- Email: [email protected]
Existing once-a-month combined injectable contraceptives
Existing once-a-month combined injectable contraceptives Mokhtar
K. Toppozada,
Department
of Obstetrics
M.D. and Gynaecology,
Shatby Hospital,
Alexandria,
Egypt
Long-acting contraception by monthly intramuscular injection is an attractive method for family planning which fills a gap in birth control technology. The main advantage of this approach over long-acting (2-6 months) progestin injectables is much better cycle control. To achieve this goal, an estrogen had to be included in the formulation with significant reduction in the progestin dose. Until 1976, there were only three monthly injectables available (Injectable No. 1, Cycloprovera and Deladroxate), but they were faced with logistic, toxicological or clinical problems. It took over 15 years to resolve many of these problems and add a new product (Mesigyna = 50 mg norethisterone enantate plus 5 mg estradiol valerate in an oily solution). Cycloprovera, at a lower dose, received the new name of Cyclofem and Defsdroxate was manufactured under the trade names of Perlutal or Topasef. The latter requires in-depth re-evaluation of its toxicological hazards. There are many other formulations currently being ‘developed with incomplete data so far on safety and efficacy. Keywords: Cyclofem,
Monthly combined injectable contraception, Deladroxate, Gravibinon, Chinese injectable
Cycloprovera, No. 1, Mesigyna.
Introduction Intramuscular administration of a long-acting (LA) fertility control agent is an attractive and desirable contraceptive modality. It suits a significant sector of the population as it fills a gap in the currently available technology. The injectable approach fulfills many of the features of an ideal contraceptive as it is highly effective, long-acting, simple to use, noninvasive, unrelated to coitus, needs minimal motivation and is relatively inexpensive. l
0 1994 Butterworth-Heinemann
Contraception
1994:49,
April
293
Existing monthly
injectable
contraceptives:
Toppozada
Need and Prevalence of Use Despite the associated clinical problems with injectables, there seems to be an increasing demand for their use by women and family planners which is a sensitive indicator of their real value. The prevalence of use depends on availability, proper counselling and on certain socio-cultural, ethnic and religious deep-rooted beliefs. It is estimated2 that around 11 million women are depending on LA (2-3 monthly) injectable steroids for birth control and about 2 million rely on monthly formulations.3 One or more types of LA injectable contraception are available in about 100 countries around the world, particularly in Latin America (e.g., Mexico and Argentina) and South East Asia (e.g., Indonesia, People’s Republic of China and Thailand). Contraceptive injectables in China are mostly monthly injectables (personal communication; Dr. Xiao Bilian, 1992, National Institute for Family Planning, Beijing). However, the actual estimate of the number of users in China is not currently available.
Advantages and Disadvantages The relative advantages and disadvantages of combined monthly injectables (compared to the 2-3 monthly progestin-only types) are presented in Table 1. Once-a-month contraceptive injections represent a valuable addition to any successful birth control “cafeteria”. They appear to be very popular in certain settings, even more than the 3-monthly formulations.4 The main indication for the contraceptive use of monthly injectables include women who are intolerant, unwilling or unable to use oral contraceptive pills, intra-uterine devices or local methods. Also, those who prefer a long-acting method and accept some menstrual irregularities are possible candidates to use these injections. Contraindications are nearly the same as those of combined oral contraceptives. TABLE 1. Relative advantages and disadvantages (2-6 months) progestin-only formulations
of combined
Advantages
Disadvantages
1. 2. 3. 4. 5. 6. 7.
1. 2. 3. 4.
Better cycle control Less endometrial suppression More rapid return of fertility More contact with health personnel Shorter inconvenience if side-effects occur Half of the progestin dose ? Similar or higher contraceptive efficacy and acceptability
?: Unresolved
294
monthly injectables compared to longer-acting
Not suitable for lactating women Shorter acting & more injections Not for women with contra-indications to use estrogens Presence of estrogen side-effects ? Long-term hazards
issue
Contraception
1994:49, April
Existing
Development
monthly
injectable
contraceptives:
Toppozada
of Monthly Injectables
Injectable contraceptives given every 2-3 months contain progestins without estrogen with prolonged steroid action via esterification (such as norethisterone enantate = NET-EN) or crystal formation (such as depotmedroxyprogesterone acetate = DMPA). Although these formulations provide very high use-effectiveness in preventing pregnancy, they induce marked menstrual cycle disruptions and amenorrhea. Such side-effects represent a major drawback to these methods and the main obstacle to large scale acceptability. Since cycle disturbances have been attributed to the hypoestrogenic endometrial state, it was believed that addition of a LA estradiol would reduce these annoying side-effects. Because it is undesirable to have high levels of estrogen in the circulation for long periods of time after a single injection, it was imperative to use an estrogen ester with a shorter duration of action than that of the combined progestin component and to have both administered on a monthly basis. Such a regimen contains about half the progestin dose compared to the 3-monthly formulations and has a relatively low total estrogenic activity. The main aim of monthly injectable contraceptives is to induce regular and predictable menstrual-like bleeding patterns. They have been under investigation for almost three decades (since the early sixties).5 Many formulations were introduced and evaluated but only the combined ones (an estrogen plus a progestin) survived the test of time. They induced much better menstrual-like bleeding patterns than the longer acting progestin-only injectables.6 However, estrogens are not without risks, a price that one may have to accept as a payment for the desired goals and merits. The monthly injectable containing only a LA progestin caused significant menstrual irregularities and, thus, is no longer being used clinically.
Currently Available Monthly Injectables From available data, monthly injectables can be grouped under three main categories according to the extent of their progress in product development and the clinical experience achieved from their use. Only combined estrogen-progestin types will be included here.
Injectables
at the Marketing
Stage
This group includes drugs with enough toxicological and clinical experience to allow their introduction into the market or those that have been commercially available for some time. Until 1976, there were only three types of contraceptive monthly injections in clinical use with sufficient background clinical experience (Cycloprovera, Deladroxate and Gravibinon or Injectable No. 1). However, all three were faced with logistic,
Contraception
1994:49,
April
295
Existing monthly
injectable
contraceptives:
toxicological or clinical problems;’ the Special Programme of Research, in Human Reproduction.
Toppozada a fourth type was later developed by Development and Research Training
1. Cycloprovera* (25 mg DMPA + 5 mg estradiol cypionate). This formulation is a microcrystalline aqueous suspension in a volume of 0.5 ml. This injectable contains DMPA which, initially, faced some controversial toxicological issues. However, such problems have been recently resolved by the drug regulatory authorities. The company which first developed this product withdrew from contraceptive research for several years and the clinical testing of Cycloprovera was completed by a network of research centres supported by the Special Programme of Research, Development and Research Training in Human Reproduction. It is now available under the trade name Cyclofem, manufactured by Aplicaciones Farmaceuticas in Mexico and P.T. Tunggal in Indonesia. 2. Deladroxate* * (150 mg dihydroxyprogesterone acetophenide + 10 mg estradiol enantate). This agent also had vague but potentially serious toxicological problems (pituitary hyperplasia in rats and breast tumours in beagle dogs). A risk of a carry-over effect and estradiol accumulation was reported in 1973 which raised many questions about this product.8 However, more recent data from several studies done in Argentina contested such information and provided more assuring results.9)10 Since this drug is widely used as a contraceptive in Latin America, there appears a real need to re-evaluate its safety with animal toxicology and continued surveillance, a task which can be appropriately sponsored by the Special Programme in Human Reproduction. Moreover, a lower dose of the steroids, especially the estrogenic ester, should be evaluated in pharmacokinetic and pharmacodynamic studies.” The recommendation is to re-evaluate this drug, as it is used in certain areas on a large scale, where family planners believe that it is an extremely effective and acceptable contraceptive. Deladroxate does not exist under this name anymore since its original manufacturer withdrew it from the market. However, it has been on the market for many years under the trade name of Perlutal (manufactured by Laboratorios Promeco de Mexico and Argentina, by Institute De Angelli in Brazil and by Europharma in Colombia). It is also available under the trademark Topasel from Europharma in Spain.9 A half-dose preparation is also available, under the trade name Yectames
‘Upjohn Company, USA and Belgium. l
296
*Squibb, USA.
Contraception
1994:49, April
Existing monthly
injectable
contraceptives:
Toppozada
(manufactured by Laboratories Grossman, Mexico), however there is only limited clinical data available on this preparation. (250 mg 17 a-hydroxyprogesterone caproate plus 5 mg 3. Gravibinon* estradiol valerate). Initially, this formulation was the first one to be tested as a contraceptive injection in 25 women in 1963 but double the dose was then used6 (500 mg & 10 mg, respectively]. At about the same time in the People’s Republic of China, a lower dose was under clinical trial which was called “Injectable No. 1”. It is administered according to different schedules with two injections administered in the first month of use then one injection monthly afterwards:4 either two injections are administered on the fifth day of the cycle or one is given on day 5 and the second on day 15 of the menstrual cycle; subsequently one injection is given on the tenth day of each cycle. Such a regimen is known to induce a high incidence of cycle irregularity particularly polymenorrhea (very short cycles), a side-effect which may be acceptable to Chinese women but is probably unacceptable in many other parts of the world. In the mid seventies, the Special Programme for Re4. Mesigyna’ search, Development and Research Training in Human Reproduction established a Task Force and a Steering Committee for long-acting systemic agents for fertility regulation. This body recognized the importance and practical needs in real life for a monthly injectable contraceptive. In view of the uncertainty concerning the monthly formulations available at the time (vide supra), the Programme evaluated existing information and designed and implemented a strategy for the development of a new monthly injectable contraceptive. l
l l
From the review of existing data, it was obvious that only combined preparations were the most reasonable approach to adopt at that time. In the pre-development stage, there were four estradiol esters (benzoate, cypionate, valerate and enantate) and two progestins (NET-EN and DMPA) that could be used to develop the product. Steroids could be injected either as microcrystals in aqueous suspension or as an oily solution. Several other variables had to be considered such as the best steroid combinations and dose-ratios, the injection volume and role of crystal sizes in the induced effects. Moreover, other factors had to be resolved later on, such as the importance of body weight and ethnic differences in the observed responses. Many investigations have been carried out over the last 15 years. Pharmacokinetic and pharmacodynamic studies of single steroids or
l l Squibb, USA. * l l Schering AG, Berlin, Germany.
Contraception
1994:49, April
297
Existing
monthly
injectable
contraceptives:
Toppozada
various combinations were performed, resulting in the exclusion of two estradiol esters (the too short-acting benzoate and the too longacting enantate) and the selection of two combined preparations.3J2m14 These were the one formerly known as Cycloprovera which received the code No. of HRP 112 and was finally given the trade name of Cyclofem (vide supra) and the combination introduced by the Programme, initially referred to as HRP102 and now to be marketed under the name of Mesigyna. Mesigyna is a combined monthly injectable containing 50 mg NETEN plus 5 mg estradiol valerate in 1 ml oily solution made of castor oil and benzyl benzoate at a ratio of 6:4. The preliminary phase I clinical trial conducted in 1977 by the Programme in Alexandria, Bombay and Bangkok demonstrated generally reasonable bleeding patterns. Multicentered phase III trials documented its high degree of contraceptive efficacy and reduced bleeding problems. In these aspects and with respect to continuation rates, Mesigyna proved to be rather similar to Cyclofem.l5-‘7 A similar formulation as well as other dosage combinations have been under testing in China since 1974 (personal communication, Dr. Xiao Bilian, 1992). However, the schedule of administration was similar to Injectable No. 1 with two injections on day 5 of the first cycle.
Other Injectables with Limited Clinical Experience This group includes monthly combined injectables for which there is only preliminary knowledge of various basic and clinical aspects or clinical information on only small numbers of women. Such incomplete data do not permit wide scale clinical use. Further clinical or toxicological evaluation is necessary before it can be decided to bring them to registration or discard them completely. 1. Unimens (150 mg 16- 17-dihydroxyprogesterone acetophenide plus 10 mg estradiol 3-benzoate 17B-butyrate). 7,18-20This formulation suffers from two major problems; it induces poor cycle control and has incomplete data on toxicology. 2. NET-EN 50 mg plus 5 mg estradiol unducelate.7J8-20 3. Lutofollin (60 mg superlutin caproate plus 10 mg estradiol valerate). 7,IS-20 4. Norgestrel 25 mg plus 5 mg estradiol hexahydrobenzoate.20 5. Megestrol acetate 25 mg plus 3.54 mg estradiol cyclopentylpropionate.6 This formulation is one of the popular monthly injectables in the People’s Republic of China2’ where it was approved for clinical use in 1977. Experience with about 21,000 cycles proved its very high useeffectiveness (99.4 per 100 women-years] and gave “normal cycles” in
298
Contraception
1994:49,
April
Existing
monthly
injectable
contraceptives:
Toppozada
87% of women.
Moreover, the continuation rate after 3 years was about 75 %. Administration is rather similar to Injectable No. 1 where two injections are given in the first cycle (day 5 and day 12), then one injection every 30-31 days from the last injection. These data may make this product eligible to join the first category, at marketing stage. 6. Chlormadinone Injectables
caproate 80 mg plus 3 mg estradiol valerate.
at an Early Stage of Development
This category includes a few products still in the stage of preliminary evaluation in the laboratory, undergoing animal toxicology testing or phase I or II human studies. The following are examples. 1. Megestrol acetate ( 1.5 mg) and estradiol valerate (5 mg) in gelatin microcapsules (SO-SO pm); this formulation is being developed and tested in the People’s Republic of China.22 2. Norethisterone (12 mg) and mestranol(l.2 mg), formulated as a microcrystalline aqueous suspension of steroid-crystals 125-177 km) in 1 ml physiological saline; w it is being evaluated in Mexico. 3. Systems with modified controlled release of steroids tailored to act on a monthly basis, e.g., polylactic and polyglycolic steroid microspheres. 4. Monolithic microspheres of progesterone and estradiol being developed in Mexico.
Conclusion A long painstaking route is required to develop a preparation and deliver it to the market ready for use by the consumer. It usually requires around 15 years and about US $10 million to reach that stage. Then, industrial facilities for mass production with proper quality control need to be established. Marketing and programme development come next with proper training for providers, application of logistic systems and study of service implications. Post-marketing surveillance and continued evaluation should be an integral part of any injectable introductory plan. It is because of these difficulties that one does not anticipate the introduction of a new monthly injectable contraceptive in the foreseeable future, at least in the next 10 years. It appears that what is generally available today are two products (Cyclofem and Mesigyna) while the former Deladroxate still requires an extensive re-evaluation prior to either clearance for general use or banning from use in humans because of toxicity. Monitoring of the possible long-term hazards of prolonged use of injectable estrogens in monthly preparations is essential. The very high use-effectiveness, long duration of action and reasonable cycle control are the most attractive aspects of the monthly combined
Contraception
1994:49,
April
299
Existing monthly
injectable
contraceptives:
Toppozada
formulations. Certain limitations, on the other hand, may exist, such as more frequent injections, product price, and the presence of estrogens. However, the overall balance appears to be in favour of the monthly combined injectables. Time truth and research is needed
will tell whether our convictions to answer all present uncertainties.
become
References 1. 2.
3. 4. 5. 6. 7. 8.
9.
10.
11.
12.
13.
14.
15.
300
Toppozada M. Injectable contraceptives. Contracept Deliv Sys 1982;3: 161-70. United Nations Population Fund. Contraceptive requirements and demand for contraceptive commodities in developing countries in the 1990s. February 1991. Hall PE. Once-a-month injectable contraceptives. IPPF Med Bull 1987;21: l-2. Liskin LS. Long acting progestins. Promise and prospects. Population Reports 1983;Vol XI, No. 2:K17-K55. Siegel I. Conception control by long-acting progestogens: Preliminary report. Obstet Gynecol 1963;21:666-8. Hall PE, Fraser IS. Monthly injectable contraceptives. In: Mishell DR, Jr., ed. Long-acting steroid contraception. New York: Raven Press, 1983:65-88. Toppozada M. The clinical use of monthly injectable contraceptive preparations. Obstet Gynecol Survey 1977;32:335-47. Gual C, Perez-Palacios G, Perez AE, et al. Metabolic fate of long-acting injectable estrogen-progestogen contraceptive. Contraception 1973;7: 271-87. Wiemeyer JCM, Guerreiro RB, Fernandez M, Sagasta CL. Experimental findings on the estrogenic activity of estradiol enantate. Arzneim Forsch/Drug Res 1986;36:1667-70. Moguilevsky JA, Wiemeyer JCM, Sagasta CL, Leiderman S. Estrogenic activities of estradiol enantate and ethinylestradiol compared at a clinical level. Arzneim Forsch/Drug Res 1986;36:1671-4. Recio R, Garza-Flores J, Schiavon R, et al. Pharmacodynamic assessment of dihydroxyprogesterone acetophenide plus estradiol enanthate as a monthly injectable contraceptive. Contraception 1986;33:579-89. Oriowo MA, Landgren B-M, Stenstrom B, Diczfalusy E. A comparison of the pharmacokinetic properties of three estradiol esters. Contraception 1980; 21:415-24. Aedo A-R, Landgren B-M, Johannisson E, Diczfalusy E. Pharmacokinetic and pharmacodynamic investigations with monthly injectable contraceptive preparations. Contraception 1985~3 1:453-69. World Health Organization, Task Force on Long-acting Systemic Agents for Fertility Regulation, Special Programme of Research, Development and Research Training in Human Reproduction. A multicentred pharmacokinetic, pharmacodynamic study of once-a-month injectable contraceptives. I. Different doses of HPR 112 and of Depoprovera. Contraception 1987;36: 441-57. World Health Organization, Task Force on Long-acting Systemic Agents
Contraception
1994:49, April
Existing monthly
injectable
contraceptives:
Toppozada
for Fertility Regulation, Special Programme of Research, Development and Research Training in Human Reproduction. A multicentred phase III comparative study of two hormonal contraceptive preparations given once-a-month by intramuscular injection. I. Contraceptive efficacy and side effects. Contraception 1988;37:1-20. 16. 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;40:53 1-5 1. two 17. Kesserii E, Aydinlik S, Etchepareborda JJ, Kaufmann J. A multicentered, year, phase III clinical trial of norethisterone enanthate 50 mg plus estradiol valerate 5 mg as a monthly injectable contraceptive. Contraception 1991; 44:589-98. 18. Toppozada M. Monthly injectable contraceptives. In: Goldmith A, Toppozada M, eds. Long acting contraception. Skokie: Johnson-Lindroth, 1983:93-103. In: Diczfalusy E, ed. 19. Benagiano G. Long acting systemic contraceptives. Regulation of human fertility. Copenhagen: Scriptor, 1977:323-60. 20. Toppozada M, Hafez ESE. Injectable contraceptives. In: Human reproduction, conception and contraception. Hagerstown: Harper and Row, 1980:604-32. 21. Yian JH, Li MG, Min HD, Hu YT, Pan JX. Mego-E injectable contraceptives: Analysis of clinical observations and laboratory findings. Reprod Contracep 1983;3:16-20. 22. Han Ziyan and Xiao Ruiqui. A follow-up study of the efficacy and safety of injectable microencapsulated megestrol acetate and a discussion on its contraceptive mechanism. Int J Gynecol Obstet 1985;23:207-11. S, Salamon-Andonie J, Diaz-Sanchez V. As23. Garza-Flores J, Jimenez-Thomas sessment of a new low-dose once-a-month injectable contraceptive. Contraception 1988;37:471-81.
Contraception
1994:49, April
301
K. Toppozada,
Department
of Obstetrics
M.D. and Gynaecology,
Shatby Hospital,
Alexandria,
Egypt
Long-acting contraception by monthly intramuscular injection is an attractive method for family planning which fills a gap in birth control technology. The main advantage of this approach over long-acting (2-6 months) progestin injectables is much better cycle control. To achieve this goal, an estrogen had to be included in the formulation with significant reduction in the progestin dose. Until 1976, there were only three monthly injectables available (Injectable No. 1, Cycloprovera and Deladroxate), but they were faced with logistic, toxicological or clinical problems. It took over 15 years to resolve many of these problems and add a new product (Mesigyna = 50 mg norethisterone enantate plus 5 mg estradiol valerate in an oily solution). Cycloprovera, at a lower dose, received the new name of Cyclofem and Defsdroxate was manufactured under the trade names of Perlutal or Topasef. The latter requires in-depth re-evaluation of its toxicological hazards. There are many other formulations currently being ‘developed with incomplete data so far on safety and efficacy. Keywords: Cyclofem,
Monthly combined injectable contraception, Deladroxate, Gravibinon, Chinese injectable
Cycloprovera, No. 1, Mesigyna.
Introduction Intramuscular administration of a long-acting (LA) fertility control agent is an attractive and desirable contraceptive modality. It suits a significant sector of the population as it fills a gap in the currently available technology. The injectable approach fulfills many of the features of an ideal contraceptive as it is highly effective, long-acting, simple to use, noninvasive, unrelated to coitus, needs minimal motivation and is relatively inexpensive. l
0 1994 Butterworth-Heinemann
Contraception
1994:49,
April
293
Existing monthly
injectable
contraceptives:
Toppozada
Need and Prevalence of Use Despite the associated clinical problems with injectables, there seems to be an increasing demand for their use by women and family planners which is a sensitive indicator of their real value. The prevalence of use depends on availability, proper counselling and on certain socio-cultural, ethnic and religious deep-rooted beliefs. It is estimated2 that around 11 million women are depending on LA (2-3 monthly) injectable steroids for birth control and about 2 million rely on monthly formulations.3 One or more types of LA injectable contraception are available in about 100 countries around the world, particularly in Latin America (e.g., Mexico and Argentina) and South East Asia (e.g., Indonesia, People’s Republic of China and Thailand). Contraceptive injectables in China are mostly monthly injectables (personal communication; Dr. Xiao Bilian, 1992, National Institute for Family Planning, Beijing). However, the actual estimate of the number of users in China is not currently available.
Advantages and Disadvantages The relative advantages and disadvantages of combined monthly injectables (compared to the 2-3 monthly progestin-only types) are presented in Table 1. Once-a-month contraceptive injections represent a valuable addition to any successful birth control “cafeteria”. They appear to be very popular in certain settings, even more than the 3-monthly formulations.4 The main indication for the contraceptive use of monthly injectables include women who are intolerant, unwilling or unable to use oral contraceptive pills, intra-uterine devices or local methods. Also, those who prefer a long-acting method and accept some menstrual irregularities are possible candidates to use these injections. Contraindications are nearly the same as those of combined oral contraceptives. TABLE 1. Relative advantages and disadvantages (2-6 months) progestin-only formulations
of combined
Advantages
Disadvantages
1. 2. 3. 4. 5. 6. 7.
1. 2. 3. 4.
Better cycle control Less endometrial suppression More rapid return of fertility More contact with health personnel Shorter inconvenience if side-effects occur Half of the progestin dose ? Similar or higher contraceptive efficacy and acceptability
?: Unresolved
294
monthly injectables compared to longer-acting
Not suitable for lactating women Shorter acting & more injections Not for women with contra-indications to use estrogens Presence of estrogen side-effects ? Long-term hazards
issue
Contraception
1994:49, April
Existing
Development
monthly
injectable
contraceptives:
Toppozada
of Monthly Injectables
Injectable contraceptives given every 2-3 months contain progestins without estrogen with prolonged steroid action via esterification (such as norethisterone enantate = NET-EN) or crystal formation (such as depotmedroxyprogesterone acetate = DMPA). Although these formulations provide very high use-effectiveness in preventing pregnancy, they induce marked menstrual cycle disruptions and amenorrhea. Such side-effects represent a major drawback to these methods and the main obstacle to large scale acceptability. Since cycle disturbances have been attributed to the hypoestrogenic endometrial state, it was believed that addition of a LA estradiol would reduce these annoying side-effects. Because it is undesirable to have high levels of estrogen in the circulation for long periods of time after a single injection, it was imperative to use an estrogen ester with a shorter duration of action than that of the combined progestin component and to have both administered on a monthly basis. Such a regimen contains about half the progestin dose compared to the 3-monthly formulations and has a relatively low total estrogenic activity. The main aim of monthly injectable contraceptives is to induce regular and predictable menstrual-like bleeding patterns. They have been under investigation for almost three decades (since the early sixties).5 Many formulations were introduced and evaluated but only the combined ones (an estrogen plus a progestin) survived the test of time. They induced much better menstrual-like bleeding patterns than the longer acting progestin-only injectables.6 However, estrogens are not without risks, a price that one may have to accept as a payment for the desired goals and merits. The monthly injectable containing only a LA progestin caused significant menstrual irregularities and, thus, is no longer being used clinically.
Currently Available Monthly Injectables From available data, monthly injectables can be grouped under three main categories according to the extent of their progress in product development and the clinical experience achieved from their use. Only combined estrogen-progestin types will be included here.
Injectables
at the Marketing
Stage
This group includes drugs with enough toxicological and clinical experience to allow their introduction into the market or those that have been commercially available for some time. Until 1976, there were only three types of contraceptive monthly injections in clinical use with sufficient background clinical experience (Cycloprovera, Deladroxate and Gravibinon or Injectable No. 1). However, all three were faced with logistic,
Contraception
1994:49,
April
295
Existing monthly
injectable
contraceptives:
toxicological or clinical problems;’ the Special Programme of Research, in Human Reproduction.
Toppozada a fourth type was later developed by Development and Research Training
1. Cycloprovera* (25 mg DMPA + 5 mg estradiol cypionate). This formulation is a microcrystalline aqueous suspension in a volume of 0.5 ml. This injectable contains DMPA which, initially, faced some controversial toxicological issues. However, such problems have been recently resolved by the drug regulatory authorities. The company which first developed this product withdrew from contraceptive research for several years and the clinical testing of Cycloprovera was completed by a network of research centres supported by the Special Programme of Research, Development and Research Training in Human Reproduction. It is now available under the trade name Cyclofem, manufactured by Aplicaciones Farmaceuticas in Mexico and P.T. Tunggal in Indonesia. 2. Deladroxate* * (150 mg dihydroxyprogesterone acetophenide + 10 mg estradiol enantate). This agent also had vague but potentially serious toxicological problems (pituitary hyperplasia in rats and breast tumours in beagle dogs). A risk of a carry-over effect and estradiol accumulation was reported in 1973 which raised many questions about this product.8 However, more recent data from several studies done in Argentina contested such information and provided more assuring results.9)10 Since this drug is widely used as a contraceptive in Latin America, there appears a real need to re-evaluate its safety with animal toxicology and continued surveillance, a task which can be appropriately sponsored by the Special Programme in Human Reproduction. Moreover, a lower dose of the steroids, especially the estrogenic ester, should be evaluated in pharmacokinetic and pharmacodynamic studies.” The recommendation is to re-evaluate this drug, as it is used in certain areas on a large scale, where family planners believe that it is an extremely effective and acceptable contraceptive. Deladroxate does not exist under this name anymore since its original manufacturer withdrew it from the market. However, it has been on the market for many years under the trade name of Perlutal (manufactured by Laboratorios Promeco de Mexico and Argentina, by Institute De Angelli in Brazil and by Europharma in Colombia). It is also available under the trademark Topasel from Europharma in Spain.9 A half-dose preparation is also available, under the trade name Yectames
‘Upjohn Company, USA and Belgium. l
296
*Squibb, USA.
Contraception
1994:49, April
Existing monthly
injectable
contraceptives:
Toppozada
(manufactured by Laboratories Grossman, Mexico), however there is only limited clinical data available on this preparation. (250 mg 17 a-hydroxyprogesterone caproate plus 5 mg 3. Gravibinon* estradiol valerate). Initially, this formulation was the first one to be tested as a contraceptive injection in 25 women in 1963 but double the dose was then used6 (500 mg & 10 mg, respectively]. At about the same time in the People’s Republic of China, a lower dose was under clinical trial which was called “Injectable No. 1”. It is administered according to different schedules with two injections administered in the first month of use then one injection monthly afterwards:4 either two injections are administered on the fifth day of the cycle or one is given on day 5 and the second on day 15 of the menstrual cycle; subsequently one injection is given on the tenth day of each cycle. Such a regimen is known to induce a high incidence of cycle irregularity particularly polymenorrhea (very short cycles), a side-effect which may be acceptable to Chinese women but is probably unacceptable in many other parts of the world. In the mid seventies, the Special Programme for Re4. Mesigyna’ search, Development and Research Training in Human Reproduction established a Task Force and a Steering Committee for long-acting systemic agents for fertility regulation. This body recognized the importance and practical needs in real life for a monthly injectable contraceptive. In view of the uncertainty concerning the monthly formulations available at the time (vide supra), the Programme evaluated existing information and designed and implemented a strategy for the development of a new monthly injectable contraceptive. l
l l
From the review of existing data, it was obvious that only combined preparations were the most reasonable approach to adopt at that time. In the pre-development stage, there were four estradiol esters (benzoate, cypionate, valerate and enantate) and two progestins (NET-EN and DMPA) that could be used to develop the product. Steroids could be injected either as microcrystals in aqueous suspension or as an oily solution. Several other variables had to be considered such as the best steroid combinations and dose-ratios, the injection volume and role of crystal sizes in the induced effects. Moreover, other factors had to be resolved later on, such as the importance of body weight and ethnic differences in the observed responses. Many investigations have been carried out over the last 15 years. Pharmacokinetic and pharmacodynamic studies of single steroids or
l l Squibb, USA. * l l Schering AG, Berlin, Germany.
Contraception
1994:49, April
297
Existing
monthly
injectable
contraceptives:
Toppozada
various combinations were performed, resulting in the exclusion of two estradiol esters (the too short-acting benzoate and the too longacting enantate) and the selection of two combined preparations.3J2m14 These were the one formerly known as Cycloprovera which received the code No. of HRP 112 and was finally given the trade name of Cyclofem (vide supra) and the combination introduced by the Programme, initially referred to as HRP102 and now to be marketed under the name of Mesigyna. Mesigyna is a combined monthly injectable containing 50 mg NETEN plus 5 mg estradiol valerate in 1 ml oily solution made of castor oil and benzyl benzoate at a ratio of 6:4. The preliminary phase I clinical trial conducted in 1977 by the Programme in Alexandria, Bombay and Bangkok demonstrated generally reasonable bleeding patterns. Multicentered phase III trials documented its high degree of contraceptive efficacy and reduced bleeding problems. In these aspects and with respect to continuation rates, Mesigyna proved to be rather similar to Cyclofem.l5-‘7 A similar formulation as well as other dosage combinations have been under testing in China since 1974 (personal communication, Dr. Xiao Bilian, 1992). However, the schedule of administration was similar to Injectable No. 1 with two injections on day 5 of the first cycle.
Other Injectables with Limited Clinical Experience This group includes monthly combined injectables for which there is only preliminary knowledge of various basic and clinical aspects or clinical information on only small numbers of women. Such incomplete data do not permit wide scale clinical use. Further clinical or toxicological evaluation is necessary before it can be decided to bring them to registration or discard them completely. 1. Unimens (150 mg 16- 17-dihydroxyprogesterone acetophenide plus 10 mg estradiol 3-benzoate 17B-butyrate). 7,18-20This formulation suffers from two major problems; it induces poor cycle control and has incomplete data on toxicology. 2. NET-EN 50 mg plus 5 mg estradiol unducelate.7J8-20 3. Lutofollin (60 mg superlutin caproate plus 10 mg estradiol valerate). 7,IS-20 4. Norgestrel 25 mg plus 5 mg estradiol hexahydrobenzoate.20 5. Megestrol acetate 25 mg plus 3.54 mg estradiol cyclopentylpropionate.6 This formulation is one of the popular monthly injectables in the People’s Republic of China2’ where it was approved for clinical use in 1977. Experience with about 21,000 cycles proved its very high useeffectiveness (99.4 per 100 women-years] and gave “normal cycles” in
298
Contraception
1994:49,
April
Existing
monthly
injectable
contraceptives:
Toppozada
87% of women.
Moreover, the continuation rate after 3 years was about 75 %. Administration is rather similar to Injectable No. 1 where two injections are given in the first cycle (day 5 and day 12), then one injection every 30-31 days from the last injection. These data may make this product eligible to join the first category, at marketing stage. 6. Chlormadinone Injectables
caproate 80 mg plus 3 mg estradiol valerate.
at an Early Stage of Development
This category includes a few products still in the stage of preliminary evaluation in the laboratory, undergoing animal toxicology testing or phase I or II human studies. The following are examples. 1. Megestrol acetate ( 1.5 mg) and estradiol valerate (5 mg) in gelatin microcapsules (SO-SO pm); this formulation is being developed and tested in the People’s Republic of China.22 2. Norethisterone (12 mg) and mestranol(l.2 mg), formulated as a microcrystalline aqueous suspension of steroid-crystals 125-177 km) in 1 ml physiological saline; w it is being evaluated in Mexico. 3. Systems with modified controlled release of steroids tailored to act on a monthly basis, e.g., polylactic and polyglycolic steroid microspheres. 4. Monolithic microspheres of progesterone and estradiol being developed in Mexico.
Conclusion A long painstaking route is required to develop a preparation and deliver it to the market ready for use by the consumer. It usually requires around 15 years and about US $10 million to reach that stage. Then, industrial facilities for mass production with proper quality control need to be established. Marketing and programme development come next with proper training for providers, application of logistic systems and study of service implications. Post-marketing surveillance and continued evaluation should be an integral part of any injectable introductory plan. It is because of these difficulties that one does not anticipate the introduction of a new monthly injectable contraceptive in the foreseeable future, at least in the next 10 years. It appears that what is generally available today are two products (Cyclofem and Mesigyna) while the former Deladroxate still requires an extensive re-evaluation prior to either clearance for general use or banning from use in humans because of toxicity. Monitoring of the possible long-term hazards of prolonged use of injectable estrogens in monthly preparations is essential. The very high use-effectiveness, long duration of action and reasonable cycle control are the most attractive aspects of the monthly combined
Contraception
1994:49,
April
299
Existing monthly
injectable
contraceptives:
Toppozada
formulations. Certain limitations, on the other hand, may exist, such as more frequent injections, product price, and the presence of estrogens. However, the overall balance appears to be in favour of the monthly combined injectables. Time truth and research is needed
will tell whether our convictions to answer all present uncertainties.
become
References 1. 2.
3. 4. 5. 6. 7. 8.
9.
10.
11.
12.
13.
14.
15.
300
Toppozada M. Injectable contraceptives. Contracept Deliv Sys 1982;3: 161-70. United Nations Population Fund. Contraceptive requirements and demand for contraceptive commodities in developing countries in the 1990s. February 1991. Hall PE. Once-a-month injectable contraceptives. IPPF Med Bull 1987;21: l-2. Liskin LS. Long acting progestins. Promise and prospects. Population Reports 1983;Vol XI, No. 2:K17-K55. Siegel I. Conception control by long-acting progestogens: Preliminary report. Obstet Gynecol 1963;21:666-8. Hall PE, Fraser IS. Monthly injectable contraceptives. In: Mishell DR, Jr., ed. Long-acting steroid contraception. New York: Raven Press, 1983:65-88. Toppozada M. The clinical use of monthly injectable contraceptive preparations. Obstet Gynecol Survey 1977;32:335-47. Gual C, Perez-Palacios G, Perez AE, et al. Metabolic fate of long-acting injectable estrogen-progestogen contraceptive. Contraception 1973;7: 271-87. Wiemeyer JCM, Guerreiro RB, Fernandez M, Sagasta CL. Experimental findings on the estrogenic activity of estradiol enantate. Arzneim Forsch/Drug Res 1986;36:1667-70. Moguilevsky JA, Wiemeyer JCM, Sagasta CL, Leiderman S. Estrogenic activities of estradiol enantate and ethinylestradiol compared at a clinical level. Arzneim Forsch/Drug Res 1986;36:1671-4. Recio R, Garza-Flores J, Schiavon R, et al. Pharmacodynamic assessment of dihydroxyprogesterone acetophenide plus estradiol enanthate as a monthly injectable contraceptive. Contraception 1986;33:579-89. Oriowo MA, Landgren B-M, Stenstrom B, Diczfalusy E. A comparison of the pharmacokinetic properties of three estradiol esters. Contraception 1980; 21:415-24. Aedo A-R, Landgren B-M, Johannisson E, Diczfalusy E. Pharmacokinetic and pharmacodynamic investigations with monthly injectable contraceptive preparations. Contraception 1985~3 1:453-69. World Health Organization, Task Force on Long-acting Systemic Agents for Fertility Regulation, Special Programme of Research, Development and Research Training in Human Reproduction. A multicentred pharmacokinetic, pharmacodynamic study of once-a-month injectable contraceptives. I. Different doses of HPR 112 and of Depoprovera. Contraception 1987;36: 441-57. World Health Organization, Task Force on Long-acting Systemic Agents
Contraception
1994:49, April
Existing monthly
injectable
contraceptives:
Toppozada
for Fertility Regulation, Special Programme of Research, Development and Research Training in Human Reproduction. A multicentred phase III comparative study of two hormonal contraceptive preparations given once-a-month by intramuscular injection. I. Contraceptive efficacy and side effects. Contraception 1988;37:1-20. 16. 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;40:53 1-5 1. two 17. Kesserii E, Aydinlik S, Etchepareborda JJ, Kaufmann J. A multicentered, year, phase III clinical trial of norethisterone enanthate 50 mg plus estradiol valerate 5 mg as a monthly injectable contraceptive. Contraception 1991; 44:589-98. 18. Toppozada M. Monthly injectable contraceptives. In: Goldmith A, Toppozada M, eds. Long acting contraception. Skokie: Johnson-Lindroth, 1983:93-103. In: Diczfalusy E, ed. 19. Benagiano G. Long acting systemic contraceptives. Regulation of human fertility. Copenhagen: Scriptor, 1977:323-60. 20. Toppozada M, Hafez ESE. Injectable contraceptives. In: Human reproduction, conception and contraception. Hagerstown: Harper and Row, 1980:604-32. 21. Yian JH, Li MG, Min HD, Hu YT, Pan JX. Mego-E injectable contraceptives: Analysis of clinical observations and laboratory findings. Reprod Contracep 1983;3:16-20. 22. Han Ziyan and Xiao Ruiqui. A follow-up study of the efficacy and safety of injectable microencapsulated megestrol acetate and a discussion on its contraceptive mechanism. Int J Gynecol Obstet 1985;23:207-11. S, Salamon-Andonie J, Diaz-Sanchez V. As23. Garza-Flores J, Jimenez-Thomas sessment of a new low-dose once-a-month injectable contraceptive. Contraception 1988;37:471-81.
Contraception
1994:49, April
301