Review of the application of levonorgestrel releasing implant for inclusion of the WHO Model List of Essential Medicines

Transcription

1 Review of the application of levonorgestrel releasing implant for inclusion of the WHO Model List of Essential Medicines The application is submitted by the Geneva Foundation for Medical Education and Research (GFMER) Background Implantable contraceptives, which has been in practical use for over 30 years, is one of measures for contraception. It is used in 11million women of more than 60 countries. 1 Jadelle is a low-dose progestogen-only implant that was developed by the Population Council, and consists of two implantable rods, each containing 75 mg of Levonorgestrel It was approved by Food and Drug Administration in Currently, it has been registered in USA and a part of European countries, and is applying for listing in the Pharmacopeia of UK, USA and WHO. The marketing of implantable contraceptives is very low in the world and in China (table 1 and table 2), which is far behind the marketing status of Sterilization and IUD, and is also less marketing than oral contraceptives, condom and vaginal barrier. Its potential demand, therefore, should be decided by systematic review of safety, effectiveness and economics. In 1984, Leiras, as produced by the Finnish manufacturer, was for the first time introduced in China. It was a Norplant-I and II implant containing Levonorgestre. In 1989, it was used as a trial. In 1990, China developed an implant like Norplant-I and II. Norplant-I and the Chinese counterpart consists of 6 implantable rods, each containing 36 mg levonorgestrel (Total 216mg). Norplant-II and the Chinese counterpart, which are the same with Jadelle, consist of two implantable rods, each containing 75 mg Levonorgestre (Total 150mg). Because the active agents, their doses and routines of use are similar with each other, and China is potentially a market for contraceptives, the data from China are of practical value for this review. Table 1: WHO world contraception 2003 Region The world Developed countries Developing countries Asian China Indonesia Women with reproductivity Years of data Traditional contraception (%) Modern contraception (%) Sterilization - Female male IUD Oral contraceptives

2 Codon Injectables &Implants * vaginal septum Others Total(%) Data from World Contraception 2003 : According to WHO (2003), the marketing use of injectables and implants is only 2.6% worldwide, 0.4% in China, but 27.1% in Indonesia. Table 2: China contraceptive data year Sterilization (%) IUD (%) pill & injectables Condo Implants Topica Others Total rate female Male (%) n (%) (%) (%) (%) (%) / Data from the official website of National Population and Family Plan Program : the statistics showed that women with productivity amount to 350 million, of which 90% adopt the conception measures. However, the implantable contraceptives decreased with a 0.4% rate since Results 1. Resources of data Table 3 Comparison of data resources Items WHO application materials Chinese materials [4] Databases and time of search CL, Medline, Embase, Popline, Lilacs, grey literature CBMdisc, CNKI;CMCC; VIP; type of study Systematic review Systematic review objectives Effectiveness, safety, economics, and social acceptability Effectiveness, safety, and social acceptability methods CSR CSR included studies Most of them are cohort studies, few are RCT RCT, CCT, observational studies, case analysis language Unknown Chinese number of studies Unknown 15 number of participants Unknown : it is estimated that the applications from WHO have not included Chinese studies. A supplemental material from China is therefore provided here. 2. Quality of included studies Table 4 Quality of included studies Classification of studies Chinese studies HTA 0 0 CSR 0 0 RCT Unknown 3 studies(3703 participants) CCT 0 2(1296)

3 Cohort study Unknown 0 Other observational study 0 9(33031) Case reports 0 1(1) Total Unknown 15(38031) Both appraise the study according to the CSR methods consists mostly of cohort studies, and Chinese studies included, from the total, 86.9% of observational studies. Significant heterogeneity exist in Chinese studies, and descriptive methods were used. 3. Effectiveness measures and outcomes Table 5 Comparison of effectiveness pregnancy rate Zero for the first 4 year, and 1% for the fifth year The relation of pregnancy rate to body weight Comparing with LNG-releasing and IUD cumulative continuation rates Comparing with copper IUD Limited to those weighing less than 80kg Similar pregnancy rate. Two years after removing, re-pregnancy rate of 92% vs. 88% Chinese materials Zero for the first 3 year, 1% for the fifth year. The 7-year cumulative pregnancy rate is 2.23% The increase of pregnancy rate positively correlates with weight Similar pregnancy rate [2-3] 3 rd year-71%; 4 th year-63%; 5 th year-55% 1 st year-95%, 2 nd year-87%; 5 th year-72.1% Two years after removing, re-pregnancy No significant different after 1 year [4-5] rate92% vs 88% Both prove that levonorgestrel releasing implant has a satisfactory low pregnancy rate The Chinese studies documented that the length of use may prolong to 7 years, with a satisfactory effectiveness, probably because the Chinese Norplant-I has more drug load of 216 mg vs.150mg. The Chinese studies indicated that better effectiveness may be achieved in less heavier population. 4. Safety Table 6 Comparison of safety The main reason for discontinuation The main reason for discontinuation is menstrual disturbances, which amounts to 45% of the total reasons Chinese materials Menstrual disturbances amounts to 70% of total reasons Comparing with LNG-releasing and IUD Comparing with copper IUD Similar discontinuation Similar discontinuation Similar rate, but the frequency of menstrual disturbances is higher, presenting with increasing menstrual volume and bradymenorrhea [2-3] Similar rate, but the frequency of menstrual disturbances is higher, presenting with increasing menstrual volume and bradymenorrhea [4-5]

4 Increase of body Unknown might induce increase of weight weight Ectopic pregnancies 0.4% 5-year rate of 0.009% Severe adverse Unknown 1 case [7] reactions Other adverse Light headache and dizziness Light headache and dizziness reactions Contraindications pregnancy; breastfeeding <6 weeks Same with WHO materials postpartum; current deep venous thrombosis or pulmonary embolism; unexplained vaginal bleeding; current and past breast cancer; active viral hepatitis; severe cirrhosis; benign and malignant liver tumors; use of drugs affecting liver enzymes (Rifampicin and certain anticonvulsants). Stop using contraceptive implant in case of current and history of ischemic heart disease or stroke; migraine with aura at any age Both proved that levonorgestrel releasing implant had the major adverse reactions of menstrual disturbances,also the major reasons for discontinuation. Few adverse reactions were identified. Nearly no ectopic pregnancies were reported in China, possibly in relation to the intensity of surveillance and clinical expertise. Chinese studies indicated that the frequency of menstrual disturbances of levonorgestrel releasing implant is higher than copper IUD and LNG-releasing, with symptoms of increased menstrual volume and bradymenorrhea. 5. Social acceptability Table 7 Comparison of social acceptability China materials The number of people 11 million(3million in Indonesia) 1.26 million that levonorgestrel releasing implant up to 2003 Requirements Trained professionals, and not as demanding as IUD The influence of geographic and occupational factors on the acceptability sanitation None An observational study [6] (19673cases) indicated that women in developed regions with higher education tend to less easily accept the use. Comparing with IUD Unknown IUD-reduced menstrual disturbances are mainly amenorrhea and menstruation decrease. levonorgestrel releasing implant has been in wide use, and has a good social accepatibility The requirements for levonorgestrel releasing implant are less demanding than IUD, but more convenient and easy-to-handle. Chinese studies showed that levonorgestrel releasing implant has a good acceptability in

5 people with less education. But IUD has better acceptability. 6. Economic issues Table 8 Comparison of economics Governmental funding 27 USD+8USD catheter needle V.S Progestoge-only contraceptives Governmental funding 3.5USD/Y LNG-IUD: Governmental funding 40USD : No cost-effectiveness study in China. indicated government funded most for LNG-IUD. The IUD in China is less expensive. China materials More expensive than IUD Conclusions Generally, levonorgestrel releasing implant is safe, effective and convenient, has a huge potential market. However, current evidence documented a small proportion of using levonorgestrel releasing implant in the world market and in China. The levonorgestrel releasing implant in China is Norplant or the Chinese counterpart. Their active agents, doses, and routine of use are very similar to JADELLE. We suggest that INN name should be used instead of commercial names. Levonorgestrel releasing implant is similar to IUD in safety and effectiveness. Chinese studies showed that IUD currently had a better acceptability and less expensive price. We suggest that more international clinical studies should be conducted to ascertain the use in different population. The current evidence of levonorgestrel releasing implant is not of high quality. Especially, there are no health economic studies. Both sexual disease infection and contraception are of both sides for a contraceptive method. Here indicates a need for further research. Reference - Bongaart J, Johansson E. (2000). Future trends in contraception in the developing world: prevalence and method mix. Policy Research Division Working Papers n141. Population Council, New York, NY. In pdfs/wp/41.pdf - Shuli Wang, Ji Gao, Shangcun Wu. Implant Comparing with LNG-releasing IUD for contraception. Chinese Journal of Obstetrics and Gynecology.1990;25(4): Shuli Wang, Shangcun Wu, Limei Xin, Juhua Chen, Ji Gao. The 36 months comparative study of LNG-releasing IUD and Norp1ant-2 Implant. Journal of Reproductive Medicine.1992;1(2): Shihui Zuo, Shonglin Wu, Juying Wu. The effect comparison of Norplant Implant and MLcu375&Tcu220cIUD. Hunan Medical Journal 1994;11(6): Xiaoqing Gong, Shuqing Li, Dan Wang. Five years review of Norplant Implant compare with IUD for contraception. Chinese Journal of Family Planning.1997; (4): Li Xue, Kejuan Fang, Ersheng Gao, Huiming Fang. The influential factor analysis of Implant discontinuation for menstrual disturbances.reproduction & Contraception.2000;20(2): Ruiying Liu, Huifang Hu, Chuanglin Gong. One case of hypersensitive asthma caused by Levonorgestrel releasing Implant-II. Qilu Medical Journal. 2003;18(3):318. Reviewers Youping Li, Director of the Chinese Cochrane Centre

6 Ying Xiong, Chinese Cochrane Centre Xin Sun, Chinese Cochrane Centre Lin He, Chinese Cochrane Centre Chen Li, Chinese Cochrane Centre Time of review Jan. 31, 2005