Once-a-month injectable contraceptives, cyclofem® and mesigyna®, in Egypt

ORIGINAL RESEARCH ARTICLE

Once-A-Month Injectable Contraceptives, Cyclofem威 and Mesigyna威, in Egypt Efficacy, Causes of Discontinuation, and Side Effects E.O. Hassan,*† N. El-Nahal,† and M. El-Hussinie‡ A clinical trial of the two once-a-month injectable contraceptives, Cyclofem威 and Mesigyna威, used for 1 year was carried out in Egypt involving a total of 2252 women living in different Egyptian localities, representing urban/rural and Upper/Lower Egyptian populations. Women were randomly assigned to either one of the two study preparations and followed a standard protocol for a comparative assessment of the efficacy, side effects, and acceptability of the two preparations. Both contraceptives proved to be highly acceptable, with continuation rates of 63.2 per 100 women-years for Cyclofem and 61.6 for Mesigyna at the end of 12 months of use. The cumulative discontinuation rates per 100 womenyears for method failure were 0.19 for Cyclofem users and 0.41 for Mesigyna users. Menstrual problems were the most frequently reported side effects in both groups. Discontinuation rates because of amenorrhea were 2.74 in the Cyclofem group compared to 1.38 in the Mesigyna group, whereas the rates of discontinuation because bleeding problems were significantly higher among Mesigyna users (11.54) compared to the Cyclofem group (7.39). There was no significant difference between the two groups regarding the discontinuation rates from other medical and personal causes. There were insignificant changes in the systolic and diastolic blood pressure values recorded at follow-up; only one Cyclofem user developed systemic hypertension (160/100 mm Hg) after 6 months of use and was discontinued for that reason. On the other hand, a constant weight gain averaging 0.33 kg/month was observed in both groups; however, weight gain was not considered a major cause of method discontinuation. CONTRACEPTION 1999; 60:87–92 © 1999 Elsevier Science Inc. All rights reserved.

*Department of Obstetrics and Gynecology, Mansoura University; †The Egyptian Fertility Care Society, Cairo, Egypt; and ‡Department of Community Medicine, Ein-Shams University Name and address for correspondence: Prof. Ezzeldin Osman Hassan, M.D., Egyptian Fertility Care Society, PO Box 126 Orman, Giza, Cairo, Egypt; Tel.: (202) 3470674; Fax: (202) 3468786 Submitted for publication February 1, 1999 Revised September 7, 1999 Accepted for publication September 8, 1999

© 1999 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

KEY WORDS:

Cyclofem, Mesigyna, efficacy, side effects, discontinuation

Introduction

M

onthly injectable contraceptives date back to the early 1960s when researchers began to look for a long-acting hormonal contraceptive as a means to substitute the combined estrogenprogestagen pills that have compliance problems, specifically, those resulting from irregular pill intake. The first report on these attempts was published in 19631 using 17-␣-hydroxyprogesterone in a dose of 500 mg given every 4 weeks. The compound inhibited ovulation but resulted in irregular and frequent bleeding problems. These side effects disappeared after the addition of 10 mg estradiol valerate. Since then, many preparations have been tested and used in many parts of the world.2 Two new preparations, namely, Cyclofem威 and Mesigyna威, have been developed by the Special Programme of Research in Human Reproduction (HRP) of the World Health Organization. Both preparations were tested in large multicenter clinical trials, proved effective and had relatively low incidence of side effects.3,4 The present article documents the results of a phase III comparative clinical trial of the two monthly injectable contraceptives, Cyclofem and Mesigyna, carried out in Egypt. Some of these results were reported and compared to selected WHO studies in published reviews.2,5

Subjects and Methods The study was designed as a randomized comparative clinical trial of the two once-a-month injectable contraceptives, Cyclofem and Mesigyna. The main objectives were to assess the efficacy and related side effects of these two preparations over a period of 1 year of use by Egyptian women. Cyclofem, also known as Cyclo-Provera or HRP112, consists of 25 mg depot-medroxyprogesterISSN 0010-7824/99/$20.00 PII S0010-7824(99)00064-5

88

Hassan et al.

one acetate and 5 mg estradiol cypionate in a form of microcrystalline suspension in 0.5 mL of aqueous solution that should be shaken well before injection. The preparation is manufactured by Upjohn Company, Mexico City, Mexico. Mesigyna, previously known as HRP102, consists of 50 mg norethisterone enanthate and 5 mg estradiol valerate in 1 mL of an oily solution, made of caster oil and benzyl benzoate in the ratio of 6:4, that should be slightly warmed before injection. The preparation is manufactured by Schering AG Company, Berlin, Germany. Both preparations should be given by deep intramuscular injection. The first injection is given during the first 5 days from the onset of normal menstruation or before week 6 postpartum for women who are not going to breastfeed their babies. The second and subsequent injections should be given at 27–33 days from the previous injection. Women who returned after 33 days after injection were terminated from the study and were included in the group “late for follow-up.” They were offered either contraceptive method. With the assumption that 50% of the recruited injectable contraceptive users will continue use of the assigned preparation at the end of the study period (12 months), and that a maximum difference of 5% in the cumulative discontinuation rate is of interest to detect, a sample size of at least 1000 women per group was deemed necessary for recruitment into the study (one-sided test, ␣ ⫽ 0.10 and power of 0.80). Criteria for subject selection Normal healthy women aged 20 –35 years, of proved fertility (had at least two children) and still menstruating at the date of admission were recruited into the study. Selected women were not pregnant nor lactating, and had regular menstrual cycles for ⱖ6 months before study admission. Both postpartum and postabortion women were to have experienced at least six regular menstrual cycles before their pregnancy and had at least one normal cycle after delivery and before admission to the study. Contraindications to study participation included: diabetes mellitus (diagnosed or being at risk), Papanicolaou smear of grade III or more, history of thromboembolism, cerebrovascular disorders, or incapacitating migraine, vaginal bleeding of unknown etiology, confirmed hypertension (systolic blood pressure ⬎140 mm Hg or diastolic blood pressure ⬎90 mm Hg), recent or severe liver disease, known or suspected malignancy, or nipple discharge. The women were not to be receiving barbiturates, anticonvulsants, rifampicin, systemic steroids, any drug affecting the cardiovascular system or liver, or any drug used for long-term prophylaxis. The women were not to have

Contraception 1999;60:87–92

received DMPA in the 6 months nor NET-EN in the 4 months before study admission. Recruitment and investigations The study was conducted in 11 University Hospitals and one Ministry of Health Teaching Hospital. This study design ensured the inclusion of different sociodemographic subgroups as well as varying service delivery settings. In the cycle before admission, potential candidates underwent a screening interview and a cervical cytology examination to ascertain appropriateness for recruitment into the study. Consent for voluntary participation in the study covered women’s agreement to rely solely on the study treatment as the method for fertility control and their right to regular services in case they decided to stop use of the study method after admission. Full general physical and gynecological examinations were done at admission, at months 3, 6, and 9 of follow-up, as well as at termination of method use, either because of the end of the study (ie, after month 12 or on discontinuation for any reason). At each follow-up visit, the participant was asked for any complaint and any treatment for controlling vaginal bleeding was recorded. Every effort was made to reassure the participants about the side effects, but they were free to discontinue at any time. Cervical cytology was also done at the time of termination of the woman from the study. Recruited women were requested to record information on menstrual cycles using the standard World Health Organization Menstrual Diary Cards, which were later collected on a monthly basis. Recruited women were randomly allocated to one of the two injectables within blocks, each of eight women, using a simple computer program generating random numbers. The study extended from November 1, 1989, until July 31, 1992. Recruitment took ⱖ1.5 years. Statistical procedures The cumulative discontinuation rates, for each cause and for either preparation, were computed using the life table techniques as documented by Farley.6 Logrank test and ␹2 with 1 degree of freedom were used to compare the cumulative discontinuation rates beTable 1. Recruited cases in each group Preparation Cyclofem Mesigyna Total

Recruited cases

Valid cases

Women-years

1137 1115 2252

1111 1093 2204

874 836 1710

Contraception 1999;60:87–92

Table 2. Percentages of follow-ups and other forms for recruited cases Form

89

Monthly Injectable Contraceptives, Cyclofem and Mesigyna

extended from the date of first injection until the estimated date of conception. Comparison between the two groups regarding characteristics at admission and follow-up visits were done using the two independent samples t test and ␹2 test when appropriate. Comparing the changes in the weight, Quetelet index (QI), and systolic and diastolic blood pressure within the same group was done using the paired t test.

% of recruited

Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 9 Cycle 10 Cycle 11 Cycle 12 Discontinuation Unscheduled visit Menstrual diary form

94.1 89.5 85.0 80.3 77.7 75.3 72.2 69.6 67.3 65.1 63.2 62.3 100.0 9.4 96.0

Results The number of participants is illustrated in Table 1. There were 1137 cases recruited for Cyclofem and 1115 women for Mesigyna. A total of 84 cases were excluded because of protocol violation; 2204 cases were analyzed, 1111 for Cyclofem and 1093 for Mesigyna. Women used the two compounds for a total of 1710 women-years, 874 for Cyclofem and 836 for Mesigna. The percentage of follow-ups at different visits decreased to 62.3% at 12 months (Table 2). Discontinuation forms were completed to all participating women; 9.4% of participants presented for unscheduled visits and menstrual diary forms were collected from 96% of cases. The two groups were comparable in all aspects except for weight and QI (Table 3). The Mesigyna group had significantly higher weight (66.9 kg) and QI (26.8) than the Cyclofem group, 65.6 and 26.3, respec-

tween the two groups. The LTA program (version 2.0) provided by HRP/WHO7 was used in that analysis. The duration of protection was calculated using the following conventions: for a woman who terminated and was seen after her last injection, the duration of use extended from the first injection to 33 days after the date of last injection, but if the woman was not seen (those lost and not located), the duration extended from the first injection to the date of last injection. For cases of method failure, the duration Table 3. Comparison between the two groups at admission Cyclofem (N ⴝ 1111) Characteristic Age, years Weight, kg* Height, cm Quetelet index* Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Days from discontinuation of last contraceptive method† Days from first day of LMP Last contraceptive used Pills IUD Injectable Other None Abortion within last 6 months Cervical cytology Grade I Grade II

Mesigyna (N ⴝ 1093)

Total (N ⴝ 2204)

Mean

SD

Mean

SD

Mean

SD

28.9 65.6 158.0 26.3 113.8 73.6 50.9 (N ⫽ 874) 2.9 N

3.7 13.0 6.0 5.3 9.1 7.0

29.2 66.9 158.2 26.8 113.9 73.6 60.5 (N ⫽ 858) 2.8 N

3.7 13.0 6.0 5.5 9.2 6.8

29.0 66.3 158.1 26.6 113.8 73.6

3.7 13.0 6.0 5.4 9.2 6.9

200.0 2.1 %

55.6 2.9 N

189.1 1.9 %

177.8 1.7 %

566 242 44 29 230 46

50.9 21.8 4.0 2.6 20.7 4.1

550 239 39 33 232 47

50.3 21.9 3.6 3.0 21.2 4.3

1116 481 83 62 462 93

50.6 21.8 3.8 2.8 21.0 4.2

1022 89

92.0 8.0

1023 70

93.6 6.4

2045 159

92.8 7.2

*p ⬍0.05 †N-cases including all women who were using another method.

90

Hassan et al.

Contraception 1999;60:87–92

Table 4. Comparison between the continuers and discontinuers in both groups Cyclofem continuers (N ⴝ 691)

Cyclofem discontinuers (N ⴝ 409)

Mesigyna continuers (N ⴝ 673)

Mesigyna discontinuers (N ⴝ 420)

Characteristic

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Age, years* Weight, kg Height, cm Quetelet index

29.1 65.5 157.9 26.3

3.7 13.0 6.2 5.2

28.5 65.8 158.2 26.3

3.8 13.0 5.6 5.4

29.5 67.3 158.1 27.0

3.5 13.5 5.9 5.6

28.6 66.3 158.2 26.5

3.8 12.3 6.1 5.2

*p ⬍0.001.

tively. However, when women were categorized into nonobese (QI ⬍ 25) and obese (Q1 ⫽ 25 or more), it was found that 54.5% in the Cyclofem group compared to 55.9% in the Mesigyna group were classified as obese, the difference being statistically insignificant. There was some center-to-center variations, eg, women from Assiut center had significantly lower weight compared to women from other centers. There were minimal differences between continuers and discontinuers regarding mean height, weight, and QI. However, the difference in age is statistically significant, indicating that discontinuation was more common among younger women (Table 4). Menstrual changes (amenorrhea or bleeding problems) were the leading complaint among users, followed by nervous symptoms (headache, migraine, dizziness), the difference between the two groups being statistically insignificant (Table 5). Amenorrhea was reported by ⬍4% of women and did not change significantly by duration of use. As a whole, there were fewer complaints of ammenorrhea among Mesigyna users compared to those using Cyclofem. On the other hand, spotting was reported by about 1% in the first cycle and diminished gradually so that, after month 7, nearly no woman complained of spotting. About 3% of women complained of bleeding in nearly all cycles and the figure did not change with the duration of use. Between 1% and 1.5% of women complained of headache, and approximately 0.5% complained of dizziness. Both groups show a progressive, steady, highly significant increase in weight and QI and the difference between the two groups was

statistically insignificant. Minimal, nonsignificant changes took place in the blood pressure over the observation period. Discontinuation rates per 100 women-years calculated on a monthly basis are presented in Table 6. At the end of 1 year, the discontinuation rate for all reasons was 38.94 for Cyclofem and 37.98 for Mesigyna, the difference is not statistically significant. The discontinuation rate for amenorrhea after that period was 2.74 for Cyclofem and 1.38 for Mesigyna. Although more women discontinued for amenorrhea in the Cyclofem group, the difference is not statistically significant. On the other hand, discontinuation for bleeding problems after 12 months was 7.39 for Cyclofem and 11.45 for Mesigyna; the difference is statistically significant. On the whole, discontinuation for menstrual disruption was significantly more with Mesigyna than with Cyclofem being 12.77 and 9.92, respectively. Discontinuation for all medical reasons was nearly the same for Cyclofem and Mesigyna (16.94 and 16.90, respectively); however, the difference is statistically significant due to the relatively small standard error of the estimates. There was center-to-center variations in the reasons for discontinuation. Two cases in the Cyclofem group and four cases in the Mesigyna group discontinued due to method failure and the occurrence of pregnancy (representing method failure rates of 0.19 and 0.41 per 100 women-years, respectively); however, the difference is not statistically significant. It was possible to follow five of the six pregnancies until delivery of normal babies.

Table 5. Frequency of complaints among participating women during 12 months

Discussion

Cyclofem

Mesigyna

System

No.

%

No.

%

Menstrual changes Nervous Musculoskeletal Other

627 133 21 35

76.8 16.3 2.6 4.3

502 157 38 52

67.0 21.0 5.1 6.9

The present randomized comparative clinical trial included 20,525 women-months of experience, 10,492 in the Cyclofem group and 10,033 in the Mesigyna group, among Egyptian women in 12 centers. This was part of a multinational phase III comparative study supported by the World Health Organization in 13 countries to evaluate the efficacy and side effects of these two once-a-month preparations.3,4

Contraception 1999;60:87–92

Monthly Injectable Contraceptives, Cyclofem and Mesigyna

91

Table 6. Life table discontinuation rates per 100 women-years by cause in the two groups Cyclofem Reason Pregnancy Amenorrhea* Heavy bleeding Prolonged bleeding Heavy and prolonged bleeding† Irregular bleeding Spotting Other bleeding problems All bleeding problems† Other medical reasons All medical reasons‡ Desire for pregnancy No further need Other personal reasons All personal reasons Method switching Missed injection Late for follow-up Lost, not located All other reasons All reasons together

Mesigyna

N

Rate

SE

N

Rate

SE

2 24 11 14 21 14 4 3 67 37 128 17 37 61 115 7 5 101 51 164 409

0.19 2.74 1.26 1.48 2.46 1.60 0.43 0.38 7.39 7.79 16.94 1.87 4.25 6.79 12.42 0.79 0.60 11.08 4.10 15.91 38.94

0.13 0.55 0.38 0.40 0.53 0.43 0.21 0.22 0.88 3.82 3.56 0.45 0.69 0.91 1.14 0.30 0.27 1.06 0.66 1.21 2.87

4 12 18 17 40 22 8 1 106 41 159 23 28 66 117 7 3 94 36 140 420

0.41 1.38 1.92 1.98 4.70 2.40 0.97 0.11 11.54 4.72 16.90 2.86 3.19 7.17 12.79 0.81 0.31 10.67 2.71 14.04 37.98

0.20 0.40 0.45 0.48 0.73 0.51 0.34 0.11 1.06 0.72 1.23 0.60 0.60 0.86 1.12 0.31 0.18 1.07 0.56 1.19 1.49

*p ⬍0.10 †p ⬍0.01 ‡p ⬍0.05

Table 7 compares the results of this study conducted by the Egyptian Fertility Care Society (EFCS) with results of the WHO multinational study that involved 2320 women and a Chinese study8 that involved 1000 women for 12 months. As a whole,

women in the EFCS study were older and heavier weightwise than those in the WHO study. However, the 1 year discontinuation rates for all reasons in the present study were comparable to the HRP/WHO study, but relatively high compared to the Chinese

Table 7. Comparison between the EFCS study, multinational and Chinese studies Characteristic Mean age, years Mean weight, kg Mean height, cm Mean Quetelet index 12-month discontinuation rates (per 100 women-years) Cyclofem Mesigyna Percentage of women without complaints First visit Second visit Discontinuation rates (per 100 women-years) Pregnancies Cyclofem Mesigyna Amenorrhea Cyclofem Mesigyna Bleeding Cyclofem Mesigyna

EFCS study

WHO multinational study

Chinese study

29.0 66.3 158.1 26.6

26.6 56.1 156.0 23.0

— — — —

38.9 38.0

35.5 36.8

26.4 18.8

92.3 94.2

78.1 92.7

— —

0.19 0.41

0.00 0.18

0.11 0.31

2.74 1.38

2.10 1.60

7.00 1.00

7.39 11.54

6.30 7.50

17.50 11.10

92

Hassan et al.

study. The difference may be due to the choice of candidates; 1.8% of recruited women in the present study stopped the method to become pregnant, whereas that figure was 0.23% in the Chinese study. The cumulative discontinuation rates per 100 women-years for method failure in the present study were 0.19 and 0.41 at the end of 12 months for Cyclofem and Mesigyna, respectively, and are comparable to those in the multinational HRP/WHO study (0.00 and 0.18) as well as to those in the Chinese study (0.11 and 0.31). In the present study, discontinuation because of amenorrhea was far less than that because of bleeding problems for both preparations, an observation encountered also in the other two studies. As well, discontinuation for amenorrhea was more in the Cyclofem than the Mesigyna group in all three studies. As for discontinuation due to bleeding problems, the figures were higher for Mesigyna in the EFCS study, showed no significant difference in the HRP/ WHO study, but were higher for Cyclofem in the Chinese study. These differences in discontinuation because of bleeding may reflect population differences in tolerance to such problems that may result from cultural or religious factors.9 However, in general, menstrual disturbances encountered during the use of once-a-month injectable contraceptives were far less than those with other progestagen-only injectable preparations.10 –12 Weight gain was common in this study, with an average of 2 kg/year for those who continued to the end of the study and 0.33 kg/month among all participants, without significant difference between the two preparations. There was less weight gain in the HRP/WHO study (0.48 kg/year), and in the Chinese study, weight gain was minimal and insignificant. It is interesting to note that although weight gain was a major cause of discontinuation in the Chinese study, only two patients discontinued in the EFCS study because of rapid and intolerable weight gain. Egyptian women appeared to gain weight with these hormonal contraceptives, but they were more tolerant of these changes. This study showed that once-a-month injectable contraceptives can be a positive addition to the contraceptive choices offered to Egyptian women. Careful selection of the proper candidates and appropriate counseling would further increase their acceptability.

Acknowledgment This study received financial support and technical assistance from the World Health Organization’s Special Programme of Research and Research Training in Human Reproduction (WHO/HRP), for which the Egyptian Fertility Care Society is deeply indebted.

Contraception 1999;60:87–92

References 1. Siegel I. Conception control by long-acting progestogens: preliminary report. Obstet Gynecol 1963;21:666 – 8. 2. Newton JR, d’Arcanggues C, Hall PE. Once-a-month combined injectable contraceptives. Obstet Gynecol 1994;14Suppl:S1–S34. 3. Hall PE. New once-a-month injectable contraceptives, with particular reference to Cyclofem/Cyclo-Provera. Int J Gynecol Obstet 1998;62(Suppl):S43–56. 4. World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction. Task Force on Long-acting Systemic Agents for Fertility Regulation. A multicentered phase III comparative study of two hormonal contraceptive preparations given once-a-month by intramuscular injection. I. Efficacy and side effects. Contraception 1988; 37:1–20. 5. World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction. Task Force on Long-acting Systemic Agents for Fertility Regulation. A multicentered phase III comparative study of two hormonal contraceptive preparations given once-a-month by intramuscular injection. II. The comparison of bleeding patterns. Contraception 1989;40:531–51. 6. Farley TMM. Life-table method for contraceptive research. Stat Med 1986;5:475– 89. 7. Pinol A. LTA: Life-table analysis program, version 2.0. World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction. Task Force on Long-acting Systemic Agents for Fertility Regulation. Statistics and Data Processing Unit. World Health Organization, Geneva. Switzerland, 1993. 8. Sang GW, Shao QX, Ge RS, et al. A multicentered phase III comparative clinical trial of Mesigyna, Cyclofem and Injectable No. 1 given monthly by intramuscular injection to Chinese women: I. Contraceptive efficacy and side effects. Contraception 1995;51:167– 83. 9. Hassan EO, El-Nahal N, El-Hussinie M. Acceptability of once-a-month injectable contraceptives Cyclofem and Mesigyna in Egypt. Contraception 1994;49:469 – 87. 10. World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction. Task Force on Long-acting Systemic Agents for Fertility Regulation. A multicentered comparative clinical trial of long-acting injectable contraceptives: L-norethisterone enanthate given in two dosage regimens and depot-medoxyprogesterone acetate. Final report. Contraception 1983;28:1–20. 11. World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction. Task Force on Long-acting Systemic Agents for Fertility Regulation. A multicentered phase III comparative clinical trial of depot-medoxyprogesterone acetate given monthly at 100 mg or 150 mg. I. Contraceptive efficacy and side effects. Contraception 1986;34:223–35. 12. Egyptian Fertility Care Society. A study of DMPA and NET-EN injectable contraceptives in Egypt. Egyptian Fertility Care Society, Final report, 1986.