Summary of analysis of efficacy and safety of Implantable Contraceptives (levonorgestrel and etonogestrel releasing implants).

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1 Expert Committee Member comment on application for Implantable contraceptives (levonorgestrel and etonogestrel releasing implants) to be added to the WHO Model List Summary of analysis of efficacy and safety of Implantable Contraceptives (levonorgestrel and etonogestrel releasing implants). Definition Implantable contraceptives are progestogen-only contraceptive implants (levonorgestrel or etonogestrel releasing implants), which were introduced into clinical practice in the 1970s. These methods are known to be highly effective in preventing pregnancy, well tolerated and without serious side effects 1, 2, 3. Levonorgestrel releasing implants exert their contraceptive action through inhibition of sperm transport, normal endometrial development and partially ovulation, while Etonogestrel/3-keto-desogestrel releasing implants work mainly by inhibiting ovulation 4. Currently there are 5 (6 including complementary listing) items for non-barrier contraception on the WHO EML, Section 18.3 Contraceptives: Hormonal contraceptives: ethinylestradiol + levonorgestrel, tablet, 30 µg µg ethinylestradiol + norethisterone, tablet, 30 µg mg levonorgestrel, tablet, 30 µg, 750 µg (pack of two), 1.5 mg norethisterone enantate, oily solution, 200 mg/ml in 1-ml ampoule complementary listing medroxyprogesterone acetate, depot injection, 150 mg/ml in 1-ml vial with the footnote stating: The public health relevance and/or efficacy and/or safety of this item has been questioned and its continued inclusion in the Model List will be reviewed at the next meeting of the Expert Committee Intrauterine devices: - copper containing device Levonorgestrel and etonogestrel are listed on the Anatomical Therapeutic Chemical (ATC) classification index with Defined Daily Doses (DDDs) (WHO Collaborating Centre for Drug Statistics Methodology), Oslo, Norway, 2004 under section G03 Sex Hormones and modulators of the genital system, subsection G03A C Hormonal Contraceptives for systemic use, Progestogens: G03A C03 Levonorgestrel; G03A C08 Etonogestrel. Efficacy and safety issues No randomized clinical trials (RCTs) were found that compared implantable contraceptives with barrier, oral or injectable contraceptive methods. The application for inclusion of both Implantable contraceptives (levonorgestrel and etonogestrel releasing implants) is supported mainly by the results of cohort studies and by clinical evidence of equal efficacy of two types of levonorgestrel releasing implants (Norplant and Norplant-2) and of equal efficacy of levonorgestrel releasing implants to levonorgestrel releasing intrauterine devices in preventing pregnancies, summarised in a newly updated Cochrane systematic review 5.

2 The conclusion of equal efficacy was drawn by the authors of the review on the basis of the only one randomised controlled trial (Wang 1992, 200 participants totally included, 100 participants in study groups) 6, included into the Cochrane systematic review 7. Levonorgestrel releasing device used in this study (Wang 1992) was Norplant 2, which consisted of two silastic capsules containing levonorgestrel, 70 mg with contraceptive life up to 3 years. Levonorgestrel releasing intrauterine device used in the study was LNG-20 IUS, containing 52 mg of levonorgestrel mixed with polydimethylsiloxane, allowing a steady, local release of 20µg levonorgestrel per day. Calculated in this Cochrane systematic review rate rations for the major efficacy and safety outcomes point at the lack of significant difference between the LNG-20 IUS versus Norplant-2 as two methods of reversible contraception: Pregnancy (95% CI 0.13 to 75.56) at one year of follow up, 3.06 (95% CI 0.12 to 75.56) at two years of follow up, 3.00 (95% CI 0.12 to 73.53) at three years of follow up; Continuation 0.89 (95% CI 0.66 to 1.2) at one year of follow up; Expulsion 7.18 (95% CI 0.37 to ) at one year of follow up; Ovarian cysts 4.10 (95% CI 0.65 to 26.04) at one year of follow up; Breast cancer none; Discontinuation (menstrual side effects) 1.03 (95% CI.023 to 4.51) at one year of follow up; Discontinuation (device problem ) 9.23 (95% CI 0.5 to ) at one year of follow up; Discontinuation (adverse events) 1.03 ( ) at one year of follow up; The Cochrane analysis provides the following risk rations, documenting the difference between the two methods in indicators of menstrual disturbances) 8 : Amenorrhoea was significantly more likely to be experienced by LNG-20 IUS users compared to Norplant-2 users with the risk ratios of 2.27 [95% CI 1.03 to 4.99] at one year follow up, [95% CI 2.62 to ] at two years' follow up and 2.65 [95% CI 0.53 to 13.20] at three years' follow up; Oligomenorrhoea was significantly more likely to be experienced by LNG-20 IUS users compared to Norplant-2 users with the risk ratio of 6.17 [95% CI 2.76 to 13.78] at two years follow up, with no significant differences at years' one and three of follow up; On the contrary: Spotting was significantly less likely to be experienced by LNG-20 IUS users compared to Norplant-2 users with the risk ratios 0.33 [95% CI 0.18 to 0.60] at one year, 0.18 [95% CI 0.07 to 0.5] at two years and 0.17 [95% CI 0.05 to 0.57] at three years; Prolonged bleeding was significantly less likely to be experienced by LNG-20 IUS users compared to Norplant-2 users with the risk ratios 0.13 [95% CI 0.05 to 0.35] at one year, 0.17 [95% CI 0.06 to 0.46] at two years and 0.15 [95% CI 0.04 to 0.64] at three years. The authors of the Cochrane review did not formulate any recommendations on the use of Norplant-2 in Implications for practice section on the basis of these findings and emphasised the vital need for the future research able to answer the queries and concerns of contraceptive users 9.

3 Additional studies Direct comparisons of levonorgestrel releasing implants versus etonogestrel releasing implants One multicentre RCT compared the contraceptive efficacy and bleeding patterns of a single-rod (Implanon etonogestrel releasing implant) and a six-capsule (Norplant levonorgestrel releasing implant) contraceptive implant for 2 years, with an optional extension of up to 4 years, among 200 healthy female volunteers in China. Both implants demonstrated excellent contraceptive performance with no pregnancies during the study period. Compared with Norplant, there was less frequent bleeding with Implanon, whereas the incidence of infrequent bleeding and amenorrhea was higher. Implanon was significantly quicker to insert and to remove than the multiple capsule system 10. Another small RCT in China (100 participants totally, 75 Implanon and 25 Norplant users) found no difference in efficacy or overall safety between two contraceptives. The methods differed only in terms of number of times of bleeding (2.25 for Implanon and 2.99 for Norplant per reference period (P < 0.05)) and the times for insertion and removal (shorter for Implanon) documenting advantages of Implanon as a single rod design 11. Single small studies provided information on ovarian function 12, endometrial histology and cervical cytology 13, heamostatic system and liver function 14, apo-lipoproteins profile 15, carbohydrate metabolism 16, selected parameters of thyroid and adrenal function 17 with the use of Implanon compared with Norplant, that did not find major significant differences between two contraceptives. The exception was minimal but statistically significant rise in fasting glycosylated hemoglobin A(1)C levels at 24 months in the Implanon group while both implants induced mild insulin resistance with no significant change in serum glucose levels 18. Reformulated levonorgestrel releasing 2 rod implants versus Norplant (6 capsules) studies A multi-center 5 year RCT compared levonorgestrel rod implant (Jadelle) with Norplant capsule (6) implants in 1198 participants (600 Norplant capsules and 598 Jadelle) at 7 centers in the USA, Finland, Bangkok, Chile, Egypt and Singapore. The study found high and equal contraceptive effectiveness for both implants and advantages of 2 rod implants compared to Norplant in their relative ease in removal 19. Another multi-center RCT in 1052 Mexican women at 8 centers followed up for 3 years with the same design found equal effectiveness, safety and acceptability of both implants 20. Conclusion The advantage of 2 rod levonorgestrel releasing implant (Norplant-2/Jadelle) over the 6 capsules implant (Norplant) and its equal efficacy with LNG20-IUS is documented. At the same time high quality clinical evidence (RCTs) on efficacy and safety of levonorgestrel and etonogestrel releasing implants for reversible contraception to date is limited. 1 Sivin I, Robertson DN, Stern J, et al. Norplant: reversible implant contraception. Studies in Family Planning 1980;11:

4 2 Sivin I. International experience with Norplant and Norplant-2 contraceptives. Studies in Family Planning 1988;19: Darney PD, Atkinson E, Tanner S, MacPherson S, Hellerstein S, Alvarado A. Acceptance and perceptions of Norplant among users in San Francisco, USA. Studies in Family Planning. journal 1990;21: Croxatto HB Mechanisms that explain the contraceptive action of progestin implants for women. Contraception, 2002, 65 (1): French R, Van Vliet H, Cowan F, Mansour D, Morris S, Hughes D, Robinson A, Proctor 6 Wang 1992{published data only} Gao J, Wang SL, Wu SC, Sun BL, Allonen H, Luukkainen T. Comparison of the clinical performance, contraceptive efficacy and acceptability of levonorgestrelreleasing IUD and Norplant-2 implants in China. Contraception 1990;41: Wang SL. [Comparative study of norplant-2 and levonorgestrel-releasing intrauterine devices]. Chung Hua Fu Chan Ko Tsa Chih 1990;25: Wang SL, Wu SC, Xin XM, Chen JH, Gao J. Three years' experience with levonorgestrel-releasing intrauterine device and Norplant-2 implants: a randomized comparative study. Adv Contracept 1992;8: French R, Van Vliet H, Cowan F, Mansour D, Morris S, Hughes D, Robinson A, Proctor 8 French R, Van Vliet H, Cowan F, Mansour D, Morris S, Hughes D, Robinson A, Proctor 9 French R, Van Vliet H, Cowan F, Mansour D, Morris S, Hughes D, Robinson A, Proctor 10 Zheng SR, Zheng HM, Qian SZ, Sang GW, Kaper RF A randomized multicenter study comparing the efficacy and bleeding pattern of a single-rod (Implanon) and a six-capsule (Norplant) hormonal contraceptive implant. Contraception Jul;60(1):1-8.

5 11 Yao XY, Du MK. [A randomized study comparing the efficacy and bleeding pattern of Implanon and Norplant hormonal contraceptive implant] Zhonghua Fu Chan Ke Za Zhi Jul;38(7): [Article in Chinese] 12 Makarainen L, van Beek A, Tuomivaara L, Asplund B, Coelingh Bennink H. Ovarian function during the use of a single contraceptive implant: Implanon compared with Norplant. Fertil Steril Apr;69(4): Mascarenhas L, van Beek A, Bennink HC, Newton J. A 2-year comparative study of endometrial histology and cervical cytology of contraceptive implant users in Birmingham, UK. Hum Reprod Nov;13(11): Egberg N, van Beek A, Gunnervik C, Hulkko S, Hirvonen E, Larsson-Cohn U, Bennink HC. Effects on the hemostatic system and liver function in relation to Implanon and Norplant. A prospective randomized clinical trial. Contraception Aug;58(2): Mascarenhas L, van Beek A, Bennink HC, Newton J. Twenty-four month comparison of apolipoproteins A-1, A-II and B in contraceptive implant users (Norplant and Implanon) in Birmingham, United Kingdom. Contraception Oct;58(4): Erratum in Contraception 1998 Dec;58(6):following Biswas A, Viegas OA, Coeling Bennink HJ, Korver T, Ratnam SS. Implanon contraceptive implants: effects on carbohydrate metabolism. Contraception Mar;63(3): Biswas A, Viegas OA, Bennink HJ, Korver T, Ratnam SS. Effect of Implanon use on selected parameters of thyroid and adrenal function Contraception Nov;62(5): Biswas A, Viegas OA, Coeling Bennink HJ, Korver T, Ratnam SS. Implanon contraceptive implants: effects on carbohydrate metabolism. Contraception Mar;63(3): Sivin I, Campodonico I, Kiriwat O, Holma P, Diaz S, Wan L, Biswas A, Viegas O, el din Abdalla K, Anant MP, Pavez M, Stern J. The performance of levonorgestrel rod and Norplant contraceptive implants: a 5 year randomized study. Hum Reprod Dec;13(12): del Carmen Cravioto M, Alvarado G, Canto-de-Cetina T, Bassol S, Oropeza G, Santos- Yung R, Valencia J, Palma Y, Fuziwara JL, Navarrete T, Garza-Flores J, Perez-Palacios G. A multicenter comparative study on the efficacy, safety, and acceptability of the contraceptive subdermal implants Norplant and Norplant-II. Contraception Jun;55(6):

Application for inclusion of levonorgestrel - releasing IUD for contraception in the WHO Model List of Essential Medicines

Application for inclusion of levonorgestrel - releasing IUD for contraception in the WHO Model List of Essential Medicines 1. Summary statement of the proposal for inclusion LNG-IUS is an effective contraceptive;