Gyriecol. Eiitfocritiol. 4 ( 1 990) 237-286
Long-term experience w oral contraceptive
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
K. Brill, J. Schnitker* and M. Albring Schevirg AG, Phavmuceiitiial Division, Medical Dept. Gevi?iuriy, 2 000 Bevliri, Gevtiiarr y ; *Imtitirte of Applied Statistics, 4800 BielCfpld, Geniiarry Abstract Oral contraception has proved to be the most efficient reversible method offertility control for over 25 years. During this period, various investigations and epidemiological studies have suggested that some risks may be involved, but, 011 the other hand, a number of noncontraceptive benefits have become obvious. The results of these investigations were taken into account when new formulations had to be developed, with an aim to improving hornional fertility control with regard to its tolerance, cycle control, and impact on metabolism. Since then, the objective of research has been to contrive new hormonal contraceptives which ensure safety to the largest possible extent, from a medical point ofview, for the sake ofthe patient, without affecting contraceptive effectiveness. The aim to reduce side-effects connected with the use of oral contraception, as well as to lower the risks possibly involved, has obviously been achieved by extensive research. Both by devising a new substance and reducing doses, the criteria of modern low-dose oral contraception have been met, as has become evident in the course of the clinical experience gathered with Fernovan@’.
Introduction Owing to its pharmacologcal properties, the new progestogen, gestodene, exerts a marked biological efficacy as compared with previous progestogens’. The dose of gestodene contained in Femovan amounts to 0.075 mg so as to fit the combination with 0.030 mg ethinylestradiol. Clinical studies have demonstrated that Femovan is well tolerated and brings about excellent cycle Correspondence to: K. Brill, Scheiing AG, Pharmaceutical Division, Medical Dept. Germany, 1000 Berlin, Germany
277
Brill, Schnitker and Albring
278
control3.".Parameters of human metabolism, including lipid and carbohydrate metabolism, blood clotting and fibrinolysis vary in the normal range'-'. The present multicenter trial was performed with a view to elucidating whether Femovan could meet the criteria of a modern oral contraceptive regarding contraceptive efficacy, tolerance and cycle control on a broad scale.
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
Patients and method The clinical assessment of Femovan was carried out by gynecologsts, both in hospitals and private practice, during the period ofDecember 1985 to February 1988. Altogether, 165 centers were involved. The clinical evaluation did not exceed 18 months. O n an average, each center evaluated 20 women. The protocol regarding inclusion and exclusion data is given in Table 1 . A total of 3267 patients were included in the trial after they had been thoroughly informed and had gven their written approval (informed consent). Of these, 1504 women (46%) starting on Femovan (pill starters) had not taken an oral contraceptive for at least the previous 3 months, whereas 1763 women (54%) were switched from other oral contraceptives to Femovan (switchers). The majority were switched from oral contraceptives containing ethinylestradiol (74%), predominantly employing a dose of more than 0.03 mg (77%). The progestogens used in these oral contraceptives were chiefly (75%) levonorgestrel, desogestrel, norethisterone and lynestrenol. Table 1 Criteria for trial inclusion or exclusion Inclusion
Exclusion
Informed consent
Pregnancy
Normal weight (Broca-Index f 10%)
Contraindications against oral contraceptives
Request for oral contraception
Less than three regular withdrawal bleeding following pregnancy o r lactation Any medication liable to interact with oral contraceptives
Standardized assessment forms were used for the documentation and evaluation ofclinical data, including undesirable side-effects. While taking Femovan, each woman had to keep a diary in which to record cycle length, strength and duration of withdrawal bleeding, as well as intermenstrual bleeding. At 3month intervals (3rd, 6th, 9th, 12th, 15th and 18th cycle), the general condition, body weight, blood pressure and cycle pattern were scrutinized. The gynecological investigation was repeated at the 6th, 12th and 18th cycle of treatment. Intermenstrual bleedings were defined according to the international nomenclature, comprising all bleeding; which occur during tablet-
Lorg-term use cf low-doje oral rontraceptive
279
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
taking, and classified either as spotting (blood loss not necessitating sanitary protection) or breakthrough bleeding. According to the study design, a descriptive statistical evaluation was carried out of the frequency distribution, minimum, maximum, mean and standard deviation.
Results The age of women involved in the trial averaged 24.7 years. Of these, 1.2%) wereagedunder 18years,25.5%from 18 to20years, 56.6%froni21 to30years, 15.6% from 31 to 35 yean, and 1.1% over 35 years. Altogether, 36771 treatment cycles were evaluated. Altogether, 2998 women took Femovan for six cycles, 1850 women for 12 cycles, and 1092 women for 18 cycles. Almost 90% of the dropouts did not return for follow-up examinations (Table 2). A total of 338 women (10.3%)discontinued treatment for intolerable side-effects such as headaches (2.4%), intermenstrual bleeding (2.7%), and weight gain (1.3%).Eight women s t o p p d a s they wished to become pregnant. Other medication was taken by 6.6% of the women, most commonly thyroid drugs. Table 2
Number of wotneti participating in the multicenter trial Drop0M ts*
Cvcle 0 3rd cycle 6th cycle 9th cycle 13th cycle 15th cycle 18th cycle
3267 (100.0%) 3226 (98.7%) 2998 (91.8%) 1934 (59.2%) 1850 (56.6%) 1157 (35.4%) 1092 (33.4%)
72 974 04 606
53 end of t r d
*women not returning for follow-up examinations
Contraceptive safety and cycle control Errors in tablet-taking were admitted by 412 womcn (12.6%). In the total course of the study, seven pregnancies were recorded altogether. Five pregnancies were due to errors in tablet-taking, two or more consecutive tablets having been omitted. Two pregnancies, however, had to be accepted as method failures. The Pearl Index of Femovan, therefore, was 0.065 for method failure and 0.16 for patient failure. Feniovan exerted a regulating effect on cycle length, especially in women with shortened, prolonged or irregular cycles (Figure 1). This cycle-regulating effect was seen particularly in women taking Femovan for the first time. Similarly, comparison of the intensity and duration of withdrawal bleeding before and during the use of Femovan confirmed the shortening effect on menstrual flow (Figure 2). Almost all women with heavy or prolonged
Brill, Sclznitker arid Albriiig
280
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
(bsisbizno3 ztuoqoib) nsrnow to o\o
Figure 1
I T
Cycle length under Feniovan
% of women (dropouts considered)
cycle 0 (control) 3rd 2 5 days
Figure 2
9th
12'h
05 4 days
Duration of withdrawal bleeding under Femovan
15th
18th cycle
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
Long-term iise of low-dose orul contruceptive
281
withdrawal bleeding (menorrhagia) experienced an irnprovenient under Femovan. However, more important than a reduction in menstrual flow was the effect on dysmenorrhea. Under Femovan, an improvement of dysmenorrhea was found in 61.9% of all affected women, which was distinct after three cycles: whereas 11.4% of all women had complained of severe pre-existing dysmenorrhea, only 1.7% still did so after three cycles of Femovan. The incidence of silent menstruation was extremely low. In 36 771 treament cycles, the rate reached onlj- 0.8%).A total of246 women (168 pill starters, 78 switchers) had silent menstruation before taking Femovan. Of these, 92.9% of the pill starters and 96.2% of the switchers had withdrawal bleeding again after the third cycle of Femovan. In the remainder, withdrawal bleeding returned to normal in the further course of treatment.
Internienstriial bleeding Intermenstrual bleeding constitutes one of the most common reasons for terminating tablet intake. Ofall the patients, 21.3% had pre-existing intermenstrual bleeding (switchers: 25.1%1,pill starters: 16.8%). Spotting and breakthrough bleeding were rare and occurred mainly during the initial cycles. Altogether, 15.9% of pill starters experienced spotting, and 8.3%) experienced breakthrough bleeding during the first three cycles. However, starting with the third cycle, the rates decreased rapidly and affected only 3.7% ofwornen during the 4 4 t h cycles (spotting: 2.1%, breakthrough bleeding: 1.6%1)(Figure 3 ) . The incidence of spotting and breakthrough bleeding was increased in cycles in which the patients had failed to take their tablets regularly. Women who had been switched from other oral contraceptives to Femovan exhibited similar rates (Figure 4), although they were slightly higher than in pill starters from the fourth cvcle onward. Body weight arzd blood pressirre The average body weight of pill starters, as well as that of switchers, remained virtually unaffected under Femovan during the total trial period (Figure 5). A comparison between body weights measured before treatment and those taken 18 months after treatment disclosed a mean difference of only 0.2 kg. Changes in body weight within the limits o f f 2 kg are generally considered to be within the physiological range. Body weights of the majority of women, i.e. 71.5%, remained within this range during 18 months of treatment. Increases as well as decreases counterbalanced each other as expressed in terms of percentage, although increases were observed primarily in women with a low initial body weight ( 7 0 kg). Mean blood pressure values did not change significantly either in pill starters or in switchers under treatment with Femovan (Figure 6). A total of 176 women had a systolic blood pressure of over 140 mmHg before starting the
Brill, Schriitkev arid Albring
282
v
% of women (dropouts considered)
j
100
80 70
60
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
50 40
30 20 10
0 cycle 1-3
cycle 4-6
0no intermenstrualbleeding Figure 3
Incidence
cycle 10-12 spotting
cycle 16 - 18 breakthrough Meeding
of intermenstrual bleeding in pill starters (no errors in tablet-
taking)
I
v 100
1
-
cycle 1-3
0no intermenstrual bleeding Figure 4 taking)
I
% of women (dropouts considered)
cycle 4-6
0spotting
1
cycle 10-12
cycle 16-18
I
breakthrough bleeding
Incidence of intermenstrual bleeding in swltchers (no errors in tablet-
-
v
*
Kg (mean SD)
80
70
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
60
50
40
I cycle 0 (control)
I
I
I
I
3rd
6th
9th
12th
pill starters
Figure 5
V
Q-
-0
I lYh
I 18Ih cycle
switchers
Mean change5 of body weight pattern under Feinovan
mmHg (mean r SD)
140 ~ - _ _ - _ _
100 -
12”
cycle 0 (control) 3d
pill starters
Figure 6
C+
15th
18th cycle
- g switchers
Mean changes of syctolic and diastolic blood preswre under Femovar
Brill, Schnitker arid Albring
284
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
regimen. In 59 of these women, the systolic blood pressure was reduced by 10-20 mmHg, and in 76 women it fell by more than 20 mmHg. In four women, the systolic blood pressure increased by 10-20 mmHg, and in one woman by more than 20mmHg. A total of 152 women had a diastolic blood pressure between 90 and 95mmHg before starting Femovan. During the use of Femovan in 102 of these women, the diastolic blood pressure was reduced by more than lOmmHg, and in 44 women by up to 10mmHg. An increase of 1-10mmHg occurred in six women. Eleven women had a pre-existing diastolic blood pressure of over 95 mmHg, but while they were on Femovan their diastolic blood pressure fell below 90 mmHg.
Tolerance The subjective complaints recorded were vomiting and nausea, vertigo, breast tension, headaches and nervousness. Symptoms that occurred for the first time under the use of Femovan were rare (Table 3 ) . Although the incidences of breast tension and headaches were somewhat higher during the first three cycles oftreatment, the rates ofthese symptoms decreased as from the fourth cycle and continued to lessen in severity during the further course of treatment. Regarding the frequency of complaints, virtually no differences between pill starters and switchers were noticed. Many women had pre-existing complaints, especiallythose who were switched from other oral contraceptives to Femovan. Altogether, these complaints were improved or disappeared in about 50-85% of these women (Table 4). Table 3
Side-effects under Femovan (%I of women)
Cycle 4-6
1-3 Breast tension Headaches Nausea Nervousness Vertigo Acne
Table 4
1G12
1618
2.3 2.0 0.9 1.1 0.8 0.6
12.2
3.0
2.5
8.8
3.9 1.1
3.9
6.9 4.4 3.3 2.0
1.8 1.5 1.1
0.8 2.1 0.9 0.8
Improvement of pre-existing side-effects under Femovan
Breast tension Headaches Nausea Nervousness Vertigo
Nuniber ofwonten affected
Disappearance follouirrg three cycles of treatnient (%)
575 513 147 453 208
66.1 62.6 81.6 47.9 70.2
Long-tern1 iise of low-dose oral contraceptive
285
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
While using Femovan, 38 women developed minor skin problems, such as a low incidence of acne, during the first three cycles. The number of women affected was reduced to 14 after 12 cycles, and even further to six after 18 cycles oftreatment. Conversely, in 377 women (11.8%),suffereing from preexisting acne, a distinct improvement or even disappearance was noticed. After three cycles, the rate of improvement or healing reached 41.4%.
Discussion A detailed record of data compiled during a trial period of up to 18 cycles allows for a comprehensive evaluation of Femovan, especially with regard to its longterm use. Contraceptive safety was in the range for low-dose oral contraceptives. The corrected Pearl Index was 0.065. The index for low-dose oral contraceptives is reported in the current literature to range between 0.03 and 0.22'. Women with unusually short, long or irregular cycles benefited especially from its cycle-regulating effect. Both the intensity (hypermenorrhea) and duration ofbleedings were reduced. Silent menstruation occurred in only 0.80/;, of the users. The incidence of intermenstrual bleeding is one of the major reasons why users discontinue a pill. The rates of spotting and breakthrough bleeding were remarkably low under Feinovan in spite of the low dose of 0.03 rng ethinylestradiol employed. The incidence of intermenstrual bleeding was highest during the first three cycles. In the further course of treatment, the spotting rate decreased to below 396, and breakthrough bleeding to under 2%. These figures are in ample agreement with the results of other investigators3.'. This finding corresponds with experience showing that the incidence of intermenstrual bleeding appears to be inversely related to the estrogen dose, as was confirmed by a special analysis ofthe data derived from the Femovan study. Women who were switched to Femovan from oral contraceptives with an ethinylestradiolcomponent in excess of0.03 mg exhibited moderately elevated intermenstrual bleeding, as compared with women who had taken oral contraceptives not exceeding this dose. This minor difference, however, should not detract from the fact that Femovan was able, during the first three cycles, to normalize the cycle in 71.7% of those switchers who had previously had intermenstrual bleeding. Presumably, the strong biologcal efficacy of gestodene accounts for the excellent cycle control4. The influence of Femovan on body weight was negligible. A mean increase of about 0.2 kg was recorded. Increases were mainly seen in women with an initially low body weight, whereas decreases were observed more frequently in women starting with an elevated body weight. In contrast to large-scale investigations (13358 women)"' employing conventional (high-dose) oral contraceptives to a vast extent (up to 50%) in women over 35 years of age, Femovan had virtually no effect on blood pressure in this study. Evidently, only minor deviations from mean values of systolic and
286
Brill, Sclznitker and Albring
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
diastolic blood pressure were recorded under the regimen as compared to untreated cycles. Headaches, including migraine-like symptoms, nervousness and breast tension lessened in severity and had a very low incidence after the initial cycles. Women who suffered from pre-existing subjective complaints benefited especially from the distinct improvement provided by Femovan.
References 1. Hammerstein, J. (1987). Contraception: an overview. A m . J . Obstet. Gynecol., 157, 1020-32 2. Elger, W., Steinbeck, H., Schillinger, E. et al. (1986). Endocrine-pharmacological profile of gestodene. A d v . Contra. Delv. Syst., 2, 183-97 3. Hoppe, G. (1988). Gestoden, an innovative progestogen. Contraception, 37, 493-501 4. Mall-Haefeli, M. (1988).Biochemische und klinische Resultate mit einem gestodenhaltigen Ovulationshemmer. gyne, 9, 144-9 5. Rabe, T., Runnebaum, B., Kohlmeier, M. et al. (1987). Clinical and metabolic effects of gestodene and levonorgestrel. Znt. J . Fertil., Suppl., 29-44 6. Fioretti, P., Fruzzetti, F., Navalesi, R. et al. (1989). Clinical and metabolic effects of a pill containing 30 pg ethinylestradiol plus 75 pg gestodene. Contraception, 40, 649-63 7. Robinson, G. E., Bounds, W., Mackie, I. J. et al. (1990). Changes in metabolism induced by oral contraceptives containing desogestrel and gestodene in older women. Contraception, 42, 263-73 8. Marz, W., Jung-Hoffmann, C., Heidt, F. et al. (1990). Changes in lipid metabolism during 12 months of treatment with two oral contraceptives containing 30 pg ethinylestradioland 75 pg gestodene or 150 pg desogestrel. Contraception, 41, 245-58 9. Vessey, M. P., Lawless, M. and Yeates, D. (1982). Efficacy of different contraceptive methods. Lancet, 1, 841-2 10. Fisch, I. R. and Frank, J. (1977). Oral contraceptives and blood pressure. J . A m . Med. Assoc., 237, 2499-503
Long-term experience w oral contraceptive
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
K. Brill, J. Schnitker* and M. Albring Schevirg AG, Phavmuceiitiial Division, Medical Dept. Gevi?iuriy, 2 000 Bevliri, Gevtiiarr y ; *Imtitirte of Applied Statistics, 4800 BielCfpld, Geniiarry Abstract Oral contraception has proved to be the most efficient reversible method offertility control for over 25 years. During this period, various investigations and epidemiological studies have suggested that some risks may be involved, but, 011 the other hand, a number of noncontraceptive benefits have become obvious. The results of these investigations were taken into account when new formulations had to be developed, with an aim to improving hornional fertility control with regard to its tolerance, cycle control, and impact on metabolism. Since then, the objective of research has been to contrive new hormonal contraceptives which ensure safety to the largest possible extent, from a medical point ofview, for the sake ofthe patient, without affecting contraceptive effectiveness. The aim to reduce side-effects connected with the use of oral contraception, as well as to lower the risks possibly involved, has obviously been achieved by extensive research. Both by devising a new substance and reducing doses, the criteria of modern low-dose oral contraception have been met, as has become evident in the course of the clinical experience gathered with Fernovan@’.
Introduction Owing to its pharmacologcal properties, the new progestogen, gestodene, exerts a marked biological efficacy as compared with previous progestogens’. The dose of gestodene contained in Femovan amounts to 0.075 mg so as to fit the combination with 0.030 mg ethinylestradiol. Clinical studies have demonstrated that Femovan is well tolerated and brings about excellent cycle Correspondence to: K. Brill, Scheiing AG, Pharmaceutical Division, Medical Dept. Germany, 1000 Berlin, Germany
277
Brill, Schnitker and Albring
278
control3.".Parameters of human metabolism, including lipid and carbohydrate metabolism, blood clotting and fibrinolysis vary in the normal range'-'. The present multicenter trial was performed with a view to elucidating whether Femovan could meet the criteria of a modern oral contraceptive regarding contraceptive efficacy, tolerance and cycle control on a broad scale.
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
Patients and method The clinical assessment of Femovan was carried out by gynecologsts, both in hospitals and private practice, during the period ofDecember 1985 to February 1988. Altogether, 165 centers were involved. The clinical evaluation did not exceed 18 months. O n an average, each center evaluated 20 women. The protocol regarding inclusion and exclusion data is given in Table 1 . A total of 3267 patients were included in the trial after they had been thoroughly informed and had gven their written approval (informed consent). Of these, 1504 women (46%) starting on Femovan (pill starters) had not taken an oral contraceptive for at least the previous 3 months, whereas 1763 women (54%) were switched from other oral contraceptives to Femovan (switchers). The majority were switched from oral contraceptives containing ethinylestradiol (74%), predominantly employing a dose of more than 0.03 mg (77%). The progestogens used in these oral contraceptives were chiefly (75%) levonorgestrel, desogestrel, norethisterone and lynestrenol. Table 1 Criteria for trial inclusion or exclusion Inclusion
Exclusion
Informed consent
Pregnancy
Normal weight (Broca-Index f 10%)
Contraindications against oral contraceptives
Request for oral contraception
Less than three regular withdrawal bleeding following pregnancy o r lactation Any medication liable to interact with oral contraceptives
Standardized assessment forms were used for the documentation and evaluation ofclinical data, including undesirable side-effects. While taking Femovan, each woman had to keep a diary in which to record cycle length, strength and duration of withdrawal bleeding, as well as intermenstrual bleeding. At 3month intervals (3rd, 6th, 9th, 12th, 15th and 18th cycle), the general condition, body weight, blood pressure and cycle pattern were scrutinized. The gynecological investigation was repeated at the 6th, 12th and 18th cycle of treatment. Intermenstrual bleedings were defined according to the international nomenclature, comprising all bleeding; which occur during tablet-
Lorg-term use cf low-doje oral rontraceptive
279
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
taking, and classified either as spotting (blood loss not necessitating sanitary protection) or breakthrough bleeding. According to the study design, a descriptive statistical evaluation was carried out of the frequency distribution, minimum, maximum, mean and standard deviation.
Results The age of women involved in the trial averaged 24.7 years. Of these, 1.2%) wereagedunder 18years,25.5%from 18 to20years, 56.6%froni21 to30years, 15.6% from 31 to 35 yean, and 1.1% over 35 years. Altogether, 36771 treatment cycles were evaluated. Altogether, 2998 women took Femovan for six cycles, 1850 women for 12 cycles, and 1092 women for 18 cycles. Almost 90% of the dropouts did not return for follow-up examinations (Table 2). A total of 338 women (10.3%)discontinued treatment for intolerable side-effects such as headaches (2.4%), intermenstrual bleeding (2.7%), and weight gain (1.3%).Eight women s t o p p d a s they wished to become pregnant. Other medication was taken by 6.6% of the women, most commonly thyroid drugs. Table 2
Number of wotneti participating in the multicenter trial Drop0M ts*
Cvcle 0 3rd cycle 6th cycle 9th cycle 13th cycle 15th cycle 18th cycle
3267 (100.0%) 3226 (98.7%) 2998 (91.8%) 1934 (59.2%) 1850 (56.6%) 1157 (35.4%) 1092 (33.4%)
72 974 04 606
53 end of t r d
*women not returning for follow-up examinations
Contraceptive safety and cycle control Errors in tablet-taking were admitted by 412 womcn (12.6%). In the total course of the study, seven pregnancies were recorded altogether. Five pregnancies were due to errors in tablet-taking, two or more consecutive tablets having been omitted. Two pregnancies, however, had to be accepted as method failures. The Pearl Index of Femovan, therefore, was 0.065 for method failure and 0.16 for patient failure. Feniovan exerted a regulating effect on cycle length, especially in women with shortened, prolonged or irregular cycles (Figure 1). This cycle-regulating effect was seen particularly in women taking Femovan for the first time. Similarly, comparison of the intensity and duration of withdrawal bleeding before and during the use of Femovan confirmed the shortening effect on menstrual flow (Figure 2). Almost all women with heavy or prolonged
Brill, Sclznitker arid Albriiig
280
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
(bsisbizno3 ztuoqoib) nsrnow to o\o
Figure 1
I T
Cycle length under Feniovan
% of women (dropouts considered)
cycle 0 (control) 3rd 2 5 days
Figure 2
9th
12'h
05 4 days
Duration of withdrawal bleeding under Femovan
15th
18th cycle
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
Long-term iise of low-dose orul contruceptive
281
withdrawal bleeding (menorrhagia) experienced an irnprovenient under Femovan. However, more important than a reduction in menstrual flow was the effect on dysmenorrhea. Under Femovan, an improvement of dysmenorrhea was found in 61.9% of all affected women, which was distinct after three cycles: whereas 11.4% of all women had complained of severe pre-existing dysmenorrhea, only 1.7% still did so after three cycles of Femovan. The incidence of silent menstruation was extremely low. In 36 771 treament cycles, the rate reached onlj- 0.8%).A total of246 women (168 pill starters, 78 switchers) had silent menstruation before taking Femovan. Of these, 92.9% of the pill starters and 96.2% of the switchers had withdrawal bleeding again after the third cycle of Femovan. In the remainder, withdrawal bleeding returned to normal in the further course of treatment.
Internienstriial bleeding Intermenstrual bleeding constitutes one of the most common reasons for terminating tablet intake. Ofall the patients, 21.3% had pre-existing intermenstrual bleeding (switchers: 25.1%1,pill starters: 16.8%). Spotting and breakthrough bleeding were rare and occurred mainly during the initial cycles. Altogether, 15.9% of pill starters experienced spotting, and 8.3%) experienced breakthrough bleeding during the first three cycles. However, starting with the third cycle, the rates decreased rapidly and affected only 3.7% ofwornen during the 4 4 t h cycles (spotting: 2.1%, breakthrough bleeding: 1.6%1)(Figure 3 ) . The incidence of spotting and breakthrough bleeding was increased in cycles in which the patients had failed to take their tablets regularly. Women who had been switched from other oral contraceptives to Femovan exhibited similar rates (Figure 4), although they were slightly higher than in pill starters from the fourth cvcle onward. Body weight arzd blood pressirre The average body weight of pill starters, as well as that of switchers, remained virtually unaffected under Femovan during the total trial period (Figure 5). A comparison between body weights measured before treatment and those taken 18 months after treatment disclosed a mean difference of only 0.2 kg. Changes in body weight within the limits o f f 2 kg are generally considered to be within the physiological range. Body weights of the majority of women, i.e. 71.5%, remained within this range during 18 months of treatment. Increases as well as decreases counterbalanced each other as expressed in terms of percentage, although increases were observed primarily in women with a low initial body weight ( 7 0 kg). Mean blood pressure values did not change significantly either in pill starters or in switchers under treatment with Femovan (Figure 6). A total of 176 women had a systolic blood pressure of over 140 mmHg before starting the
Brill, Schriitkev arid Albring
282
v
% of women (dropouts considered)
j
100
80 70
60
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
50 40
30 20 10
0 cycle 1-3
cycle 4-6
0no intermenstrualbleeding Figure 3
Incidence
cycle 10-12 spotting
cycle 16 - 18 breakthrough Meeding
of intermenstrual bleeding in pill starters (no errors in tablet-
taking)
I
v 100
1
-
cycle 1-3
0no intermenstrual bleeding Figure 4 taking)
I
% of women (dropouts considered)
cycle 4-6
0spotting
1
cycle 10-12
cycle 16-18
I
breakthrough bleeding
Incidence of intermenstrual bleeding in swltchers (no errors in tablet-
-
v
*
Kg (mean SD)
80
70
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
60
50
40
I cycle 0 (control)
I
I
I
I
3rd
6th
9th
12th
pill starters
Figure 5
V
Q-
-0
I lYh
I 18Ih cycle
switchers
Mean change5 of body weight pattern under Feinovan
mmHg (mean r SD)
140 ~ - _ _ - _ _
100 -
12”
cycle 0 (control) 3d
pill starters
Figure 6
C+
15th
18th cycle
- g switchers
Mean changes of syctolic and diastolic blood preswre under Femovar
Brill, Schnitker arid Albring
284
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
regimen. In 59 of these women, the systolic blood pressure was reduced by 10-20 mmHg, and in 76 women it fell by more than 20 mmHg. In four women, the systolic blood pressure increased by 10-20 mmHg, and in one woman by more than 20mmHg. A total of 152 women had a diastolic blood pressure between 90 and 95mmHg before starting Femovan. During the use of Femovan in 102 of these women, the diastolic blood pressure was reduced by more than lOmmHg, and in 44 women by up to 10mmHg. An increase of 1-10mmHg occurred in six women. Eleven women had a pre-existing diastolic blood pressure of over 95 mmHg, but while they were on Femovan their diastolic blood pressure fell below 90 mmHg.
Tolerance The subjective complaints recorded were vomiting and nausea, vertigo, breast tension, headaches and nervousness. Symptoms that occurred for the first time under the use of Femovan were rare (Table 3 ) . Although the incidences of breast tension and headaches were somewhat higher during the first three cycles oftreatment, the rates ofthese symptoms decreased as from the fourth cycle and continued to lessen in severity during the further course of treatment. Regarding the frequency of complaints, virtually no differences between pill starters and switchers were noticed. Many women had pre-existing complaints, especiallythose who were switched from other oral contraceptives to Femovan. Altogether, these complaints were improved or disappeared in about 50-85% of these women (Table 4). Table 3
Side-effects under Femovan (%I of women)
Cycle 4-6
1-3 Breast tension Headaches Nausea Nervousness Vertigo Acne
Table 4
1G12
1618
2.3 2.0 0.9 1.1 0.8 0.6
12.2
3.0
2.5
8.8
3.9 1.1
3.9
6.9 4.4 3.3 2.0
1.8 1.5 1.1
0.8 2.1 0.9 0.8
Improvement of pre-existing side-effects under Femovan
Breast tension Headaches Nausea Nervousness Vertigo
Nuniber ofwonten affected
Disappearance follouirrg three cycles of treatnient (%)
575 513 147 453 208
66.1 62.6 81.6 47.9 70.2
Long-tern1 iise of low-dose oral contraceptive
285
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
While using Femovan, 38 women developed minor skin problems, such as a low incidence of acne, during the first three cycles. The number of women affected was reduced to 14 after 12 cycles, and even further to six after 18 cycles oftreatment. Conversely, in 377 women (11.8%),suffereing from preexisting acne, a distinct improvement or even disappearance was noticed. After three cycles, the rate of improvement or healing reached 41.4%.
Discussion A detailed record of data compiled during a trial period of up to 18 cycles allows for a comprehensive evaluation of Femovan, especially with regard to its longterm use. Contraceptive safety was in the range for low-dose oral contraceptives. The corrected Pearl Index was 0.065. The index for low-dose oral contraceptives is reported in the current literature to range between 0.03 and 0.22'. Women with unusually short, long or irregular cycles benefited especially from its cycle-regulating effect. Both the intensity (hypermenorrhea) and duration ofbleedings were reduced. Silent menstruation occurred in only 0.80/;, of the users. The incidence of intermenstrual bleeding is one of the major reasons why users discontinue a pill. The rates of spotting and breakthrough bleeding were remarkably low under Feinovan in spite of the low dose of 0.03 rng ethinylestradiol employed. The incidence of intermenstrual bleeding was highest during the first three cycles. In the further course of treatment, the spotting rate decreased to below 396, and breakthrough bleeding to under 2%. These figures are in ample agreement with the results of other investigators3.'. This finding corresponds with experience showing that the incidence of intermenstrual bleeding appears to be inversely related to the estrogen dose, as was confirmed by a special analysis ofthe data derived from the Femovan study. Women who were switched to Femovan from oral contraceptives with an ethinylestradiolcomponent in excess of0.03 mg exhibited moderately elevated intermenstrual bleeding, as compared with women who had taken oral contraceptives not exceeding this dose. This minor difference, however, should not detract from the fact that Femovan was able, during the first three cycles, to normalize the cycle in 71.7% of those switchers who had previously had intermenstrual bleeding. Presumably, the strong biologcal efficacy of gestodene accounts for the excellent cycle control4. The influence of Femovan on body weight was negligible. A mean increase of about 0.2 kg was recorded. Increases were mainly seen in women with an initially low body weight, whereas decreases were observed more frequently in women starting with an elevated body weight. In contrast to large-scale investigations (13358 women)"' employing conventional (high-dose) oral contraceptives to a vast extent (up to 50%) in women over 35 years of age, Femovan had virtually no effect on blood pressure in this study. Evidently, only minor deviations from mean values of systolic and
286
Brill, Sclznitker and Albring
Gynecol Endocrinol Downloaded from informahealthcare.com by AUT Auckland University of Technology on 11/09/14 For personal use only.
diastolic blood pressure were recorded under the regimen as compared to untreated cycles. Headaches, including migraine-like symptoms, nervousness and breast tension lessened in severity and had a very low incidence after the initial cycles. Women who suffered from pre-existing subjective complaints benefited especially from the distinct improvement provided by Femovan.
References 1. Hammerstein, J. (1987). Contraception: an overview. A m . J . Obstet. Gynecol., 157, 1020-32 2. Elger, W., Steinbeck, H., Schillinger, E. et al. (1986). Endocrine-pharmacological profile of gestodene. A d v . Contra. Delv. Syst., 2, 183-97 3. Hoppe, G. (1988). Gestoden, an innovative progestogen. Contraception, 37, 493-501 4. Mall-Haefeli, M. (1988).Biochemische und klinische Resultate mit einem gestodenhaltigen Ovulationshemmer. gyne, 9, 144-9 5. Rabe, T., Runnebaum, B., Kohlmeier, M. et al. (1987). Clinical and metabolic effects of gestodene and levonorgestrel. Znt. J . Fertil., Suppl., 29-44 6. Fioretti, P., Fruzzetti, F., Navalesi, R. et al. (1989). Clinical and metabolic effects of a pill containing 30 pg ethinylestradiol plus 75 pg gestodene. Contraception, 40, 649-63 7. Robinson, G. E., Bounds, W., Mackie, I. J. et al. (1990). Changes in metabolism induced by oral contraceptives containing desogestrel and gestodene in older women. Contraception, 42, 263-73 8. Marz, W., Jung-Hoffmann, C., Heidt, F. et al. (1990). Changes in lipid metabolism during 12 months of treatment with two oral contraceptives containing 30 pg ethinylestradioland 75 pg gestodene or 150 pg desogestrel. Contraception, 41, 245-58 9. Vessey, M. P., Lawless, M. and Yeates, D. (1982). Efficacy of different contraceptive methods. Lancet, 1, 841-2 10. Fisch, I. R. and Frank, J. (1977). Oral contraceptives and blood pressure. J . A m . Med. Assoc., 237, 2499-503
