days 7 and 12), and 1 missed 1 pill. These failures occurred in the eighteenth, eighth, and first cycles. Using the Pearl Index, the overall pregnancy rate was 0.22 per 100 women years. Menstrual efects Cycle control. Of the total of 16,345 on-therapy cycles studied to date, 14,662(89.7 %) were comparable to pre-therapy values for cycle length. The mean pre-therapy cycle length was 28.8 days. For comparable cycles, the mean on-therapy cycle length was 27.9 days, shorter than the pre-therapy interval by nearly 1 full day. 657
Clinical experience with a low dose oral contraceptive containing norethisterone and ethinyl oestradiol
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Table 11. Comparison of pre-therapy with on-therapy cycle length
Pre-therapy cycle length (days)
Mean on-therapy cycle length (days)
Irregular Less than 21 21 to 24 25 to 26 27 to 29 30 to 35 36 to 42 43 and over
27.9 28.0 27.9 28.0 27.9 27.9 28.2 21.9
No. patient cycles 571 2 210
483 8798 3624 51 7
The ability of the preparation to control cycle length is apparent from a comparison of pre-therapy and on-therapy cycle lengths (Table 11).As will be seen, 82.2 % of all measured therapy cycle lengths were within the range of 27 through 35 days. Mean on-therapy cycle length was identical, i.e. 27.9 days, whether medication was taken correctly or incorrectly. Table 111. Comparison of pre-therapy with on-therapy days of menstrualflow
Menstrual flow Deceased No change lncreased Not comparable Total
No. cycles
yototal
8626 4176 1989 1554
52.8 25.5 12.2 9.5
16,345
100.0
Table I11 displays alterations in the duration of menstrual flow associated with therapy. Mean flow prior to therapy for all patients was 4.7 days. Of the 16,345 on-therapy cycles, 14,791 (90.5 %) were comparable to pre-therapy values. The mean of days of flow for these on-therapy cycles was 3.8. This represents an average decrease of 0.9 days of flow per patient cycle. Days of flow was 5 days or less in 82.6 % of all measured on-therapy cycles. The amount of flow reported for each menstrual period was rated as follows: 0 =none, 1 =light, 2 =moderate, and 3 =heavy. Prior to therapy, the calculated mean amount of flow for all patients was 2.0, or moderate. For on-therapy cycles, amount of flow was recorded for 14,876 (91.0%) of the 16,345 cycles studied. The mean calculated on-therapy amount of flow for these patients was 1.7. There was, in fact, a decrease or no change in flow compared to pre-therapy values in 82.5 % of all recorded cycles (Table IV). Menstrual irregularities Amenorrhoea. Amenorrhoea was defined as the absence of bleeding for 60 days or more. This condition has been reported as a side-effect in low-dose progestindominant combinations. Because amenorrhoea may be a sign of pregnancy or have other adverse psychological effects on patients, and because of growing medical concern about the effect of exogenous sex steroids on pregnancy, an effective low 658
E. M. Morigi and S. A. Pasquale
Table IV. Comparison of pre-therapy with on-therapy amount of menstrual flow
Menstrual flow Decreased No change Increased Not comparable
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Total
No. cycles
4110
total
8108
29.2 53.3
1398 1469
9.0
16,345
100.0
8.5
oestrogen oral contraceptive with a low cycle incidence of amenorrhoea is obviously a particularly desirable modality. The overall cycle incidence of amenorrhoea was 1
.ox.
Spotting. Spotting was defined as intermenstrual bleeding in amounts insufficient to require sanitary protection. The experience with this preparation paralleled that with other combination oral contraceptives in that cycle incidence was highest in the first cycle (1 6.0%) and then rapidly tapered off until a stable level was reached within a few months. The rate of spotting dropped to 9.1 % in the third cycle and to 5.9 % in the sixth cycle. This resulted in an overall cycle rate of 6.1 % for 53 cycles. Breakthrough bleeding. Breakthrough bleeding was defined as intermenstrual blood flow in amounts sufficient to require sanitary protection. As was the case with spotting, here again the cycle incidence was highest in the first cycle (13.1 %), with a considerably lower and stable level achieved within a few cycles. The rate of breakthrough bleeding dropped to 6.9 % in the third cycle and to 5.6 % in the sixth cycle. The overall incidence of breakthrough bleeding was 5.1 % for 53 cycles. Dysmenorrhoea and pre-menstrual tension. Tables V and VI present data on the severity of on-therapy dysmenorrhoea and pre-menstrual tension (where degree Table V. Incidence of dysmenorrhoea and pre-menstrual tension on therapy: percentage of total cycles
Incidence
Dysmenorrhoea
Pre-menstrual tension
None Slight Moderate Severe Not stated
86.1 5.9 2.5 0.5 5.0
89.9 3.6 1.2 0.3 5.0
Table VI. Comparison of on-therapy with pre-therapy incidence of dysmenorrhoeaand pre-menstrual tension: on-therapy cycles as percentage of pre-therapy reports
Incidence
Dysmenorrhoea
Pre-menstrual tension
Decreased
42.2 49.4 3.1 5.3
27.1 64.6
N o change Increased Not comparable
2.1
5.6
659
Clinical experience with a low dose oral contraceptive containing norethisterone and ethinyl oestradiol
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stated), and a comparison of the on-therapy versus pre-therapy incidence of these two conditions (utilizing comparable data). During therapy, dysmenorrhoea was absent in 86.1 % of cycles and slight or absent in 92.0 %. This condition was reported as decreased or unchanged in 91.6 % of cycles compared to pre-therapy findings. Pre-menstrual tension was absent in 89.9 % of on-therapy cycles and slight or absent in 93.5 % of cycles. This condition was decreased or unchanged in 91.7 % of cycles compared to pre-therapy reports. Non-menstrual side-effects Any medical complaint reported by patients during therapy, or any pertinent physical finding by the investigator was reported, whether or not it was considered drug related. These complaints are discussed below by general category. Incidents were recorded by cycle, so that an individual patient may be represented more than once if a complaint recurred during two or more cycles. Weight changes. A comparison of pre-therapy weight to last reported on-therapy weight was made in a total of 1,007 patients, or 94.8 % of the total study population. These data are reported in Table VII. There was no weight change in the remaining 11.O % of these patients. Table VII. Comparison of pre-therapy weight with last reported on-therapy weight: percentage of 1007 patients
Weight gain
Weight loss
Greater than 15
26.2 12.5 5.2 4.4
24.8 9.6 4.2 2.1
Total
48.3
40.7
Weight (lbs) ~
~
~
1 to5 6 to 10 11 to 15
Note: no weight change in 11% patients
Gastro-intestinal complaints. Gastro-intestinal disturbances were reported in 270 patients, or 23.1 % of the total enrollment. The overall cycle incidence was 3.5 %, of which nausea accounted for 3.1 % and vomiting for 0.4 %. Nervous system Complaints.O fa total of 1,086nervous system complaints, the largest percentage (64.5 %) was for simple headaches, or 700 incidents reported during the entire study. The other most frequently reported complaints were decreased libido, 17 (1.6%); depression, 23 (2.1 %); vertigo, 127 (11.7%); drowsiness, 20 (1.8%); migraine headache, 10 (0.9 %) ; and nervousness/irritability/anxiety,157 (14.5 %). Cardiovascular complaints. There were a total of 114 (0.7 %) reported incidence of elevated blood pressure in 16,345 cycles of use where readings were recorded. All of these incidents were reported in 50 patients who experienced one or more episodes of elevated blood pressure. Of this number, 24 patients experienced 1 episode while 14 patients experienced2 episodes, 4 patients 3 episodes, and the remaining 8 patients 660
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E. M. Morigi and S . A, Pasquale
experienced 4 or more episodes of elevated blood pressure. A total of 10 patients, or 0.9 % of the total enrollment, were discontinued from therapy because of elevated blood pressure. One incident of thrombophlebitis was reported in a patient who underwent a cholecystectomyand excision of a paraovarian cyst during her third cycle on-therapy. She was seen in the emergency room at the hospital for a post-operative complication with symptoms of thrombophlebitis 13-days’ post-surgery. The patient refused admittance. Complete bed rest was prescribed. During this time, hospital personnel were not aware that she was using an oral contraceptive. Four months later, at her semi-annual check-up, these facts were revealed and oral contraceptive therapy was discontinued. At that time, the patient was asymptomatic with regard to her earlier diagnosis of thrombophlebitis. Genito-urinary complaints. Of a total of 946 genito-urinary complaints, 169 (17.9 %) were of cervical discharge; 126 (13.3 %) were of amenorrhoea; 120 (12.7 %) were of cervical erosion; 16 (1.7%) were of dysmenorrhoea; 14 (1.5%) were of trichomoniasis; and 13 (1.4 %) were of hypomenorrhoea. Other complaints. Significant other complaints were mastalgia and breast engorgement - 60 reported (0.4 % of total cycles) ; chloasma - 42 (0.3%) ; backache - 23 (0.1 %); pain in extremities - 14 (0.1%); acne - 13 (0.1 %); weakness - 11 (0.1 %); oedema - 1 1 (0.1 %); and fatigue - 10 (0.1 %). Patient drop-out Of the 1,168 patients who participated in the study, 74.4% dropped out for nontherapy related reasons. Major non-therapy related reasons were : study terminated, patient moved to another area, patient planned pregnancy, personal reasons, and husband sterilized. Only 14.2% dropped out for menstrual disorders and irregularities, and the remainder for other medically associated complaints or reactions.
Discussion The oral contraceptive combination of norethisterone and ethinyl oestradiol used in this study was designed to reduce hormonal intake while maintaining efficacy, safety, and patient compliance. Use of the medication through 16,345cycles in 1,168 private and clinic patients in the United States (including Puerto Rico), Canada and Mexico has now resulted in an overall pregnancy rate (Pearl Index) of 0.22 per 100 woman years. The 3 pregnancies that occurred to date were all the result of patient failure to take the medication as indicated. There were no method failures. The preparation produced effective cycle control with a low incidence of amenorrhoea. The highest incidence of breakthrough bleeding and spotting was limited to the first few cycles of therapy and then decreased in succeeding cycles. Patient drop-out during 53 cycles 661
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Clinical experience with a low dose oral contraceptive containing norethisterone and ethinyl oestradiol
of therapy was 14.2% for menstrual disorders and irregularities, and 1 1.4 % for other medically associated complaints or reactions. The data presented represent the results of a continuing investigation of a low oestrogen oral contraceptive whose formulation was arrived at as the end result of a factorial study of five oestrogen/progestin formulations. The combination chosen, 0.5 mg norethisterone and 0.035 mg ethinyl oestradiol (‘Modicon’, ‘Ovysmen’) gave the most favourable results in regard to efficacy, patient acceptance, and tolerability. Analysis of the updated data shows no statistically significant differences from that previously p ~ b l i s h e dThis . ~ combination has thus proved to be an effective and welltolerated lower dose oral contraceptive.
References 1 . Boston Collaborative Drug Surveillance Programme, (1973). Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease and breast tumors. Lancet, 1, 1399-1404. 2. Breuer, H., (1970). Metabolism of progestagens. Lancet, 2,615-616. 3. Goldzieher, I., Moses, L. E., Averkin, E., Scheel, C., and Taber, B. Z., (197 1). Placebo controlled double-blind cross over investigation of the side-effects attributed to oral contraceptives. Fertil. Steril., 22,609-623. 4. Inman, W. H. W., andVessey, M. P., (1968). Investigation of deaths from pulmonary, coronary, andcerebral thromboembolismandembolismin women of child-bearing age. Br. Med. J.,2,193-199. 5 . Pasquale, S. A., and Yuliano, E., (1975). Clinical results with a new low dose oral contraceptive utilizing norethindrone/ethinyl estradiol. Contraception, 12,495-503. 6. Royal College of General Practitioners, (1974). “Oral Contraceptives and Health”. Pitman Medical, London. 7. Sartwell, P. E., Masi, A. T., Arthes, F. G., Greene, G. R., and Smith, H. E., (1969). Thromboembolism and oral contraceptives: an epidemiological case-control study. Am. J. Epidemiol., 90,365-380. 8. Townsley, J. D., and Brodie, H. J., (1970). Low conversion of 19-nortestosterone to urinary oestrogen. Lancet, 2,1039. 9. Vessey, M. P., and Doll, R., (1968). Investigation of relation between use of oral contraceptives and thromboembolic disease. Br. Med. J., 2, 199-205. 10. Vessey, M. P., and Doll, R., (1969). Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br. Med. J., 2,651-657.
662
Current Medical Research and Opinion
Vol. 5, No. 8, 1978
Clinical experience with a low dose oral contraceptive containing norethisterone and ethinyl oestradiol
E. M. Morigi, M.D., Ph.D.,
Curr. Med. Res. Opin., (1978), 5, 655.
Received: 1st June 1978
and
S. A. Pasquale, M.D. Oriho Pharmaceutical Coup., Rariian, New Jersey, U.S.A.
Summary The results are presented of a clinical investigation of an oral contraceptive containing 0.5 mg norethisterone and 0.035 mg ethinyl oestradiol. The medication was administered orally as a 21-day cyclic regimen in 1,168 women. Duration of use wasfrom I to 53 cycles with an overall total of 16,345 cycles. When the preparation was taken as directed, no pregnancies occurred. Three women conceived during the course of this study; however, these subjects missed 3, 2, and I prescribed tablets, respectively, and their pregnancies are thus judged due to patient failure. The overall pregnancy rate was 0.22 per 100 woman years of use calculated as a Pearl Index. Intermenstrual bleeding (spotting andlor breakthrough bleeding) was noted primariljj in the earlj cycles, soon tapering of to a lower and stable level. The overall cumulative cyclic incidence of amenorrhoea was I .O%. Key words: Norethisterone - ethinyl oestradiol - contraceptives, oral
Introduction Combination oral contraceptive pills were approved for general human use in 1961. Since that time, all approved products have borne a generic resemblance in that each has contained a synthetic progestin in combination with an oestrogen. While there is little question that oral contraceptives represent a major contribution to public health, there has also been a move toward lower oestrogen formulations in order to minimize side-effects. Earlier work by Vessey9.10 and Inman4 in the U.K. and Sartwell’ in the United States suggested a possible association between the use of oral contraceptives and the occurrence of thromboembolic disease. More recent retrospective studies’ and, more importantly, a large prospective English study6 have reported an increased risk of the occurrence of thromboembolic side-effectswith usage of ‘the pill’. Furthermore, data from the above-cited continuing investigation by the Royal College of General Practitioners showed a 28 % lower incidence of deep vein thrombosis for subjects using oral contraceptives containing 50 mcg oestrogen as compared with those using combinations with a higher oestrogen content. These studies suggested that a lower oestrogen level in the pill was associated with a lower incidence of thromboembolic disorders while at the same time maintaining effective contraception. Thus, by the late 1960s, pills containing 50 mcg oestrogen were in common use, and in 1973 655
Curr Med Res Opin Downloaded from informahealthcare.com by Tufts University on 12/10/14 For personal use only.
Clinical experience with a low dose oral contraceptive containing norethisterone and ethinyl oestradiol
products containing even less than 50 mcg oestrogen were first introduced into the market. These products have been reported to be associated, however, with an increased frequency of irregular menstrual episodes and amenorrhoea, and in some cases with lower efficacy. In order to lower progestin/oestrogen levels while maintaining efficacy and patient acceptance, five combinations of norethisterone, an essentially non-oestrogenic progestin,*,e and ethinyl oestradiol, a commonly utilized oestrogen, have been investigated. All five combinations were studied by several researchers employing a special factorial technique. The various dosage combinations were tested for efficacy and for incidences of the following : pregnancy, spotting, breakthrough bleeding, and amenorrhoea. Ultimately, factorial analysis of these variables led to the conclusion that the formulation of 0.5 mg norethisterone and 0.035 mg ethinyl oestradiol (‘Modicon’t, ‘Ovysmen’*) represented the lowest effective dose of oestrogen while displaying minimal side-effects. Clinical studies were conducted on this preparation in the United States (including Puerto Rico) and Canada in clinic and private patients, and in Mexico in a clinic population. Results were reported earlier5 for 14 studies on clinic populations in the United States and Canada. Data were presented on 613 subjects who had experienced an aggregate of 8,738 cycles of use. The purpose of the present paper is to provide further data covering the work of 33 investigators in the locations and in the types 0f populations cited above. Experience is now available for 1,168 subjects who had an aggregate of 16,345 cycles of use.
Material and methods A total of 1,168 sexually active women were accepted into the study. The average age of the 1,152 subjects for whom age was recorded was 25.6 years with a range of from 13 to 54 years. Subjects between the ages of 19 and 36 represented 84.7 % of the total (Table I). Table I. Age distribution of patients in study ~
~~
Age range (yrs) 13 to 21 22 to 30 31 to 39 40 to 48 49 to 54 Not stated Total
No. patients
~
~~~
%total
330 583 213 23 3 16
28.3 49.9 18.2 2.0 0.3 1.3
1168
100.0
The average age of reported menarche was 12.9 years. (This statistic was not reported for 1 subject). Menarche occurred between the ages of 11 and 15 years in 92.1 %. Of all enrolled patients, 87.1 % had areported gravidaof oneor more; 12.9 % ttrade mark, Ortho Pharmaceutical Corp. U S A . *trade mark, Ortho Pharmaceutical Ltd., U.K.
656
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E. M. Morigi and S. A. Pasquale
were nulligravidae. Mean gravida per patient was 2.8, the mean number of deliveries was 2.4, and the mean number of abortions was 0.4. Concerning previous oral contraceptive use, 454 patients (38.9 %) reported “none previously used” and 714 (61.1 %) reported having previously taken an oral contraceptive. Selection of patients was determined by the following criteria: good general health, absence of pregnancy, reproductive age, regular menstrual periods, regular coitus and absence of history or evidence of disorders regarded as a contra-indication to sex steroid therapy, including significant past or present illness, any chronic disease, thrombophlebitis/pulmonary embolism or cerebrovascular disorders. Complete histories and results of physical examinations, with special emphasis on breast and pelvic areas, were recorded for each patient prior to admittance to the study. Routine laboratory analysis and ophthalmological examinations were performed in randomly selected patients. Full physical examinations were carried out at least annually, and patients were seen at least once every 3 months. The preparation was administered orally as a 21-day cyclic regimen, 3 weeks on medication followed by 1 week off. Each tablet contained 0.5 mg norethisterone, together with 0.035 mg ethinyl oestradiol. Tablets were packed in the manufacturer’s traditional tablet dispenser. Each patient was instructed to begin medication on Day 5 of her menstrual period and to take 1 tablet each day for 21 days, then stop for 7 full days. She was instructed to resume the next cycle of tablets on the 8th day, whether or not she was still experiencing withdrawal bleeding. Each patient was provided with a calendar, on which she was instructed to record tablet-taking days as well as bleeding episodes. These cards were reviewed at each return visit.
Results Eficacy A total of 1,168 women participated in the study and were followed through an aggregate of 16,345cycles with a range of 1 to 53 cycles for an average of 14.0 cycles per patient. No pregnancies occurred when the medication was taken as directed. There were thus no method failures. Three patients did report unplanned pregnancies while on therapy. However, these subjects did not take the medication according to the recommended method and their pregnancies are thus considered patient failures. One patient missed 3 consecutive pills, 1 missed 2 pills (Cycle days 7 and 12), and 1 missed 1 pill. These failures occurred in the eighteenth, eighth, and first cycles. Using the Pearl Index, the overall pregnancy rate was 0.22 per 100 women years. Menstrual efects Cycle control. Of the total of 16,345 on-therapy cycles studied to date, 14,662(89.7 %) were comparable to pre-therapy values for cycle length. The mean pre-therapy cycle length was 28.8 days. For comparable cycles, the mean on-therapy cycle length was 27.9 days, shorter than the pre-therapy interval by nearly 1 full day. 657
Clinical experience with a low dose oral contraceptive containing norethisterone and ethinyl oestradiol
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Table 11. Comparison of pre-therapy with on-therapy cycle length
Pre-therapy cycle length (days)
Mean on-therapy cycle length (days)
Irregular Less than 21 21 to 24 25 to 26 27 to 29 30 to 35 36 to 42 43 and over
27.9 28.0 27.9 28.0 27.9 27.9 28.2 21.9
No. patient cycles 571 2 210
483 8798 3624 51 7
The ability of the preparation to control cycle length is apparent from a comparison of pre-therapy and on-therapy cycle lengths (Table 11).As will be seen, 82.2 % of all measured therapy cycle lengths were within the range of 27 through 35 days. Mean on-therapy cycle length was identical, i.e. 27.9 days, whether medication was taken correctly or incorrectly. Table 111. Comparison of pre-therapy with on-therapy days of menstrualflow
Menstrual flow Deceased No change lncreased Not comparable Total
No. cycles
yototal
8626 4176 1989 1554
52.8 25.5 12.2 9.5
16,345
100.0
Table I11 displays alterations in the duration of menstrual flow associated with therapy. Mean flow prior to therapy for all patients was 4.7 days. Of the 16,345 on-therapy cycles, 14,791 (90.5 %) were comparable to pre-therapy values. The mean of days of flow for these on-therapy cycles was 3.8. This represents an average decrease of 0.9 days of flow per patient cycle. Days of flow was 5 days or less in 82.6 % of all measured on-therapy cycles. The amount of flow reported for each menstrual period was rated as follows: 0 =none, 1 =light, 2 =moderate, and 3 =heavy. Prior to therapy, the calculated mean amount of flow for all patients was 2.0, or moderate. For on-therapy cycles, amount of flow was recorded for 14,876 (91.0%) of the 16,345 cycles studied. The mean calculated on-therapy amount of flow for these patients was 1.7. There was, in fact, a decrease or no change in flow compared to pre-therapy values in 82.5 % of all recorded cycles (Table IV). Menstrual irregularities Amenorrhoea. Amenorrhoea was defined as the absence of bleeding for 60 days or more. This condition has been reported as a side-effect in low-dose progestindominant combinations. Because amenorrhoea may be a sign of pregnancy or have other adverse psychological effects on patients, and because of growing medical concern about the effect of exogenous sex steroids on pregnancy, an effective low 658
E. M. Morigi and S. A. Pasquale
Table IV. Comparison of pre-therapy with on-therapy amount of menstrual flow
Menstrual flow Decreased No change Increased Not comparable
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Total
No. cycles
4110
total
8108
29.2 53.3
1398 1469
9.0
16,345
100.0
8.5
oestrogen oral contraceptive with a low cycle incidence of amenorrhoea is obviously a particularly desirable modality. The overall cycle incidence of amenorrhoea was 1
.ox.
Spotting. Spotting was defined as intermenstrual bleeding in amounts insufficient to require sanitary protection. The experience with this preparation paralleled that with other combination oral contraceptives in that cycle incidence was highest in the first cycle (1 6.0%) and then rapidly tapered off until a stable level was reached within a few months. The rate of spotting dropped to 9.1 % in the third cycle and to 5.9 % in the sixth cycle. This resulted in an overall cycle rate of 6.1 % for 53 cycles. Breakthrough bleeding. Breakthrough bleeding was defined as intermenstrual blood flow in amounts sufficient to require sanitary protection. As was the case with spotting, here again the cycle incidence was highest in the first cycle (13.1 %), with a considerably lower and stable level achieved within a few cycles. The rate of breakthrough bleeding dropped to 6.9 % in the third cycle and to 5.6 % in the sixth cycle. The overall incidence of breakthrough bleeding was 5.1 % for 53 cycles. Dysmenorrhoea and pre-menstrual tension. Tables V and VI present data on the severity of on-therapy dysmenorrhoea and pre-menstrual tension (where degree Table V. Incidence of dysmenorrhoea and pre-menstrual tension on therapy: percentage of total cycles
Incidence
Dysmenorrhoea
Pre-menstrual tension
None Slight Moderate Severe Not stated
86.1 5.9 2.5 0.5 5.0
89.9 3.6 1.2 0.3 5.0
Table VI. Comparison of on-therapy with pre-therapy incidence of dysmenorrhoeaand pre-menstrual tension: on-therapy cycles as percentage of pre-therapy reports
Incidence
Dysmenorrhoea
Pre-menstrual tension
Decreased
42.2 49.4 3.1 5.3
27.1 64.6
N o change Increased Not comparable
2.1
5.6
659
Clinical experience with a low dose oral contraceptive containing norethisterone and ethinyl oestradiol
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stated), and a comparison of the on-therapy versus pre-therapy incidence of these two conditions (utilizing comparable data). During therapy, dysmenorrhoea was absent in 86.1 % of cycles and slight or absent in 92.0 %. This condition was reported as decreased or unchanged in 91.6 % of cycles compared to pre-therapy findings. Pre-menstrual tension was absent in 89.9 % of on-therapy cycles and slight or absent in 93.5 % of cycles. This condition was decreased or unchanged in 91.7 % of cycles compared to pre-therapy reports. Non-menstrual side-effects Any medical complaint reported by patients during therapy, or any pertinent physical finding by the investigator was reported, whether or not it was considered drug related. These complaints are discussed below by general category. Incidents were recorded by cycle, so that an individual patient may be represented more than once if a complaint recurred during two or more cycles. Weight changes. A comparison of pre-therapy weight to last reported on-therapy weight was made in a total of 1,007 patients, or 94.8 % of the total study population. These data are reported in Table VII. There was no weight change in the remaining 11.O % of these patients. Table VII. Comparison of pre-therapy weight with last reported on-therapy weight: percentage of 1007 patients
Weight gain
Weight loss
Greater than 15
26.2 12.5 5.2 4.4
24.8 9.6 4.2 2.1
Total
48.3
40.7
Weight (lbs) ~
~
~
1 to5 6 to 10 11 to 15
Note: no weight change in 11% patients
Gastro-intestinal complaints. Gastro-intestinal disturbances were reported in 270 patients, or 23.1 % of the total enrollment. The overall cycle incidence was 3.5 %, of which nausea accounted for 3.1 % and vomiting for 0.4 %. Nervous system Complaints.O fa total of 1,086nervous system complaints, the largest percentage (64.5 %) was for simple headaches, or 700 incidents reported during the entire study. The other most frequently reported complaints were decreased libido, 17 (1.6%); depression, 23 (2.1 %); vertigo, 127 (11.7%); drowsiness, 20 (1.8%); migraine headache, 10 (0.9 %) ; and nervousness/irritability/anxiety,157 (14.5 %). Cardiovascular complaints. There were a total of 114 (0.7 %) reported incidence of elevated blood pressure in 16,345 cycles of use where readings were recorded. All of these incidents were reported in 50 patients who experienced one or more episodes of elevated blood pressure. Of this number, 24 patients experienced 1 episode while 14 patients experienced2 episodes, 4 patients 3 episodes, and the remaining 8 patients 660
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E. M. Morigi and S . A, Pasquale
experienced 4 or more episodes of elevated blood pressure. A total of 10 patients, or 0.9 % of the total enrollment, were discontinued from therapy because of elevated blood pressure. One incident of thrombophlebitis was reported in a patient who underwent a cholecystectomyand excision of a paraovarian cyst during her third cycle on-therapy. She was seen in the emergency room at the hospital for a post-operative complication with symptoms of thrombophlebitis 13-days’ post-surgery. The patient refused admittance. Complete bed rest was prescribed. During this time, hospital personnel were not aware that she was using an oral contraceptive. Four months later, at her semi-annual check-up, these facts were revealed and oral contraceptive therapy was discontinued. At that time, the patient was asymptomatic with regard to her earlier diagnosis of thrombophlebitis. Genito-urinary complaints. Of a total of 946 genito-urinary complaints, 169 (17.9 %) were of cervical discharge; 126 (13.3 %) were of amenorrhoea; 120 (12.7 %) were of cervical erosion; 16 (1.7%) were of dysmenorrhoea; 14 (1.5%) were of trichomoniasis; and 13 (1.4 %) were of hypomenorrhoea. Other complaints. Significant other complaints were mastalgia and breast engorgement - 60 reported (0.4 % of total cycles) ; chloasma - 42 (0.3%) ; backache - 23 (0.1 %); pain in extremities - 14 (0.1%); acne - 13 (0.1 %); weakness - 11 (0.1 %); oedema - 1 1 (0.1 %); and fatigue - 10 (0.1 %). Patient drop-out Of the 1,168 patients who participated in the study, 74.4% dropped out for nontherapy related reasons. Major non-therapy related reasons were : study terminated, patient moved to another area, patient planned pregnancy, personal reasons, and husband sterilized. Only 14.2% dropped out for menstrual disorders and irregularities, and the remainder for other medically associated complaints or reactions.
Discussion The oral contraceptive combination of norethisterone and ethinyl oestradiol used in this study was designed to reduce hormonal intake while maintaining efficacy, safety, and patient compliance. Use of the medication through 16,345cycles in 1,168 private and clinic patients in the United States (including Puerto Rico), Canada and Mexico has now resulted in an overall pregnancy rate (Pearl Index) of 0.22 per 100 woman years. The 3 pregnancies that occurred to date were all the result of patient failure to take the medication as indicated. There were no method failures. The preparation produced effective cycle control with a low incidence of amenorrhoea. The highest incidence of breakthrough bleeding and spotting was limited to the first few cycles of therapy and then decreased in succeeding cycles. Patient drop-out during 53 cycles 661
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Clinical experience with a low dose oral contraceptive containing norethisterone and ethinyl oestradiol
of therapy was 14.2% for menstrual disorders and irregularities, and 1 1.4 % for other medically associated complaints or reactions. The data presented represent the results of a continuing investigation of a low oestrogen oral contraceptive whose formulation was arrived at as the end result of a factorial study of five oestrogen/progestin formulations. The combination chosen, 0.5 mg norethisterone and 0.035 mg ethinyl oestradiol (‘Modicon’, ‘Ovysmen’) gave the most favourable results in regard to efficacy, patient acceptance, and tolerability. Analysis of the updated data shows no statistically significant differences from that previously p ~ b l i s h e dThis . ~ combination has thus proved to be an effective and welltolerated lower dose oral contraceptive.
References 1 . Boston Collaborative Drug Surveillance Programme, (1973). Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease and breast tumors. Lancet, 1, 1399-1404. 2. Breuer, H., (1970). Metabolism of progestagens. Lancet, 2,615-616. 3. Goldzieher, I., Moses, L. E., Averkin, E., Scheel, C., and Taber, B. Z., (197 1). Placebo controlled double-blind cross over investigation of the side-effects attributed to oral contraceptives. Fertil. Steril., 22,609-623. 4. Inman, W. H. W., andVessey, M. P., (1968). Investigation of deaths from pulmonary, coronary, andcerebral thromboembolismandembolismin women of child-bearing age. Br. Med. J.,2,193-199. 5 . Pasquale, S. A., and Yuliano, E., (1975). Clinical results with a new low dose oral contraceptive utilizing norethindrone/ethinyl estradiol. Contraception, 12,495-503. 6. Royal College of General Practitioners, (1974). “Oral Contraceptives and Health”. Pitman Medical, London. 7. Sartwell, P. E., Masi, A. T., Arthes, F. G., Greene, G. R., and Smith, H. E., (1969). Thromboembolism and oral contraceptives: an epidemiological case-control study. Am. J. Epidemiol., 90,365-380. 8. Townsley, J. D., and Brodie, H. J., (1970). Low conversion of 19-nortestosterone to urinary oestrogen. Lancet, 2,1039. 9. Vessey, M. P., and Doll, R., (1968). Investigation of relation between use of oral contraceptives and thromboembolic disease. Br. Med. J., 2, 199-205. 10. Vessey, M. P., and Doll, R., (1969). Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br. Med. J., 2,651-657.
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