Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/17/14 For personal use only.
Current Medical Research and Opinion
Vol. 3, No. 3, 1975
Clinical evaluation of a new oral contraceptive, ‘Pregnon’
and
J. van de Walle, Phar.D.,
M. J. Weijers, M.D. Medical Unit,Scientific Development Group, Organon International BY, O.w, The NetJierlands
Curr. med. Res. Opin., (1975), 3, 151.
Received: 18th March 1975
Summary ‘Pregnon’, a new oral contraceptive containing 1 mg. lynestrenol and 0.05 mg. ethinyl oestradiol, was administered cyclically to 639 women of fertile age over a total of 9,159 cycles. There were no pregnancier. In most cases the withdrawal bleeding resembled normal menstruation. The incidence of metrorrhagia was relatively low and when it did occur it was usually conjined to the early treatment cycles and was of very limited duration. The objective and subjective tolerance was excellent. Key words: Contraceptives, oral - lynestrenol - ethinyl oestradiol
Introduction The first clinical trial with oestrogen and progestagen combined for the purpose of contraception was carried out in Puerto Rico in 1956.4 Oral contraceptives came into regular clinical use in 1957 and now, less than 20 years later, they are used by more than 20 million women throughout the world.3 To minimise the various side-effects seen with the early preparations new types of oral contraceptives and different methods of administration have been introduced. Nevertheless, the combination of oestrogen and progestagen is still the most widely used form of oral contraception. Whereas the early preparations contained large amounts of oestrogen and progestagen, recent years have seen reductions, sometimes considerable, in the dosages of these steroids. However, this reduction in dosage, motivated by the wish to minimise side-effects, should never endanger efficacy. ‘Pregnon’t is a new low-dosage ovulation-inhibiting agent containing 1 mg. lynestrenol and 0.05 mg. ethinyl oestradiol in each tablet. In this multi-centre trial particular attention was paid to the following points: (i) contraceptive efficacy; (ii) cycle regularity and the frequency and intensity of any rnetrorrhagia; and (iii) the incidence and severity of side-effects. The data were collected from different Belgian clinics and evaluated by the Medical Unit of Organon in Belgium and The Netherlands. ttrade mark, Organon. Also marketed under the name of ‘Ovostat’ 28 or ‘Pregnon’ 28 in which each pack contains 22 active plus 6 placebo tablets. 151
Clinical evaluation of a new oral contraceptive, ‘Pregnon’
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/17/14 For personal use only.
Patients and treatment Patients ‘Pregnon’ was administered as a contraceptive agent to women from different parts of Belgium, within the framework of a multi-centre trial. Such trials have the advantage of providing a good cross-section of patients, which seems especially worthwhile in studies of oral contraception where subjective complaints are apt to differ in frequency and pattern of symptoms in different groups of patients. During the present trial, 639 women of fertile age were monitored during 9,159 cycles (average number of cycles per patient: 14.3). Every woman underwent clinical and gynaecological examinations before treatment and again after every 2 or 3 months. During these periodic check-ups details concerning the taking of the tablets, the occurrence of side-effects, the duration and intensity of withdrawal bleeding and the frequency and intensity of any metrorrhagia were carefully recorded on a special form so that the data could be easily transferred to a computer. Standard definitions were used to ensure uniformity in reporting. ‘Withdrawal bleeding’ was defined as bleeding which begins in the tablet-free period ; ‘spotting’ as a scanty bleeding outside the tablet-free period, not requiring any hygienic measures or, at most, one sanitary towel per day; and ‘breakthrough bleeding’ (B.T.B.) as a bleeding which is not spotting and which cannot be considered a withdrawal bleeding. The maximum duration of administration of ‘Pregnon’ was 36 consecutive cycles. The cycle distribution is recorded in Figure 1. Figure 1. Cycle distribution 640 r 600
-
500
-
400
-
5
!$ 300. i? 200-
100-
2
152
4
6
>
10
12 14 16 18 20 22 No. completed cycles
24
26
28 30
32
34 36
J. van de Walle and M. J. Weijers
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/17/14 For personal use only.
Treatment The ‘Pregnon’ pack used in this trial contained 22 tablets, each tablet consisting of 1 mg. lynestrenol and 0.05 mg. ethinyl oestradiol. Treatment was begun by taking the first tablet on the first day of menstruation and was continued for 22 days followed by a 6-day tablet-free interval during which withdrawal bleeding normally occurs.
Results Contraceptive eflcacy No pregnancy occurred during the 9,159 cycles studied in this trial. The Pearl Index was therefore zero, establishing the reliability of ‘Pregnon’ as an oral contraceptive (confidence limit =0 to 0.4). Cycle regularity Latent period: The time elapsing between the taking of the last tablet of a series and the onset of withdrawal bleeding was 2 to 4 days in 96.7 % of the cycles, less than 2 days in 2.4% of the cycles, and more than 4 days in only 0.9% of the cycles, (Figure 2). Figure 2. Time of onset of withdrawal bleeding
Number of days
Duration: The duration of the withdrawal bleeding was 3 to 5 days in 81.7% of the cycIes, (Figure 3). When compared with that prior to treatment this was shorter in 39.3 % of the cycles and longer in 2 %. I53
Clinical evaluation of a new oral contraceptive, 'Pregnon'
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/17/14 For personal use only.
Duration of withdrawal bleeding
Number o l ' d ~ y ,
Figure 4. Intensity of withdrawal bleeding 6(
5c
4C
-
@J
,.-J
," 3c 0
-. 20
10
0
154
I
J. van de Walle and M. J. Weijers
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/17/14 For personal use only.
Withdrawa1,flow: As shown in Figure 4, the intensity of the withdrawal bleeding was within the normal range in 57.3 % of the cycles, slight in 41.7% and heavy in 1 %. The influence on menstrual flow manifested itself as a decrease in 32.3% of the cycles and an increase in 5.2 % of the cycles. Metrorrhugia - amenorrhoea, (Table I). Spotting occurred in 3.1 % of the cycles. Heavier metrorrhagia, i.e. breakthrough bleeding, was observed in 2.9 % of the cycles. In 23 cases both spotting and breakthrough bleeding appeared during the same cycle (0.2 % of the cycles). Generally speaking, they occurred in the first three cycles and were of very limited duration. Amenorrhoea was observed in 2.9% of the cycles. Table I. Incidence of amenorrhoea or metrorrhagia
No. cases
YOcycles
Amenorrhoea
263
2.9
Breakthrough bleeding Spotting Breakthrough bleeding +spotting (same cycle)
264 286 23
2.9 3.1 0.2
Total incidence of metrorrhagia
573
6.2
Irregularity in bleeding ~~
~~
~~
Side-effects Table I1 shows the frequency of side-effects observed during treatment and also the decrease in or disappearance of those side-effects which had existed before treatment. No significant change in body weight was observed. Mean systolic and diastolic blood pressures before and during treatment were 124/77 mm.Hg. and 126/78 mm.Hg. respectively. Table II. Influence of ‘Pregnon’ on incidence of side-effects ~~
Side-effects
Nausea Vomiting Headache Breast tenderness ‘Heavy’ legs Leucorrhoea Nervousness Depression Libido decrease
Appearance/aggravat i on
Disappearance/decline cycles
No. cases
yocycles
No. cases
95 28 297 192 167 132 265 1 I7 67
1 0.3 3.2 2.1
135 22 25 1
0.2 2.7
101
1.1
1.8 1.4
159
1.8 2.3 2.4 I 1 .9
2.9 1.3
0.7
210
224 92 178
O/ ,O
1.5
Reasons for discontinuation of treatment Only 46 patients discontinued treatment for reasons which could be connected with the product; this represents an acceptability level of about 43 %, (Table 111). 155
Clinical evaluation of a new oral contraceptive, ‘Pregnon’
Table UI. Reasons for discontinuation of treatment
Reason
% women
No. women
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/17/14 For personal use only.
~
Metrorrhagia Nervousness Gastro-intestinal complaints Weight gain Headache Breast tenderness Fatigue Hypertension Libido decrease Rashes ‘Heavy’ legs
23
Total
46
5 4
3 3 2 2
1
~~
3.6 0.8 0.6 0.5
0.5 03 0.3
1 1
0.15 0.15 0.15
1
0.15
7.2
Discussion Assessment of the efficacy of a contraceptive agent is made on its ability to lower the birth rate to zero. Although this can only be truly estimated on the basis of many thousands of cycles, the results of this trial, carried out over 9,159 cycles did demonstrate the high degree of contraceptive efficacy of ‘Pregnon.’ In assessing the acceptability of an oral contraceptive both objective (cycle control, metrorrhagia) and subjective (side-effects) criteria of tolerance must be taken into account. Cycle control with ‘Pregnon’ was excellent and the incidence of metrorrhagia was low despite the low dosages of the steroids involved. Intermenstrual bleeding was usually slight and decreased as treatment progressed. The subjective tolerance to ‘Pregnon’ was also excellent, especially when it is considered that the side-effectsof oral contraceptivescannot always with certainty be attributed to the product. Aznar-Ramosl and Goldzieher2have demonstrated the importance of the placebo effect in the occurrence of gastro-intestinal complaints, headache, nervousness, decrease in libido, and, above all, weight increase (30 % of the women in the placebo group claimed a weight increase of more than 2 kg. after 4 cycles). Acknowledgements We gratefully acknowledge the assistance received from Dr. G. Albertyn, Antwerp; Dr. A. Beuselinck, Louvain; Dr. J. Callaerts, Herentals; Dr. J. Figoureux, Antwerp; Dr. P. Godts, Antwerp; Dr. E. de Muylder, Brussels and Dr. P. Servais, Huy who performed the relevant clinical trials. We would also like to thank the Statistics Department of Organon International BV for evaluating the data. References Aznar-Ramos, R., Giner-Velhzquez, J., Lara-Ricalde, R., and Martinez-Manautou, J., (1969). Incidence of side-effects with contraceptive placebo. Amer. J . Obsrer. Gynec., 105,1144. 2. 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. Steril., 22, 609. 3. Law, B., (1973). The present state of oral contraception. Med. Gynaec. Androl. Sociol., 6, (a), 5. 4. RiceWray, E., (1957). Field study with Enovid as a contraceptive agent. In: “Proceedings of a Symposium on 19-nor progestational steroids.” G. D. Searle & Co., Chicago, Illinois, pp. 78-85. 1.
156
Current Medical Research and Opinion
Vol. 3, No. 3, 1975
Clinical evaluation of a new oral contraceptive, ‘Pregnon’
and
J. van de Walle, Phar.D.,
M. J. Weijers, M.D. Medical Unit,Scientific Development Group, Organon International BY, O.w, The NetJierlands
Curr. med. Res. Opin., (1975), 3, 151.
Received: 18th March 1975
Summary ‘Pregnon’, a new oral contraceptive containing 1 mg. lynestrenol and 0.05 mg. ethinyl oestradiol, was administered cyclically to 639 women of fertile age over a total of 9,159 cycles. There were no pregnancier. In most cases the withdrawal bleeding resembled normal menstruation. The incidence of metrorrhagia was relatively low and when it did occur it was usually conjined to the early treatment cycles and was of very limited duration. The objective and subjective tolerance was excellent. Key words: Contraceptives, oral - lynestrenol - ethinyl oestradiol
Introduction The first clinical trial with oestrogen and progestagen combined for the purpose of contraception was carried out in Puerto Rico in 1956.4 Oral contraceptives came into regular clinical use in 1957 and now, less than 20 years later, they are used by more than 20 million women throughout the world.3 To minimise the various side-effects seen with the early preparations new types of oral contraceptives and different methods of administration have been introduced. Nevertheless, the combination of oestrogen and progestagen is still the most widely used form of oral contraception. Whereas the early preparations contained large amounts of oestrogen and progestagen, recent years have seen reductions, sometimes considerable, in the dosages of these steroids. However, this reduction in dosage, motivated by the wish to minimise side-effects, should never endanger efficacy. ‘Pregnon’t is a new low-dosage ovulation-inhibiting agent containing 1 mg. lynestrenol and 0.05 mg. ethinyl oestradiol in each tablet. In this multi-centre trial particular attention was paid to the following points: (i) contraceptive efficacy; (ii) cycle regularity and the frequency and intensity of any rnetrorrhagia; and (iii) the incidence and severity of side-effects. The data were collected from different Belgian clinics and evaluated by the Medical Unit of Organon in Belgium and The Netherlands. ttrade mark, Organon. Also marketed under the name of ‘Ovostat’ 28 or ‘Pregnon’ 28 in which each pack contains 22 active plus 6 placebo tablets. 151
Clinical evaluation of a new oral contraceptive, ‘Pregnon’
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/17/14 For personal use only.
Patients and treatment Patients ‘Pregnon’ was administered as a contraceptive agent to women from different parts of Belgium, within the framework of a multi-centre trial. Such trials have the advantage of providing a good cross-section of patients, which seems especially worthwhile in studies of oral contraception where subjective complaints are apt to differ in frequency and pattern of symptoms in different groups of patients. During the present trial, 639 women of fertile age were monitored during 9,159 cycles (average number of cycles per patient: 14.3). Every woman underwent clinical and gynaecological examinations before treatment and again after every 2 or 3 months. During these periodic check-ups details concerning the taking of the tablets, the occurrence of side-effects, the duration and intensity of withdrawal bleeding and the frequency and intensity of any metrorrhagia were carefully recorded on a special form so that the data could be easily transferred to a computer. Standard definitions were used to ensure uniformity in reporting. ‘Withdrawal bleeding’ was defined as bleeding which begins in the tablet-free period ; ‘spotting’ as a scanty bleeding outside the tablet-free period, not requiring any hygienic measures or, at most, one sanitary towel per day; and ‘breakthrough bleeding’ (B.T.B.) as a bleeding which is not spotting and which cannot be considered a withdrawal bleeding. The maximum duration of administration of ‘Pregnon’ was 36 consecutive cycles. The cycle distribution is recorded in Figure 1. Figure 1. Cycle distribution 640 r 600
-
500
-
400
-
5
!$ 300. i? 200-
100-
2
152
4
6
>
10
12 14 16 18 20 22 No. completed cycles
24
26
28 30
32
34 36
J. van de Walle and M. J. Weijers
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/17/14 For personal use only.
Treatment The ‘Pregnon’ pack used in this trial contained 22 tablets, each tablet consisting of 1 mg. lynestrenol and 0.05 mg. ethinyl oestradiol. Treatment was begun by taking the first tablet on the first day of menstruation and was continued for 22 days followed by a 6-day tablet-free interval during which withdrawal bleeding normally occurs.
Results Contraceptive eflcacy No pregnancy occurred during the 9,159 cycles studied in this trial. The Pearl Index was therefore zero, establishing the reliability of ‘Pregnon’ as an oral contraceptive (confidence limit =0 to 0.4). Cycle regularity Latent period: The time elapsing between the taking of the last tablet of a series and the onset of withdrawal bleeding was 2 to 4 days in 96.7 % of the cycles, less than 2 days in 2.4% of the cycles, and more than 4 days in only 0.9% of the cycles, (Figure 2). Figure 2. Time of onset of withdrawal bleeding
Number of days
Duration: The duration of the withdrawal bleeding was 3 to 5 days in 81.7% of the cycIes, (Figure 3). When compared with that prior to treatment this was shorter in 39.3 % of the cycles and longer in 2 %. I53
Clinical evaluation of a new oral contraceptive, 'Pregnon'
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/17/14 For personal use only.
Duration of withdrawal bleeding
Number o l ' d ~ y ,
Figure 4. Intensity of withdrawal bleeding 6(
5c
4C
-
@J
,.-J
," 3c 0
-. 20
10
0
154
I
J. van de Walle and M. J. Weijers
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/17/14 For personal use only.
Withdrawa1,flow: As shown in Figure 4, the intensity of the withdrawal bleeding was within the normal range in 57.3 % of the cycles, slight in 41.7% and heavy in 1 %. The influence on menstrual flow manifested itself as a decrease in 32.3% of the cycles and an increase in 5.2 % of the cycles. Metrorrhugia - amenorrhoea, (Table I). Spotting occurred in 3.1 % of the cycles. Heavier metrorrhagia, i.e. breakthrough bleeding, was observed in 2.9 % of the cycles. In 23 cases both spotting and breakthrough bleeding appeared during the same cycle (0.2 % of the cycles). Generally speaking, they occurred in the first three cycles and were of very limited duration. Amenorrhoea was observed in 2.9% of the cycles. Table I. Incidence of amenorrhoea or metrorrhagia
No. cases
YOcycles
Amenorrhoea
263
2.9
Breakthrough bleeding Spotting Breakthrough bleeding +spotting (same cycle)
264 286 23
2.9 3.1 0.2
Total incidence of metrorrhagia
573
6.2
Irregularity in bleeding ~~
~~
~~
Side-effects Table I1 shows the frequency of side-effects observed during treatment and also the decrease in or disappearance of those side-effects which had existed before treatment. No significant change in body weight was observed. Mean systolic and diastolic blood pressures before and during treatment were 124/77 mm.Hg. and 126/78 mm.Hg. respectively. Table II. Influence of ‘Pregnon’ on incidence of side-effects ~~
Side-effects
Nausea Vomiting Headache Breast tenderness ‘Heavy’ legs Leucorrhoea Nervousness Depression Libido decrease
Appearance/aggravat i on
Disappearance/decline cycles
No. cases
yocycles
No. cases
95 28 297 192 167 132 265 1 I7 67
1 0.3 3.2 2.1
135 22 25 1
0.2 2.7
101
1.1
1.8 1.4
159
1.8 2.3 2.4 I 1 .9
2.9 1.3
0.7
210
224 92 178
O/ ,O
1.5
Reasons for discontinuation of treatment Only 46 patients discontinued treatment for reasons which could be connected with the product; this represents an acceptability level of about 43 %, (Table 111). 155
Clinical evaluation of a new oral contraceptive, ‘Pregnon’
Table UI. Reasons for discontinuation of treatment
Reason
% women
No. women
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/17/14 For personal use only.
~
Metrorrhagia Nervousness Gastro-intestinal complaints Weight gain Headache Breast tenderness Fatigue Hypertension Libido decrease Rashes ‘Heavy’ legs
23
Total
46
5 4
3 3 2 2
1
~~
3.6 0.8 0.6 0.5
0.5 03 0.3
1 1
0.15 0.15 0.15
1
0.15
7.2
Discussion Assessment of the efficacy of a contraceptive agent is made on its ability to lower the birth rate to zero. Although this can only be truly estimated on the basis of many thousands of cycles, the results of this trial, carried out over 9,159 cycles did demonstrate the high degree of contraceptive efficacy of ‘Pregnon.’ In assessing the acceptability of an oral contraceptive both objective (cycle control, metrorrhagia) and subjective (side-effects) criteria of tolerance must be taken into account. Cycle control with ‘Pregnon’ was excellent and the incidence of metrorrhagia was low despite the low dosages of the steroids involved. Intermenstrual bleeding was usually slight and decreased as treatment progressed. The subjective tolerance to ‘Pregnon’ was also excellent, especially when it is considered that the side-effectsof oral contraceptivescannot always with certainty be attributed to the product. Aznar-Ramosl and Goldzieher2have demonstrated the importance of the placebo effect in the occurrence of gastro-intestinal complaints, headache, nervousness, decrease in libido, and, above all, weight increase (30 % of the women in the placebo group claimed a weight increase of more than 2 kg. after 4 cycles). Acknowledgements We gratefully acknowledge the assistance received from Dr. G. Albertyn, Antwerp; Dr. A. Beuselinck, Louvain; Dr. J. Callaerts, Herentals; Dr. J. Figoureux, Antwerp; Dr. P. Godts, Antwerp; Dr. E. de Muylder, Brussels and Dr. P. Servais, Huy who performed the relevant clinical trials. We would also like to thank the Statistics Department of Organon International BV for evaluating the data. References Aznar-Ramos, R., Giner-Velhzquez, J., Lara-Ricalde, R., and Martinez-Manautou, J., (1969). Incidence of side-effects with contraceptive placebo. Amer. J . Obsrer. Gynec., 105,1144. 2. 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. Steril., 22, 609. 3. Law, B., (1973). The present state of oral contraception. Med. Gynaec. Androl. Sociol., 6, (a), 5. 4. RiceWray, E., (1957). Field study with Enovid as a contraceptive agent. In: “Proceedings of a Symposium on 19-nor progestational steroids.” G. D. Searle & Co., Chicago, Illinois, pp. 78-85. 1.
156
