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

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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.
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