Your search found 34 Results
BMJ Sexual and Reproductive Health. 2018 Jan; 44(1):66-68.Following publication of the author's trial on the effects of postnatal depot medroxyprogesterone acetate (DMPA) compared with the copper intrauterine device (IUD) on postnatal depression in this journal in July 2016, they have sought to evaluate contraceptive discontinuation in our study sample. Postnatal contraception is promoted as part of the WHO strategy to reduce the unmet need for family planning in low- and middle-income countries (LMICs) and to reduce preventable maternal and child mortality. However, little is known about discontinuation rates associated with postnatal contraception use in these settings. From the trial, 75 of 242 participants were contactable two or more years after randomisation and 54 consented to a follow-up interview, which was conducted by a Masters student from the University of Fort Hare (NDY). Twenty-three women had received DMPA and 31 women an IUD. In the DMPA and IUD arms, respectively, 48% (11/23) and 42% (13/31) had discontinued their contraceptive methods by the time of the interview. All participants who discontinued did so within the first year, 10 within 3 months of allocation (DMPA=4, IUD=6), and 17 within 6 months (DMPA=7, IUD=10). Six of the participants allocated to DMPA (26%) and five allocated to the IUD (16%) became pregnant following discontinuation.
Swiss Medical Weekly. 2017 Jun 21; 147:w14432.PURPOSE: Sayana(R) was introduced as the first depot medroxyprogesterone acetate-containing contraceptive that is administered via subcutaneous injection. Within 10 months, the Regional Pharmacovigilance Centre (RPVC) Zurich received several anonymous reports of serious local reactions after Sayana(R) administration. In this retrospective study, individual case safety reports (ICSRs) on local adverse drug reactions (ADRs) related to Sayana(R) were analysed from the WHO pharmacovigilance database. METHODS: International, national and regional ICSRs during Sayana(R) administration up to 1 January 2016 were examined. Data on ADRs were retrieved from the WHO Global Database VigiBase. Demographic data, drug administration information, duration of Sayana(R) treatment, latency time of the ADR, and its course, severity and outcomes were analysed. RESULTS: Worldwide, 398 ICSRs after Sayana(R) use were registered in the database. We identified 20 reported terms that were potentially used to describe a persistent lipodystrophy. When only cases containing one or more of these 20 reported terms were selected, 323 (81.2%) international ICSRs remained for analysis. Of those, 91.6% (n = 296) were categorised as serious. The majority of the reactions (n = 193, 54.4%) did not recover. In the 67 Swiss ICSRs, 77 ADRs were reported using 10 different terms including severe or persistent local reactions like lipodystrophy, atrophy or fat necrosis. Thirty-two patients (47.7%) did not recover. All 11 regional cases reported to the RPVC Zurich were categorised as serious ADRs. For the majority of the patients (n = 7, 63.6%) the interval between the application of Sayana(R) and development of the lipodystrophy was between 2 and 4 months. Most of the reactions were irreversible (n = 9, 81.8%). One patient underwent plastic surgery for artificial infill of the dent. CONCLUSIONS: Persistent local injection site reactions such as lipodystrophy, fat tissue necrosis or atrophy occur frequently after subcutaneous Sayana(R) use. These adverse drug reactions were recently integrated in the Swiss product information. Physicians and patients should be informed and advised about these potentially irreversible effects.
Journal of Family Planning and Reproductive Health Care. 2008 Oct; 34(4):269-70.User choice is central to contraceptive practice, as opposed to therapeutic care where the view of the prescriber tends to prevail. Provider organisations have to make difficult decisions in selecting the methods of contraception that are offered, particularly with the multitude of new products and the controversies that have surrounded the value of some of them. The World Health Organization (WHO) Model List of Essential Medicines is a valuable tool in strengthening the provision of contraceptive commodities as part of international development efforts.
Contraception. 1984 Dec; 30(6):505-22.The World Health Organization (WHO) conducted a randomized comparative trail of th effects of hormonal contrception on milk volume and infant growth. The 341 study participants, drawn from 3 obstetric centers in Hungary and Thailand, were 20-35 years of age with 2-4 live births and previous successful experience with breastfeeding. Subjects who chose oral contraception (OC) were randomly allocated to a combined preparation containing 150 mcg levonorgestrel and 30 mcg ethinyl estradiol (N=86) or to a progestin-only minipill containing 75 mcg dl-norgestrel (N=8). 59 Thai women receiving 150 mg depot medroxyprogesterone (DPMA) intramuscularly every 3 months were also studied. An additional 111 women who were using nonhormonal methods of contraception or no contraception served as controls. Milk volume was determined by breast pump expression. No significant differences in average milk volume were noted between treatment groups at the 6 week baseline visit. However, between the 6th and 24th weeks, average milk volume in the combined OC group declined by 41.9%, which was significantly greater than the declines of 12.0% noted in the progestin-only group, 6.1% among DMPA users, and 16.7% among controls. The lower expressed milk volume among combined OC users did not impair infant growth. No significant differences were observed between treatment groups in terms of average infant body weight or rate or weight gain. Users of combined OCs may have compensated for their decreased milk volume by providing more extensive supplementary feeding or more prolonged suckling episodes. These results suggest that the estrogen content of combined OCs adversely affects the capacity of the breast to produce milk; thus, family planning programs should make nonestrogen-containing methods available to breastfeeding mothers. Although no effects on infant growth were noted in this study, the possibility of such efects cannot be excluded in populations where infant growth largely depends on the adequacy of unsupplemente d lactation.
Geneva, Switzerland, WHO, 1978. (World Health Organization Technical Report Series No. 619) 54 pStudies on steroid contraception (SC) and risk of neoplasia are reviewed. Methodological issues in neoplasia etiology studies include: 1) possibility of a latent period between exposure to cause and disease development; 2) cumulative effects of prolonged or repeated SC exposure; 3) discontinued drugs or dosage schedules; 4) time of exposure (adolescence or prenatal, e.g.); 5) isolation of specific causes among multiple risks; and 6) variations in neoplasma diagnoses. The 4 epidemiological approaches to SC-associated neoplasia studies have inherent shortcomings, but cohorts yield significant associations. Relative risk (ratio of disease incidence among exposed vs. nonexposed persons) is an index of association only, not evidence of cause and effect. Benign breast neoplasia risk was reduced by current SC use of >2 years, and weak evidence points to a residual protective effect, apparently associated with progestogen dose. Aggregated breast cancer data show no clear adverse or beneficial effect of SC use; however, evidence suggests SCs may increase breast cancer risk in population subgroups (e.g., young women). Only short-term evidence is available; hence, no inference of long-term SC breast cancer effects is possible. No beneficial effect of SCs on uterine fibroids is evident, but sequential SCs, no longer marketed, may have increased risk to endometrial carcinoma. Inconclusive data suggest SCs may decrease ovarian cancer risk. Increased risk of cervical dysplasia and carcinoma in situ is associated with SC use, especially long-term use by women with predisposing factors. Risk of hepatocellular adenoma of the liver increases with prolonged SC exposure, especially high dose. Relevance of existing data from more developed countries to disease risk in less developed ones is discussed, and recommendations made.
IPPF MEDICAL BULLETIN. 1992 Apr; 26(2):4.At a meeting in November 1991, the International Medical Advisory Panel (IMAP) of the International Planned Parenthood Federation (IPPF) was asked by the South Asia Region of IPPF to consider a report by the Bangladesh Family Planning Program concerning the operational implications of using more than one formulation of injectable contraceptive in a geographic area. The report states that depot medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) are very similar in terms of continuation rates, use-effectiveness levels, and reported side effects. However, they differ in administration schedule (DMPA is given at three month intervals; the other is given at two) and viscosity (NET-EN is more viscous and requires a larger bore needle than the other), which can lead to delivery problems for outreach programs. 50% of the contraceptive methods offered and used in these programs are injectables. Maintaining both types of injectables can lead to fieldworker confusion and error, disruption of fieldworker work routines, managerial burden, and supply shortages. IMAP recommends that family planning program managers select one progestogen-only injectable formulation and keep to it, to ensure that only one formulation is used in a particular geographic area. DMPA and NET-EN should not be considered medically interchangeable. They have different formulations and different periods of effectiveness. There is no data on the medical consequences of women receiving the two interchangeably because of program problems or errors.
CONTRACEPTION. 1994 Mar; 49(3):185-8.Depot-medroxyprogesterone acetate (DMPA) is currently used for contraception by about nine million women in more than 90 countries. DMPA injected intramuscularly at a dose of 150 mg every 3 months, is among the most effective reversible contraceptive methods. The reluctance of the US Food and Drug Administration (FDA) to approve DMPA in 1992 was attributed to the occurrence of mammary neoplasia in beagle dogs and of endometrial cancer in two of sixteen rhesus monkeys after long-term DMPA treatment. The beagle dog responds to DMPA with a release of growth hormone which is probably the cause of the tumorigenic effect of DMPA on the mammary gland. Around 1990 findings were published from a WHO multicenter study in Kenya, Mexico and Thailand and studies from Costa Rica and New Zealand. In 1993, a WHO meeting of experts reviewed the available data on use of DMPA and cancer risk in women as well as recent toxicology data. DMPA exerts a protective effect against endometrial cancer. The epidemiological studies report no association between the risk of ovarian cancer and the use of DMPA. There was a lack of an association between cervical cancer and DMPA. Two well-designed epidemiological studies did not provide evidence for an increase in overall risk of breast cancer among women having used DMPA. However, both studies reported a weak association between current and recent use of DMPA and breast cancer although there was no evidence of increased risk for women who had stopped using DMPA several years ago. Women who were less than 35 years old at diagnosis, an age at which breast cancer is rare, also showed a slightly increased risk. DMPA can cause an irregular bleeding pattern, it is not immediately irreversible, and there is a relatively slow return of fertility after discontinuation. Yet for women who wish for medium- or long-term contraception, DMPA is one of the alternatives to be considered.
PROGRESS IN HUMAN REPRODUCTION RESEARCH. 1992; (23):2-3.A study sponsored by the Special Program of Research, Development and Research Training in Human Reproduction of the World Health Organization was carried out in Thailand involving groups of women with 1573 accidental pregnancies. There were 830 accidental pregnancies while using the injectable contraceptive depot-medroxyprogesterone acetate (DMPA), while 743 women had become pregnant before use. There were also 601 accidental pregnancies in oral contraceptive (OC) users. The comparison group of a total of 2587 controls comprised women whose pregnancies were planned as opposed to the exposed group. Women using DMPA had more pregnancy risk factors compared to other groups owing to low socioeconomic status, lower maternal weight and height, smoking and alcohol use during pregnancy, and unplanned pregnancy. However, even after adjusting for these factors, DMPA users had a 50% higher than normal risk of having a low-birth-weight child. The same level of statistically not significant risk was also found among the OC users. Among those who had had accidental pregnancies during DMPA use, and in whom conception was estimated to have occurred within 4 weeks of a DMPA injection, the risk of low birth weight was 90% higher than that in the control group. The increase in risk appeared to decline to 50% when the interval between conception and DMPA injection was 5-8 weeks, and to 20% when the interval between conception and DMPA injection was 5-8 weeks, and to 20% when the interval was >or= 9 weeks. This trend was highly significant. Early, high-dose exposure in utero to DMPA seemed to affect fetal growth. There was no increase in the risk of mortality in the 1st year of life for infants exposed to OCs as compared to infants not exposed. However, infants from DMPA-exposed pregnancies had an 80% higher than normal risk of dying during the 1st year of life. Therefore, some infants born out of accidental pregnancies that occur during DMPA use may be at an increased risk of infant death.
PACIFIC BASIN MATERNAL AND CHILD HEALTH RESOURCE CENTER WHAT'S NEW IN.... 1991 Dec; 3(58):1-2.The WHO has published partial results of an epidemiological study of the safety with respect to breast cancer of the injectable contraceptive depomedroxyprogesterone acetate, known as DMPA or Depo-Provera. The WHO Special Program of Research, Development and Research Training in Human Reproduction has been conducting a collaborative retrospective study of cancer and DMPA in 3 developed and 8 developing countries. Results from Kenya, Mexico and Thailand are published in Lancet on October 5, 1991. Comparing 869 women with breast cancer <64 years old and 11,890 matched hospital-based controls, the relative risk was 1.21, not statistically significant. 12.5% of the cases and 12.2% of the controls had used DMPA. Fine analysis pointed to a possibility of increased risk over the 1st 4 years of use. The data were not compatible with the hypothesis that DMPA. Fine analysis pointed to a possibility of increased risk over the 1st 4 years of use. The data were not compatible with the hypothesis that DMPA causes cancer, but only that it may speed the growth of early pre-existing cancer. When contemplating the choice of DMPA, people should evaluate their risks relative to the excellence of DMPA as a highly effective, convenient, long-acting, but reversible method.
CONTRACEPTION. 1988 Aug; 38(2):165-79.Researchers recruited 1216 females to study changes in amenorrhea patterns with successive injections of the long acting injectable contraceptive depot-medroxyprogesterone acetate (DMPA). The women received an injection of either 100 mg or 150 mg DMPA on the day of randomization and 3 additional injections at 90 day intervals. 1151 (94.7%) women completed a menstrual diary that could be used, but only diaries of at least 60 days were considered in each reference period (90 days). Of the 99 who received only 1 100mg injection, 23 had amenorrhea. Of the 361 receiving 4 injections, 142 experienced no amenorrhea in any of the injection intervals and 30 had amenorrhea in all 4 intervals. Overall 281 women out of 576 who received 1-4 injections of 100 mg DMPA did not experience amenorrhea at all. For those in the 150 mg sample receiving 1-4 injections, 237 out of 575 women did not have amenorrhea. Analysis of change over time suggested an increase incidence of amenorrhea following the 2nd injection. In terms of the probability of a woman accepting a injection, women who experienced amenorrhea with the 1st injection were less likely to accept a 2nd, especially in the 150 mg DMPA group. Additionally, the trend in amenorrhea pattern demonstrated that a 3rd injection was adversely affected by amenorrhea in the 2nd injection interval in the 150 mg group but not the 100 mg group. Nevertheless, the decision to have a 4th injection appeared adversely affected by amenorrhea in the 3rd injection interval in both groups. The conditional probabilities used in this research can also be applied to examine continuation or survival rates in a follow-up study based on any prognostic factors.
ECONOMIC AND POLITICAL WEEKLY. 1986 Jun 14; 21(24):1079-80.NET-EN was marketed initially in 1967 and almost 15 years following its use the Twelfth Annual Report of the World Health Organization (WHO), published in 1983, states that questions exist regarding the effectiveness and safety of DMPA and NET-EN that call for more research. Yet, in 1982, the Toxicology Review Panel of WHO had found NET-EN to be a safe contraceptive and had recommended its use in family planning programs. According to Iris Kapil, studies by WHO have failed thus far to identify any health risk associated with the use of Depo Provera and have shown no adverse effect on the composition or yield of breast milk. In 1983, however, the Federal Health Office of West Germany, where the parent company manufacturing NET-EN is based, revised its ruling with specific reference to the use of NET-EN and DMPA during lactation. If Kapil would not be so awed by the WHO and the ICMR and would take the time to identify their own admissions, she too would question the basis on which the injectables are being declared safe. Factors governing the rate of metabolism of contraceptive hormones are not well understood. The rate of decline of circulating norethisterone in patients having multiple injection was significantly slower, suggesting a decrease in the metabolism of the steroid. In the WHO multicenter trial of 1977 no systematic differences in factors could be identified to account for the high failure rate. Little is known about the basic mechanisms of bleeding disturbances especially those related to steroidal contraceptions. A satisfactory approach to the management of prolonged or heavy bleeding due to the injectable contraceptive has not been developed as yet. Nothing is known about whether synthetic progestogens have any effects on normal hormonal changes in the early infant which may in turn affect the latter's sexual development. Little information from human studies is available on long acting injectable contraceptives and the risk of neoplasia. Other important aspects such as immuno-supressive effect of the injectable on the woman and her breastfed infant, the possibility of irreversible pituitary ovarian and endometrial atrophy have not been studied. Kapil cities a "well-reported" project from South India to support her case. What is apparent is that the list of disadvantages identified appear to be written from the perspective of how it would affect continuation rates. Nowhere does it appear to stem from a concern for the health of the women involved.
Lancet. 1985 May 4; 1(8436):1046.As part of a study on acute febrile pelvic inflammatory disease and IUDs, reported elsewhere, a significantly lower risk of PID was observed in women using injectable contraceptives. The World Health Organization coordinated the multinational case-control study in 1979-79. Diagnostic criteria were fever, suprapubic tenderness with guarding, cervical or adnexal tenderness or a pelvic mass. 319 cases and 639 matched controls were matched for age, parity, marital status and hospital status. Data were taken from questionnaires. 10 cases (3.1%) currently used injectable contraceptives, mainly Depo-Provera, compared to 38 controls (6.0%). Thus the risk of getting PID was half as great among injectable users, similar in magnitude to risks reported for women using oral contraceptives, barrier methods and sterilization in developing countries.
BULLETIN OF THE WORLD HEALTH ORGANIZATION. 1986; 64(3):375-82.This memorandum from a World Health Organization (WHO) meeting held in 1985 summarizes available epidemiologic data from human studies, including the WHO Collaborative Study of Neoplasia and Steroid Contraceptives, on the association between depot-medroxyprogesterone acetate (DMPA) use and neoplasia. The WHO Collaborative Study is collecting data on cases and controls from 14 collaborating centers in 11 countries. Analysis of preliminary findings regarding cancers of the endometrium, ovary, liver, and breast suggest that there is no increased risk in DMPA users. The relative risk estimates for these sites are 0.3 for endometrial cancer, 0.7 for ovarian cancer, 1.0 for liver cancer, and 1.0 for breast cancer. The issue of a causal association between DMPA use and cervical cancer is less clear. The adjusted relative risk for cervical cancer was a nonsignificant 1.2; however, somewhat higher risks were noted in subgroups of longterm (over 4 years) users. Although the WHO study is the 1st to provide reliable data on DMPA and neoplasia, its findings must be regarded as tentative. At this point the data are insufficient to assess the influence of DMPA on risk among longterm users or risk long after initial exposure.
In: Zatuchni GL, Goldsmith A, Shelton JD, Sciarra JJ, ed. Long-acting contraceptive delivery systems. Philadelphia, Pa., Harper and Row, 1984. 1-19. (PARFR Series on Fertility Regulation)Depo-Provera (depomedroxy-progesterone acetate, or DMPA) and NORPLANT (the Population Council's registered trade name for subdermal implants) are focused on in this literature review. Over the past 17 years, more than 1 million individual doses of Depo-Provera have been supplied in Thailand. Currently 6,000 women a month use the method. Depo-Provera has proved outstandingly successful in Bangladesh for years. The basic disadvantage of long-acting steroid systems is that return to fertility is slow and unpredictable. Other disadvantages include menstrual distrubances and weight gain. Acceptability of injectable contraceptives has been studied primarily by the World Health Organization (WHO). In 1976, the Task Force on Acceptability of Research and Family Planning explored preferences among 3 routes of contraceptive administration: 1)oral; 2)intravaginal; and 3)injection. The study was conducted in Indonesia, Korea, Pakistan, and Thailand. Although the oral route was generally preferred by most women, many respondents still chose the injectable. A WHO III multicentered trial comparing the use, effectiveness, side effects and bleeding patterns of Depo-Provera and norethisterone enanthate (NET-EN) was terminated after only 1 year because of excessively high pregnancy rates with NET-EN. A total sample of about 250 women in Manila and Alexandria were interviewed. Results indicated that the 2 most important considerations were effectiveness and menstrual bleeding. Depo-Provera did not affect menstruation. Various types of subdermal implants releasing a contraceptive Silastic implant, is placed beneath the skin of the forearm or upper arm and provides 5 or more years' protection against pregnancy. The 6 capsules are not biodegradable and require surgical removal under local anesthesia.
Breast cancer, cervical cancer, and depot medroxyprogesterone acetate. [WHO Collaborative Study of Neoplasia and Steroid Contraceptives] [letter].
Lancet. 1984 Nov 24; 2(8413):1207-8.This letter presents the preliminary findings of a collaborative, multinational, hospital-based, case-control study being conducted under the auspices of the World Health Organization to assess the influence of depot medroxyprogesterone acetate (DMPA) on risks of mammary, gynecological, and hepatobiliary malignancies. The frequency of ever-use of DMPA was greater in breast cancer cases (15/246, or 6,0%) than in controls (381/4162, or 9.2%). When adjusted for age, center, age of birth of 1st child, and nulliparity, the relative risk in women who had ever used DMPA was 0.7. The lowest risk was noted in women who had used DMPA for 3 or more years, but no decreasing trend in risk with duration of use was evident. The reducton in risk of breast cancer in DMPA users was largely confined to women with 1st exposure after age 30 years. In terms of cervical cancer, a history of DMPA use was reported by slightly more cases (67/469, or 14.3%) than controls (269/2704, or 9.9%). Use of oral contraceptives, number of cervical smears, and number of pregnancies were the variables most strongly related to cervical or having the greatest influence on relative risk estimates for users of DMPA. When controlled for these 4 factors and age and center, the relative risk in DMPA was 1.13. The highest relative risk was found in longterm users, although there was no clear trend of increasing risk with duration of DMPA use. These preliminary findings provide no evidence that DMPA increases the risk of breast cancer. The relative risk for cervical cancer for DMPA users obtained in this study could be due to chance or to incomplete control for the confounding effect of sexual variables. Although the absence of a trend of increasing risk with duration of use tends to rule out a causal connection between DMPA use and cervical cancer, the doubling of risk in women who used DMPA for 5 years or more is of potential concern.
In: United States. Food and Drug Administration. Depo-Provera Public Board of Inquiry. Official transcript of proceedings, Food and Drug Administration. Depo-Provera Board of Inquiry. Vol. 3. January 12, 1983. Arlington, Virginia, TIW Reporting Group, . 40-55.In this testimony to the US Food and Drug Administration (FDA) Deop-Provera Public Board of Inquiry, Pramila Senanayake, Medical Director of the International Planned Parenthood Federation (IPPF), urges the FDA to reconsider its decision not to approve Depo-Provera for use in the US. It is noted that over 15 years of clinical experience with Depo-Provera has demonstrated that the drug represents a safe and effective method of fertility regulation. Over 11 million women worldwide have used Depo-Provera and more than 2 million women are currently using it. IPPF has estimated that the drug is significantly available in 10 of the 14 developed countries where it is licensed for contraceptive use. Depo-Provera represents an attractive option for women in need of highly effective contraception but who have difficulty complying with the daily routine required by oral contraception or who cannot tolerate the IUD. Since Depo-Provera contains only a long-acting progestogen, it does not involve the side effects related to estrogen. Moveover, it represents a safe contraceptive choice for women over 35 years of age who smoke. Approval of Depo-Provera for longterm contraceptive use would increase the options open to users and physicians, enhancing the possibility of meeting the specific contraceptive needs of a greater number of couples. If the US reaffirms its decision not to approve the use of Depo-Provera for contraceptive purposes, there is the danger that many other countries will feel compelled to take similar action, depriving women in these countries of access to this method.
In: United States. Food and Drug Administration. Depo-Provera Public Board of Inquiry. Official transcript of proceedings, Food and Drug Administration. Depo-Provera Board of Inquiry. Vol. 3. January 12, 1983. Arlington, Virginia, TIW Reporting Group, . 7-13.Dr. S. Holck, a member of the World Health Organization (WHO) Secretariat, described WHO's Special Program of Research and Human Reproduction and introduced the representative of the program who will address specific questions raised by the board in this inquiry. The program was eastblished in 1972 for the purpose of promoting family planning research and development. 1 area of research which the program focuses on is assessing the safety and effectiveness of existing contraceptives. The program helps developing countries conduct large scale studies through a network of WHO centers. The use of the same protocal for collecting inforamtion in all centers facilitates interpopulation comparison ans ensures that data is collected on large population samples. The safety of Depo-Provera has been assessed by the program on a continuing bases. In 1978 the program convened a meeting of its Toxicology Review Panel, scientist, and members of drug regulatory agencies to examine the findings of animal and human studies in the 2 currently available injectable contraceptives. i.e., Depo-Provera and norethisndrone enanthate. The members concluded that the findings did not substantiate that there were serious associated with Depo-Provera for humans; however, they noted that there was a need to continue monitoring Depo-Provera in order to assess whether prolonged use of the drug produced serious adverse affects. In 1981 the program convened another meeting to assess injectable contraceptives in light of the findings of more recent animal and human studies. The participants saw no reason to reverse their earlier decision regarding Depo-Provera. Depo-Provera has been used for 15 years and there is no evidence that the drud is associated eith any more adverse than other hormonal contraceptives. The program is continuing to conduct extensive research on injectable contraceptives. Studies include: 1) phase 3 and phase 4 clinic trial; 2) a large comparative study of the 2 injectables; 3) a case control study of neoplasia and steroid contraceptives, including Depo-Provera; 4) an investigation of the effects of Depo-Provera on exposed infants; 5) several investigations to identify any longterm effects of Depo-Provera; and 6) several studies on the drug's metabolic, lipid and protein effects and pharmocology.
Multinational comparative clinical trial of long-acting injectable contraceptives: norethisterone enanthate given in two dosage regimens and depot-medroxyprogesterone acetate. A preliminary report.
Contraception. 1982 Jan; 25(1):1-11.A multicenter phase 3 clinical trial compared norethisterone enanthate (NET-EN) given by 2 different treatment regimens and depot-medroxyprogesterone acetate (DMPA). After 18 months of observation, preliminary findings are reported for 790 women who received NET-EN 200 mg every 60 days; for 796 women who recieved NET-EN every 60 days (200 mg) for 6 months, then 200 mg every 84 days, and for 1589 women who received DMPA 150 mg every 90 days. Overall discontinuation rates and discontinuation for bleeding and personal reasons were similar for all 3 groups after 18 months observation (61.8-63.5/100 women). Terminations due to amenorrhea were significantly higher among DMPA users (12.1 and 17.4/100 women at 12 and 18 months) than among both NET-EN groups (6.8-8.2/100 women at 12 months and 10.4-10.9/100 women at 18 months). The only significant difference in pregnancy rates observed among the 3 groups was a higher rate at 18 months among NET-EN (84 days) users (1.6/100 women), than among DMPA users (0.2/100 women). There was no overall significant difference between the 2 NET-EN groups, although between the 6 and 18 month follow-ups when the 2 NET-EN regimens diverged, the NET-EN (84 days) users' pregnancy rates rose significantly, whereas in the NET-EN (60 days) group, the pregnancy rate did not change. Weight gain was significantly higher in those subjects using NET-EN at 60 day intervals than at 84-day intervals. (author's modified)
Injectable Contraceptives Newsletter. 1982 Apr; (9):1-2.Noristerat is the trade name for a long-acting injectable contraceptive. It is a formulation of Norethisterone enanthate (NET-OEN) in 4 parts of Benzobenzoate and 6 parts of castor oil. The active principle of the drug is Norethisterone which is released from intramuscular depot following hydrolysis of the enanthate side-chain by unspecified tissue. NET-OEN is registered at this time in 36 European, African, Asian, Central and South American countries. Extensive ongoing clinical trials have been and are being carried out by several international organizations including the World Health Organization (WHO). Extended preclinical drug safety testing has been carried out in the U.S. The 1st pilot studies with NET-OEN were performed in 1958; regular clinical studies were started in October 1964. Peru was the 1st country to register and market NET-OEN, followed by Chile, Brazil, and Argentina. When toxicity studies revealed breast and liver tumors in rats NET-OEN was discontinued worldwide. Up to 1973 further toxicological studies had been completed in monkeys. These studies could not demonstrate any pathological effects on the experimental animals. Thus, NET-OEN was released again for further studies in February 1973. Investigations revealed that the development of mammarian and hepatic tumors in rats were not restricted to NET-OEN and could be provoked by administration of other substances. It was concluded that the findings in rats cannot be applied to humans. Schering's toxicological studies on NET-OEN include acute toxicity studies, chronic drug safety studies, and combined drug safety and carcinogenicity studies. With regard to the profile of endocrine activity, NET-OEN has been shown to have progestational and no estrogenic activity in humans. Clinical trials with NET-OEN have been performed in more than 20 different countries, and WHO has conducted 2 multi-center studies on long-acting injectable contraceptives comparing NET-OEN with medroxyprogesterone acetate. The data on use-effectiveness obtained from the 1st WHO study showed a higher failure rate for NET-OEN, i.e., 3.6/100 woman years, but a markedly better tolerance for NET-OEN was found. WHO began a 2nd multicenter trial in February 1976 with a modified application scheme. The results obtained thus far showed that by using these modified application schemes the contraceptive reliability of NET-OEN greatly increased.
Activities of the Special Program of Research, Training and Development in Human Reproduction, World Health Organization in the field of long acting contraceptives.
In: Bangladesh Fertility Research Program. Workshop on Injectable Contraceptives: Noristerat, Dacca, Bangladesh, April 25, 1980. [Dacca, Bangladesh, BFRP, 1980]. 70-80.Following a brief introduction to the World Health Organization (WHO) Special Program of Research, Development and Research Training in Human Reproduction, established in 1972, focus is on what has been achieved thus far with long-acting injectable fertility regulating agents based on steroidal hormones and possessing a duration of action of at least 1 month. Over the last 20-year period, several estrogen-progestin combinations have been developed as monthly injectable contraceptives. The Special Program has initiated a series of clinical pharmacological studies aimed at developing new and improved estrogen progestin injectable formulations. 1 preparation, composed of norethisterone enanthate (50 mg) plus 5 mg of estradiol valerate, has shown promise in preliminary clinical studies. 3 progestogen only preparations with a duration of action of several months have been tested clinically: clormadinone acetate, depo-medroxyprogesterone acetate and norethisterone-enanthate. The 1st clinical trials utilizing the heptanoic acid ester of norethisterone raised considerable hopes, for no pregnancies were observed in 70 highly fertile women given the drug every 90 days. In a WHO trial preliminary data on Depo-Provera (DMPA) bleeding irregularities were responsible for the discontinuation of 9.3 subjects/100 women-years; prolonged amenorrhea accounted for the termination of 11.5 subjects/100 women years. There are several ongoing studies to evaluate the effects of the injectables on users. Norethisterone enanthate, although not possessing the same degree of effectiveness as DMPA, when adminstered every 3 months, remains an attractive injectable because of its lower incidence of amenorrhea.
A preliminary pharmacokinetic and pharmacodynamic evaluation of depot-medroxyprogesterone acetate and norethisterone oenanthate.
Fertility and Sterility. 1980 Aug; 34(2):131-9.2 populations attending WHO centers, one in Sweden and one in India, participated in a comparative, pilot trial of 2 increasingly popular injectable progestin-only female contraceptives, Depo-Provera and Norigest. The purpose of the study was to assess the pharmacokinetic and pharmacodynamic properties of the 2 formulations (depot medroxyprogesterone acetate and norethisterone enanthate). Differences were found between Swedish women and Indian women in their reactions to the 2 drugs: 1) Norigest was detectable in blood samples a significantly shorter time after injection of the agent in Indian women than in Swedish women; this difference was not apparent with Depo-Provera. 2) Although there was no difference at the 2 centers in the time of ovulation return for subjects receiving Norigest, 0 of 4 Swedish women ovulated more than 156 days after Depo-Provera injection, whereas all 4 Indian women ovulated within 73 days of Depo-Provera injection; in the Swedish women, the levels of medroxyprogesterone were undetectable at time of return to ovulation, whereas Indian women had levels of .6 ng/ml when ovulation resumed. 3) In both cultures, Depo-Provera users had significantly more episodes of bleeding and spotting than Norigest users. This preliminary report emphasizes the variety of responses possible to injection of different contraceptive progestins among various populations and points to the need for further culturally comparative studies.
Report to USAID of the Ad Hoc Consultative Panel of Depot Medroxyprogesterone, New York City, December 7-8, 1978.
[Unpublished] . 59 p.An Ad Hoc Consultative Panel on Depot Medroxyprogesterone Acetate (DMPA) reviewed the results of animal toxicology studies and available information on the use, benefits, and risks of DMPA in humans in the U.S. and abroad. It also reviewed the conclusions of the World Health Organization (WHO) Toxicological Review Panel. Based on the information available, the Ad Hoc Consultative Panel recommended that the USAID make DMPA available to nations which request it. At present, DMPA is approved in the U.S. for treatment of endometrial cancer, but not for use as a contraceptive. It is approved for contraception in 76 developed and developing countries and has unusual popularity in many settings. The Panel found that DMPA has been used widely for clinical gynecologic uses at doses higher than that recommended for contraception, and no reports have been made of significant adverse effects. DMPA is the only available long-acting injectable contraceptive and has a higher use effectiveness than any other reversible contraceptive method. It has no relation to coitus, requires infrequent administration, and is provided outside the home. There is a mild effect on carbohydrate tolerance and a mild adrenal suppressive effect, but these are probably less than similar effects caused by oral contraceptives. Menstrual side effects are the most important complaints. Initially, there is irregular spotting, staining or bleeding; later, amenorrhea develops in 60% of women. No reason was found to support the Federal Drug Administration's decision not to approve DMPA as a contraceptive in the U.S.
INTERNATIONAL JOURNAL OF GYNAECOLOGY AND OBSTETRICS. 1979; 17(3):297-9.A report in Family Planning Perspectives (11:47, 1979) that 2 of 12 rhesus monkeys given 50 times the human dose of depot medroxyprogesterone acetate (DMPA) by body weight for 10 years had developed endometrial carcinoma (CA) instigated a retrospective survey of all hospital admissions for proven endometrial CA in 2 Thai provinces where DMPA contraceptive injections have been used since 1965. From 1974-78, 16 women were hospitalized with endometrial CA. None of the 9 women followed up had previously used injectable or oral contraceptives. The recorded incidence of endometrial CA has not increased in these provinces. The McCormick Hospital's Family Planning Department has administered 864,692 DMPA injections (150 mg. into the deltoid muscle every 12 weeks usually) to 86,511 acceptors for a total of 207,694 years usage. Over 300 women have used DMPA continuously for 10-13 years. This study concludes that the monkey dosage and incidence rates of CA do not apply to women taking normal dosage for long periods of time. DMPA should continue to be used and will be recommended to the Toxicology Review Panel of the World Health Organization's Special Programme of Research, Development and Research Training in Human Reproduction.
Multinational comparative clinical evaluation of two long-acting injectable contraceptive steroids: norethisterone oenanthate and medroxyprogesterone acetate. 1. Use-effectiveness.
Contraception. 1977 May; 15(5):513-533.A 10-center study of the use-effectiveness of long-acting systemic contraceptive agents is reported. 200 mg of norethisterone enanthate (NET-EN) was administered every 12 weeks + or -5 days to 832 women and 150 mg of depot medroxyprogesterone acetate (DMPA) was administered to 846 women on the same schedule. The cumulative 12-month gross pregnancy rate/100 woman-years was 3.6 + or -.7 for NET-EN and .7 + or -.4 for DMRA. 54% of all the pregnancies in the NET-EN group was contributed by 2 of the 10 centers. 75% of the NET-EN pregnancies occurred during the 1st injection period, primarily in the last 4 years. The admission weight of NET-EN women who became pregnant was significantly lower than those for whom the method was successful. This difference was absent in the DMPA group. The cumulative discontinuation rate for medical reasons at 12 months was 16.9 + or -1.4/100 woman-years for NET-EN and 23.4 + or -1.7 for DMPA. The discontinuation rate for amenorrhea was significantly higher for DMPA than for NET-EN. Differences between the drugs for bleeding irregularities were insignificant as were discontinuations for nonmedical reasons. This study represents a successful attempt at comparing the use-effectiveness of 2 drugs under highly standardized conditions using a large sample drawn from a number of internationally representative settings.
In: Diczfalusy, E., ed. Regulation of human fertility. (Proceedings of the WHO Symposium on Advances in Fertility Regulation, Moscow, USSR, November 16-19, 1976) Copenhagan, Denmark, Scriptor, 1977. p. 323-360Long-acting systemic contraceptives inhibit fertility either at a central or peripheral level. In some instances, a mixed reaction is likely to be working: during the 1st portion of the drug's life-span the contraceptive effect is exerted at a hypothalamic central level, whereas later on--when ovulation is restored--the action is on the cervix or uterus. The most important factor holding back utilization of long-acting agents is serious interference with regularity of the menstrual cycle, and delivery systems must be devised with zero-order release rates to improve cycle control and acceptability. Monthly injectables consisting of synthetic progestins alone proved unsuitable for contraception because of frequent and prolonged amenorrhea. Addition of an estrogenic substance helped cycle control, and a dihydroxyprogesterone acetophenide plus estradiol enanthate combination seems most worthy of clinical investigation; so far, 15,000 woman-months of experience have yielded no unwanted pregnancies. Few bleeding pattern irregularities were reported, but premenstrual tension, dysmenorrhea, and libido changes occurred. Reversibility of drug-induced anovulation has been shown by spontaneous ovulation resumption 12-42 weeks after cessation. Tri-monthly injections of Depo Provera resulted in pregnancy rates averaging .5/100 woman-years of use. Biannual injectable and sustained release systems are discussed and data are presented.