Facts About an Implantable Contraceptive: Memorandum from a WHO Meeting*

Bulletin ofthe World Health Organization, 63 (3): 485-494 (1985) © World Health Organizationi 1985

Facts about an implantable contraceptive: Memorandum from a WHO Meeting*

This Memorandum reviews the results of research undertaken in animals and human subjects on the implantable contraceptive, Norplant, and where relevant, its components, levonorgestrel and Silastic. Results from clinical trials, including effectiveness and side- effects, are evaluated and service delivery aspects commented on. The Memorandum concludes with a statement regarding the use of Norplant as an option for long-term reversible contraception.

Through its Special Programme of Research, delivery of lipophilic drugs (1), and it was subse- Development, and Research Training in Human quently proposed for use in the delivery of contra- Reproduction, the World Health Organization ceptive steroids (2). After studies with several steroids provides advice to Member States and responds to (3-7), the ICCR selected levonorgestrel as- the drug questions from governments, other organizations of with which the Silastic subdermal implant would be the United Nations system, and the scientific com- developed further (6, 8). Levonorgestrel is used exten- munity on the safety and effectiveness of existing and sively as a progestogen for contraception in both new methods of fertility regulation. In response to a combined progestogen-estrogen and progestogen request from the United Nations Fund for Population only oral contraceptive pills (9) and in other Activities (UNFPA) to evaluate proposals for the injectable and implantable systems, intrauterine introduction into family planning programmes of the devices, and vaginal rings currently under new implantable contraceptive, Norplant, a development (10). consultation was convened by the Special Programme Since 1975, clinical studies on Norplant have been to review all data available from animal and human initiated in several centres by ICCR. In more recent studies on this method of fertility regulation. years, other investigators, funded by other agencies, The only implantable contraceptive that can have also become involved. To date, studies have currently be considered for introduction into family been undertaken in the following countries: Brazil, planning programmes is Norplant, which was devel- Chile, Colombia, Denmark, Dominican Republic, oped by the Population Council, New York, USA, Ecuador, Egypt, Finland, India, Indonesia, Jamaica, primarily through its International Committee for Sweden, Thailand, and the United States of Contraception Research (ICCR). It is registered America. under the Population Council's trademark as a The Norplant system consists of six capsules, each subdermal implant for the release of levonorgestrel containing 36 mg of levonorgestrel and having a and is manufactured under licence from the diameter of 2.4 mm and a length of 3.4 cm. The six Population Council by Huhtamaki Oy/Leiras capsules appear to release levonorgestrel at a rate of Pharmaceuticals, Finland. It was approved for con- approximately 80 ug per 24 h during the first 6-18 traceptive use in November 1983 by the Finnish months of use. This rate declines over the next few National Board of Health and is presently under con- months and thereafter the capsules deliver approxi- sideration by the Swedish National Board of Health mately 30 ,g of levonorgestrel per 24 h. This latter and Welfare. Submissions are expected to be made to rate of release is maintained for at least 5 years. The the drug regulatory agencies of some 40 additional capsules are inserted subdermally, usually in the inner countries within the next two years. aspect of the upper arm or in the palmar aspect of the About 20 years ago it was shown that Silastic (poly- forearm, by means of a specially designed 10-gauge dimethylsiloxane) could be used for the long-term trocar which is introduced through a single 2-mm * This Memorandum was drafted by the signatories listed on incision. p.492, on the occasion of a Consultation convened by the World A second-generation system is also being developed Health Organization in Geneva in October 1984. Requests for reprints should be addressed to the Director, Special Programme of by the Population Council which utilizes only two Research, Development and Research Training in Human Repro- implants and is known as Norplant-2. This system duction, World Health Organization, 1211 Geneva 27, Switzerland. A French translation of this Memorandum will appear in a later issue consists of two rods in which levonorgestrel is of the Bulletin. homogeneously dispersed within a Silastic matrix and 4545 -485- 486 MEMORANDUM covered by a layer of Silastic. The rods are 2.4 mm in more than 1260 mg/kg of body weight in neonatal diameter and 4.4 cm long and have been shown to rats. The dose administered to women by implants deliver amounts of levonorgestrel equivalent to those may be estimated to be about 1 gg/kg of body weight released by Norplant. Norplant-2 is currently being per day. No toxicity relevant to the human was seen in tested in phase III clinical trials. animal studies, which indicates a wide margin of The only other implantable system for contra- safety. ception that could be available to family planning programmes this decade is the Capronor device, Subacute and chronic toxicity developed by the Contraceptive Development Branch of the US National Institute of Child Health and A considerable amount of information is available Human Development in collaboration with the WHO from long-term studies of d,I-norgestrel and levonor- Special Programme of Research, Development, and gestrel in mice, rats, dogs, and monkeys. The chronic Research Training in Human Reproduction (10). toxicity studies with levonorgestrel, in dogs and monkeys, are summarized in Table 1. These studies, Capronor consists of a single biodegradable capsule conducted by Wyeth Laboratories, USA, were that delivers levonorgestrel for a period of approxi- reported in detail to the FDA, and have been incor- mately 18 months. This system is at an early stage of development; preliminary clinical trials have been porated in files on Norplant submitted by the completed (11, 12) and studies will shortly be Population Council to the FDA, and by Huhtamaki Pharmaceuticals to the Finnish National to cover safety and efficacy. Oy/Leiras expanded Board of Health. The Toxicology Review Panel noted that studies in ANIMAL STUDIES the beagle dog showed no adverse effects relevant to human use, but nevertheless restated its opinion that the beagle dog is an unsuitable toxicological model The Toxicology Review Panel of the Special for the study of progestogens. The studies were has reviewed the animal data available on Programme completed before the Panel's opinion on the and the two components of the system, levonorgestrel relevance of the beagle model was first published in Silastic, as well as on Norplant itself. Toxicological 1982 (13). studies on levonorgestrel have been conducted in One 10-year study in the rhesus monkey, in which accordance with the requirements of the United the animals received the drug orally in capsules, has Kingdom Committee on the Safety of Medicines and recently been completed. The highest dose given was the United States Food and Drug Administration equivalent to 1000 times the human implant dose. No (FDA), among others. It should be noted that these toxic effects attributable to the treatment were studies refer to both the racemic mixture, d,l-nor- found. gestrel and to its biologically active enantiomer, Extensive chronic toxicological studies have been levonorgestrel, which comprises 50Gb of the racemic conducted to evaluate the systemic effects of levonor- mixture. Originally, d,l-norgestrel was used in gestrel. Dosing schedules have included daily in more recent it hormonal contraceptives but times administration, as well as cyclic administration has largely been replaced by levonorgestrel. comparable to the human use of contraceptives. The studies have served as a basis for the approval by the Acute toxicity FDA of oral contraceptives with the following The acute toxicity of d,l-norgestrel is over composition: 500 ug of d,l-norgestrel with 50 1tg of 5000 mg/kg of body weight (LD5o) as determined by ethinylestradiol; 300 ug of d,l-norgestrel with 30 ug oral administration in dogs and by various routes of of ethinylestradiol; 150 jg of levonorgestrel with administration in adult mice and rats. The LD50 value 30 jg of ethinylestradiol; and 75 jg of d,l-norgestrel is 950 mg/kg of body weight in neonatal mice and alone.

Table 1. Chronic toxicity studies on levonorgestrel

Species Highest dose Route Multiple of Duration (mg/kg of body weight) daily implant dose Dog 0.5. cyclic Capsules 500 7 years Dog 0.125, cyclic Capsules 125 7 years Monkey 1 .0, cyclic Capsules 1000 10 years AN IMPLANTABLE CONTRACEPTIVE 487

Effects on reproduction Even though it is well established that impervious or semipermeable subcutaneous implants induce local Teratological and reproduction studies have been sarcomas in rats (15), this observation is not undertaken in rats and rabbits. Both d,l-norgestrel considered to be relevant to man in the light of the and levonorgestrel have been used in doses corres- very extensive and long-term use of Silastic in ponding to more than 100 times and 50 times the malignant tumours have not human dose, respectively. No adverse effects that humans, during which would suggest a risk for humans were found. In been observed. another study, in which covered rods releasing 3.5 Ag of levonorgestrel per 24 h were inserted between Conclusions implantation sites in the uterus of the pregnant rabbit, The Toxicology Review Panel concluded that the there was no evidence of any teratological effects on toxicological and teratological data from animal the progeny (ICCR, unpublished data). Masculini- studies on both levonorgestrel and Silastic provide a zation was observed in offspring of rats, but this has sufficient indication that Norplant may be considered been reported with other progestogens and is not safe for use in humans. considered to be relevant to human subjects. No other fetal abnormalities or malformations were found and the duration of gestation was not altered. Offspring HUMAN STUDIES reserved for subsequent breeding were normal with respect to survival age and reproductive capacity. A substantial number of clinical trials have been Three dose levels of d,l-norgestrel were given to undertaken on Norplant, including several major lactating rats, the highest dose being 150 times the phase III studies supported by the ICCR and other human dose. No significant effect was seen in the agencies. Use-effectiveness and side-effects have mothers, in the young, or on lactation. been evaluated in studies that have continued for more than 5 years. However, because the method is Relevance of animal tests to the implant dosage only now becoming widely available, there have, as form yet, been no epidemiological studies of long-term safety. Long-term animal tests of levonorgestrel have been carried out using oral administration. Several factors must be considered in weighing the relevance of these Release rates tests to the implant mode of administration. These The amount of levonorgestrel released from include the relative bioavailability of the drug by implants has been calculated from the difference different routes of administration and the relative between the steroid content at time of placement and constancy of exposure to the drug. When plasma the amount remaining after a known period of use. levels of the drug have been measured, the bio- An analysis of steroid loss from 42 sets of implants availability by the oral route has been reported as 9% used for periods ranging from 1.3 to 6.3 years gave an for the rat, 22% for the dog, 9% for the monkey, but average release rate of 30 yg per 24 h (16). These data 87% for the human (14). Plasma levels of levonor- were later supplemented by similar analyses from an gestrel in Norplant users are lower than those additional 117 sets of capsules recovered at various observed with oral administration and do not fluc- time intervals up to about 8 years from subjects in tuate. In view of these considerations the toxico- several clinics. The data suggest an initial release rate logical studies involving oral administration were of approximately 80 zg per 24 h, which declines over considered pertinent to the safety of the drug released the first 6-18 months to an approximately constant from the implanted drug delivery system. release rate of about 30 tg per 24 h. Safety ofsilicone rubber in implants Peripheral blood levels of levonorgestrel Silicone rubber materials have been used to make Several studies have reported data on peripheral implants of various kinds, such as heart valves and blood levels of levonorgestrel (16-21). Extensive data drainage tubes, for use in humans over long periods. from unpublished studies were also made available to It was estimated that, by 1974, 200 000 shunts had the consultation by the ICCR. In all of the studies, been implanted in patients with hydrocephalus, and analyses for levonorgestrel were carried out by radio- many thousands more have been used in the subse- immunoassay. The results show that immediately quent 10 years. The Silastic tubing used to make the after implantation of the devices there is a rapid rise in shunts is of the same type and diameter as that used in peripheral levonorgestrel levels, to 3-4.5 nmol/litre the Norplant capsules. after 24 hours. From results derived from other 488 MEMORANDUM studies on levonorgestrel, levels of this magnitude are absence of elevated progesterone levels, indicating likely to be more than sufficient to inhibit ovulation follicular activity and no ovulation (17, 18). (22, 29). During the subsequent 6-18 months, the mean plasma levels gradually decline to 1-1.5 nmol/litre. The mean values in individual Effects on cervical mucus subjects appear to remain constant thereafter for a The effect of levonorgestrel on cervical mucus also further 5 years, after which there is a substantial contributes to its contraceptive efficacy. During decrease. Norplant use, the cervical mucus becomes viscous and As with all other constant delivery systems for scanty, and in a few subjects from whom it was pos- levonorgestrel, there is considerable between-subject sible to obtain cervical mucus, poor sperm pen- variation in circulating levels of levonorgestrel. One etration was seen compared with control subjects. In of the factors that contribute to this variation is the another study, post-coital tests have also shown poor large difference in sex-hormone binding globulin sperm penetration (ICCR, unpublished data). (SHBG) levels observed between normal individuals (23, 26). Unlike several other progestogens, levonorgestrel has a high binding affinity to SHBG, and Effects on the endometrium there is thus a correlation between circulating levels of SHBG and levonorgestrel. Levonorgestrel also Endometrial biopsies from 41 women who used suppresses SHBG levels, resulting in a decrease in Norplant for between 6 and 110 weeks have been both SHBG and levonorgestrel levels. Moreover, studied (30). Using the criteria of Noyes et al. (31), subjects starting with a high level of SHBG show a 5 endometria were normal, 12 were diagnosed as greater suppression in SHBG and hence levonor- irregular secretory, and 24 demonstrated suppressed gestrel than those with lower initial levels of SHBG. activity. These findings are similar to those obtained Thus significant between-subject variation in with other low-dose progestogen delivery systems peripheral levonorgestrel levels is found (24-26). Two (29). There was no evidence of endometrial inflam- studies on Norplant users have shown similar results mation, atrophy, hyperplasia, carcinoma, or other (27; ICCR, unpublished data). pathological processes. Following the removal of the implants, plasma levonorgestrel becomes unmeasurable within a few days. A removal half-life of some 18 hours can be Other endocrine effects calculated (ICCR, unpublished data), which is in Although one study claimed a significant increase good agreement with that reported by other investi- in peripheral androstenedione and some increase in gators for other modes of administration of levonor- testosterone levels after 6 months' use of Norplant gestrel (17, 28, 29). (32), two other studies demonstrated contrary results (27, 33). One of these, a cross-sectional study, showed significantly lower testosterone levels in users Effects on ovarian function of Norplant after 51 months than in IUD users (33), The ovarian response to levonorgestrel released while the other, a longitudinal study, showed a from the Norplant implants shows considerable vari- decline in testosterone, androstenedione, and SHBG ation, both within and between subjects, as has been levels (27). Increases in prolactin levels have been observed with other low-level levonorgestrel delivery observed, but were within normal limits (34). systems (29). When periods of treatment were With regard to effects on adrenal function, a evaluated in 6-week segments, elevated plasma pro- decrease in peripheral levels of cortisol, of approxi- gesterone levels ( > 10 nmol/litre) were observed in mately 30% over 12 months, has been observed, 4401 of the segments, but the mean increase in pro- although the values were within the normal range and gesterone level was less than that observed in ovula- remained so during 3 years of observation (35). tory cycles in normal menstruating women. There was Similar results were obtained in another study over also a marked suppression of the luteinizing hormone one year (36). The adrenal response to adrenocortico- surge. It is not known whether the periodic increases tropic hormone (ACTH) stimulation has been shown in progesterone levels seen in Norplant users and in to be normal (37). Regarding thyroid function, no subjects using other low-dose progestogen formu- alterations have been observed in thyroxine and lations (29) reflect the occurrence of ovulation, since thyroid-stimulating hormone (TSH) levels; a decrease monitoring by ultrasound has as yet yielded incon- was found in triiodothyronine levels, although the clusive results. In other treatment segments, increases levels remained within the normal range (33). Thus, in estradiol were observed, which varied in amplitude Norplant does not appear to disturb significantly the (up to 2 nmol/litre) and duration (5-20 days), in the function of the thyroid and adrenal glands. AN IMPLANTABLE CONTRACEPTIVE 489

Metabolic effects with familial diabetes and, in both, glucose tolerance Several cross-sectional and longitudinal studies returned to normal at the next test. While the data are have been undertaken to determine the metabolic and limited, Norplant appears to have no deleterious biochemical effects of Norplant at intervals of up to 3 effect on carbohydrate metabolism. years. Coagulation studies before treatment, and at 1, 3, Studies on lipid metabolism have given inconsistent and 6 months were undertaken in one study (43). Two results: triglycerides were reported to be significantly groups of subjects taking oral contraceptives were decreased, as were cholesterol and low-density lipo- used as controls. Nine clotting factors and nine other protein (LDL)-cholesterol levels, with up to 37 haematological parameters were measured. An months of use (33, 38, 39; ICCR, unpublished data). increase in factor VII and a decrease in antithrombin Widely discrepant changes in high-density lipoprotein III were the only significant changes observed in (HDL)-cholesterol have been reported, however, Norplant users after 6 months; these changes were including: no change (33); decrease (39); and no significantly less than those observed in the groups change initially, but a significant increase at 12 taking oral contraceptives. Moreover, the oral months (38). Two laboratories reported decreases in contraceptive users showed significant changes in HDL-cholesterol levels and in total cholesterol, many of the other factors measured, whereas the giving an unchanged cholesterol/HDL-cholesterol Norplant users did not. ratio (ICCR, unpublished data). In the centre reporting increased HDL-cholesterol levels, the Use-effectiveness and discontinuation rates cholesterol/HDL-cholesterol ratio was reduced at 6 Experience with more than 14 000 insertions of months and further at 12 months. A recent study with Norplant has shown a low pregnancy rate and a high rods releasing equivalent amounts of levonorgestrel continuation rate (44-48; ICCR, unpublished data). has shown alterations in some subfractions of lipo- The aggregate interim results from a number of proteins; HDL-2a, HDL-2b, and HDL-3 were clinical trials conducted by the ICCR, involving 992 reduced after 1-2 months of use; these decreases were women, indicate a gross cumulative pregnancy rate at less pronounced at 6 months and there was a return to 5 years of 2.6 per 100 woman-years. The annual normal levels after 12 months (40). The studies pregnancy rates during the first 5 years ranged from carried out so far used different methodologies, tech- 0.2 to 1.3. Data on 100 women entering the 6th year niques of quality control, and populations, and show a pregnancy rate of 2.9 (with a standard error further studies are still needed to clarify the effects of of± 1.4), which suggests a reduction in efficacy levonorgestrel released from Norplant on lipids and although the rate is not significantly different from lipoproteins. the rates for the first 5 years. Liver function has been evaluated at several centres In a clinical trial in 3 countries conducted between (41; ICCR, unpublished data). Slight non-significant the years 1978 and 1983, the continuation rate at 1 increases in total serum protein and albumin were year was 81.4 per 100 women and at 4 years was 49.1 observed. A reduction in ceruloplasmin levels at 6 per 100 women (44). In a number of other studies months was reported, as well as small increases in undertaken in developing countries, continuation bilirubin and bile acids in the first month; these levels rates at 1 year were higher (45-48). Continuation rates returned to normal over the next 5 months (41). No were lowest among younger women and those other changes in liver function were seen. In two other desiring a pregnancy (44). These continuation rates cross-sectional studies (33, 42), after 51 months of are comparable to those commonly quoted for the use, liver function was not significantly different IUD. from that observed in control subjects using intra- The major medical reason for termination has been uterine devices. menstrual irregularities, the aggregate cumulative Measurements of urea nitrogen, uric acid, sodium, rate for several centres being 14.1 per 100 women at 4 potassium and calcium (33, 42; ICCR, unpublished years (44). It should be noted that these data are from data) showed no changes. A significant decrease in clinical trials and therefore may not be representative inorganic phosphorus was observed, but levels of discontinuation rates that might be seen in pro- remained within the normal range (33). No changes in gramme use. It is difficult to compare the results of immunoglobulins have been observed. these studies with those on other contraceptive Mean blood glucose levels have been shown to be methods since the contraceptive in question has a elevated, but within the normal range, after 12-51 known duration of action of 5 years and the acceptors months of Norplant use (ICCR, unpublished data). are thus likely to be highly motivated to continue In one study, oral glucose tolerance tests were done at contraceptive use for such a period. intervals of 6 months for 3 years in 9 subjects (35). A total of 11 pregnancies have been reported to be Abnormal glucose tolerance was observed in 2 women due to method failure. Of these, there were 2 ectopic 490 MEMORANDUM pregnancies, both from the same centre, giving an should be considered. Normal regular menstrual incidence of ectopic pregnancy of 0.8 per 1000 bleeding can be expected to resume shortly after, woman-years (44). Although the number of events is unless the bleeding has another pathogenesis. small, the method does not appear to increase the incidence of ectopic pregnancy. However, should a Insertion and removal ofNorplant pregnancy occur in a woman using Norplant, atten- Extensive clinical experience has been accumulated tion must be paid to the possibility of an ectopic on the insertion and removal of Norplant. More than pregnancy. 14 000 women have had these capsules inserted and In a cohort of 992 women, a mean increase in 10-15% have had them removed. The experience weight of 1.4 kg occurred during the first year of gained has indicated that, to minimize the risk of use of Norplant. However, although weight was infection, both insertion and removal should be increased in 52% of the women, 35% of the subjects performed in a clinic setting. It is of utmost showed a decrease (49). No significant changes in importance that sterile techniques be maintained systolic or diastolic blood pressure were found during throughout both procedures. the first 3 years of use of Norplant; no data are Norplant should be inserted during the first 7 days available for a longer duration of use. In the studies after the onset of menstruation in order to minimize reported by ICCR, headache was the second pre- the risk of insertion during an undiagnosed preg- dominant spontaneously reported complaint after nancy. Insertion can also be done immediately after bleeding disturbances, accounting for 3.2% of the abortion and in non-breast-feeding women im- discontinuations during the first 3 years of use (44). mediately postpartum. At this stage of knowledge, it However, it has not appeared to be a problem in most is not possible to make a recommendation on the use clinical trials of Norplant in other countries of Norplant in lactating women. (45-48). The preferred sites of insertion are the upper arm or the forearm. It is important that the capsules be Bleeding patterns inserted superficially, as deeper insertion makes As with other progestogen-only contraceptives, the removal more difficult. In one study, removal was major side-effect of Norplant is the disruption of the difficult in 1201 of the subjects primarily because the menstrual cycle; about 40% of Norplant users report capsules had been inserted too deeply (ICCR, a regular bleeding pattern during the first year of use. unpublished data). Sutures are not required to close Most abnormal bleeding episodes are characterized the small incision and the scar is usually minimal, by an increased frequency, an increased number of although keloid formation has been reported to occur bleeding days, or irregular bleeding and spotting. occasionally (ICCR, unpublished data). Local Heavy bleeding episodes are uncommon and the complications following insertion are uncommon and prevalence of abnormal bleeding decreases with the cumulative local infection rate is 0.3%o. Expulsion duration of use. of capsules is rare and has occurred only in the In a study of a cohort of 104 Norplant users who presence of infection. Only one instance of migration completed 4 years of use, 25% reported bleeding of a capsule has been reported (ICCR, unpublished episodes lasting more than 11 days in the first year, data). while only 10% had such bleeding episodes during the The capsules should be removed after 5 years of use second, third and fourth years of use (44). In another as the effectiveness of the method declines after this cohort of 54 women, 50Gb of users reported bleeding time. However, in the event that a woman does not and spotting for more than 96 days during the first return for scheduled removal, no deleterious effects year of use; only 20% reported this during the third would be expected, other than the risk of unplanned year (50). While the menstrual problems do diminish pregnancy. If a woman wants to continue this method markedly with time, these complaints are the major of contraception, a new set of implants may be reason for discontinuation in the first year of use (45, inserted. Removal of the capsules is more time- 48,51,52). consuming than the insertion: for example, in one In a small study, the mean amount of monthly clinic the mean time for insertion was 7 minutes, and blood loss in Norplant users decreased, although not for removal, 21 minutes (ICCR, unpublished data). significantly, from 30 ml pretreatment to 24 ml When the capsules are removed because of compli- during the first year of use (53). Mean haemoglobin cations related to the method or if the woman wants levels increased slightly but significantly in Norplant to conceive, blood levels of levonorgestrel decline users and evidence of anaemia from the use of rapidly, becoming undetectable within two days, and Norplant, even in women with frequent bleeding ovulation resumes promptly. Of patients having episodes, has been rare (49). If a user develops severe Norplant removed in order to conceive, 40% had and prolonged bleeding, removal of the capsules become pregnant by 3 months, 76% by 1 year and AN IMPLANTABLE CONTRACEPTIVE 491

90070 by 24 months (44). These rates are similar to CONCLUSIONS normal rates of fecundity. The implants should be removed whenever requested by the woman or in the The Norplant subdermal implant is a very efficient case of an accidental pregnancy that the woman method of contraception, which remains effective for wishes to carry to term. at least 5 years. This long duration of contraceptive action is particularly advantageous to women who Contraindications for the use ofNorplant wish an extended period of contraceptive protection, Since Norplant is a new method of contraception, irrespective of whether a subsequent pregnancy is there has been insufficient time for large-scale, long- planned. term studies of rare adverse effects; thus, contraindi- Animal studies on levonorgestrel, the progestogen cations and possible warnings regarding Norplant use released by the implant, provide a sufficient indi- must be based on extrapolation from information on cation that the drug may be considered safe for use in other hormonal methods. Until further information humans. Extensive clinical studies have so far not is available it is considered inadvisable to use shown any major adverse side-effects. Silastic, from Norplant as a method of contraception in women which the capsule is made, has been used in human undergoing anticoagulant therapy, or with undiag- subjects since 1950 for extended periods and has nosed abnormal uterine bleeding, known or suspected shown no adverse effects. pregnancy, haemorrhagic diathesis, or active hepato- The clinical trial data available to date on more cellular disease. than 4000 women have shown high continuation rates, ranging from 60%7o to 950% at the end of the first year, and about 50070 at the end of the fifth year. As with other progestogen-only contraceptives, the most SERVICE DELIVERY ASPECTS common side-effect and the principal reason for discontinuation is bleeding irregularities. These occur Service delivery issues arising from the intro- at some time in the majority of women using this duction of Norplant must be addressed if utilization method, although bleeding problems tend to diminish of this method in family planning programmes is to be with increasing duration of use. Women have successful. Although clinical trials have provided reported irregular bleeding, spotting and, to a lesser extensive experience with Norplant, there is limited extent, amenorrhoea. Heavy and prolonged bleeding information on service aspects, which will be needed has rarely occurred. by both family planning programme administrators Because of the constant release of small amounts of and clinic staff. The cost-effectiveness of the method the contraceptive drug (approximately 30 jig per 24 h relative to other methods of contraception remains to after the first 6-18 months of use), the total amount be determined. of drug to which the body is exposed is small, being Since Norplant utilizes a new mode of drug less than 100 mg of levonorgestrel over 5 years. Thus, delivery, requiring insertion and later removal, potential side-effects of the contraceptive steroid are considerable attention must be given to training for minimized and there appears to be little significant these procedures. Available information suggests that effect on metabolic or other physiological param- both physicians and other health personnel can easily eters. Furthermore, exposure to the drug can be be trained to insert and remove the capsules (51). In terminated at any time by removal of the device. addition, clinic staff should be familiar with the This modality is just beginning to be widely bleeding disturbances that are particularly common introduced, thus little information has been generated during the first year, and need to be trained to counsel on rare or long-term effects. It is recommended that users accordingly. It is important to identify specific appropriate surveillance activities be developed to centres that can serve as national or regional resources evaluate its long-term safety. As with other hormonal for the training of health personnel. Similarly, refer- contraceptive methods, additional research is also ral or back-up facilities need to be identified, needed on the use of Norplant during lactation, since especially in rural areas. few data are available on the effect of levonorgestrel From the outset, it is essential that government on the growth and development of children exposed health agencies be involved in the introduction of the to the steroid via breast milk. method. Experience with the introduction of other The insertion and removal of Norplant, whether by new methods of contraception has shown the essential trained physicians or by other health personnel, role that "pre-introductory trials" play in this pro- require appropriate clinic facilities. It is essential that cess. These trials can be of use in identifying training adequate training programmes be established requirements and other method-related service for clinic personnel prior to introduction of delivery issues. Norplant into a family planning programme. 492 MEMORANDUM

"Pre-introductory" trials, prior to widespread concluded that Norplant provides an effective and introduction, are important for providing training reversible long-term method of fertility regulation. It and information about service delivery issues, and to is considered suitable for use in family planning pro- assess the local acceptability of the method. it is grammes, along with other currently available contra- important to note that the skill of the provider at ceptive preparations and devices, since it provides an insertion will largely determine the ease of removal. important option for women desiring long-term In summary, the participants in the Consultation contraception.

* * *

K. Adadevoh, Ebute Metta, Lagos, Nigeria Representatives from Huhtamaki Oy/Leiras B. Affandi, University of Indonesia, Jakarta, Pharmaceuticals, Finland Indonesia H. Allonen U. Borell, Karolinska Institute, Stockholm, Sweden H. Voipio E. Diczfalusy, Karolinska Institute, Stockholm, S. Jarvela Sweden K. W. von Eickstedt, Bundesgesundheitamt, Berlin (West) Representative from Finnida, Helsinki, Finland M. Elder, University of London, London, England U.-M. Finskas R. Gray, Johns Hopkins University, Baltimore, MD, USA Representative from UNFPA S. Koetsawang, Mahidol University, Bangkok, Thailand H. Corvalan, New Delhi, India Suman Mehta, Indian Council of Medical Research, New Delhi, India Secretariat (World Health Organization, Geneva, D. Mishell, University of Southern California, Los Switzerland) Angeles, CA, USA P. E. Hall, Special Programme of Research, S. Ratnam, University of Singapore, Singapore Development, and Research Training in Human Pramilla Senanayake, International Planned Reproduction (Secretary) Parenthood Federation, London, England P. Corfman, Special Programme of Research, M. Shaaban, University of Assiut, Assiut, Egypt Development, and Research Training in Human R. Shearman, University of Sydney, Sydney, Reproduction Australia (Chairman) S. E. Holck, Special Programme of Research, K. H. Yang, Korea Advanced Institute of Science and Development, and Research Training in Human Technology, Seoul, Republic of Korea Reproduction A. Mundigo, Special Programme of Research, Representatives from the Population Council, Development, and Research Training in Human New York, USA Reproduction W. Bardin P. J. Rowe, Special Programme of Research, G. Brown Development, and Research Training in Human F. Greenslade Reproduction H. Nash M. Ten Ham, Pharmaceuticals D. Robertson

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