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

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Herbert Parker
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1 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; it is comparable to IUDs containing > 250 mm 2 copper and more effective than IUDs containing =/<250 mm 2 copper. It is equally effective compared to implantable (Norplant -2) methods. No data from randomized controlled trials, comparing LNG-IUS with oral or injectable methods or barrier methods are available. Complications are rare and are described as perforation during insertion, expulsion or infection. The most common side effects are bleeding irregularities, acne, breast tenderness, nausea, and headache. LNG-IUS should not be used with the following conditions: ongoing pregnancy, cancer of the cervix and uterus, breast cancer, anatomical abnormalities distorting the uterine cavity, pelvic inflammatory disease (PID) current or within the last 3 months. LNG-IUS provides non-contraceptive benefits, such as treatment for hypermenorrhea. LNG-IUS is registered in most European countries, USA and in increasing number of countries in the developing world. 2. Name of the focal point in WHO submitting application Dr Catherine d Arcangues, coordinator, UNDP/UNFPA/WHO/World Bank Special Programme for Research in Human Reproduction, Department of Reproductive Health and Research, Family and Community Health Cluster (WHO/RHR). 3. Name of the organization consulted and supporting the application The Geneva Foundation for Medical Education and Research (GFMER; is submitting the application. GFMER is a WHO Collaborating Centre in Education and Research in Human Reproduction. Staff at GFMER has extensive experience in conducting systematic reviews, critically appraising the literature and the development of recommendations. 4. International Nonproprietary Name (INN, generic name) of the medicine Levonorgestrel-releasing Intrauterine System, LNG-20 IUS (Mirena ) 5. Whether listing is requested as an individual medicine or as an example of a therapeutic group Listing as an individual medicine. 6. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population) 1

2 145 million women are using Intrauterine Device (IUD) worldwide, which represents 14% of women in reproductive age. Generally, IUDs are the second most popular contraceptive method after sterilization (1). LNG-releasing IUD is available in 47 countries (2). 7. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostic or treatment facilities and skills) Dosage: 52 mg of levonorgestrel is contained in the reservoir of the intrauterine system (IUS). A steady and local release of 20 µg levonorgestrel per day occurs during the first year, 11 µg per day after 5 years with an average of 14 µg per day over 5 years. Duration: LNG-releasing IUS is effective for five years. Diagnostic: LNG-releasing IUS used for reversible contraception. Treatment facilities: The IUS should be installed during the first seven days of the cycle. Post-partum insertion can be done six weeks after normal delivery and twelve weeks after caesarean section. LNG-20 IUS is licensed in several countries for treatment of idiopathic hypermenorrhea. 8. Summary of comparative effectiveness in a variety of clinical settings: Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data) The Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, Popline and Lilacs were systematically searched covering the period from 1972 to November Pharmaceutical companies, individuals and organizations involved in LNG-IUS research were also contacted for unpublished or ongoing studies. A Cochrane systematic review comparing hormonally impregnated intrauterine systems versus other forms of reversible contraceptives as effective methods of preventing pregnancy has been identified (3). Studies considered for the review were randomized controlled trials and controlled clinical (i.e. quasi-randomized) trials comparing IUSs with other forms of reversible contraceptives concerning their contraceptive efficacy, tolerability and acceptability. Trials were assessed and included if they had adequate concealment of allocation, randomization procedure and follow-up. Hormonally impregnated IUSs (LNG-20 IUS) compared with non-hormonal IUDs (copper IUDs>250mm 2 and IUDs=/<250mm 2, non-medicated IUDs) and subdermal implants (Norplant-2) were included. Participants were women aged years. Quality assessment and data extraction were conducted by two reviewers independently. A quality checklist was designed to identify general methodological and contraceptive specific factors which could bias results. The outcome measures were pregnancy due to method/user failure at 1, 2, 3, 4 and 5 years after starting the contraceptive method, continuation of the contraceptive method after 1, 2, 3, 4 and 5 years, amenorrhea, device expulsion, prolonged bleeding and spotting. 2

3 Twenty-one trials comparing impregnated intrauterine systems to a reversible contraceptive method were included in the study. Outcomes : 1. There was no difference in pregnancy rates observed between the LNG-20 IUS and copper IUD>250mm 2 users for the first year (1 trial, RR 1.01, 95% 0.71 to 5.82) and for the fifth year of use (1 trial, RR 0.66, 95% CI 0.25 to 1.75). 2. Compared to women using copper IUD =/<250mm 2, those using the LNG-20 IUS were significantly less likely to become pregnant, for the first (2 trials, RR 0.12, 95% CI 0.03 to 0.49) and for the fifth year of use (2 trials, RR 0.08, 95% CI 0.04 to 0.18). 3. Women using the LNG-20 IUS were more likely to experience amenorrhea at 3 months (1 trial, RR % CI 1.31 to 3.56) and 3 years (1 trial, RR 7.24, 95% CI 4.14 to 12.65) compared to copper IUDs>250mm 2 users. 4. LNG-20 IUS users were significantly more likely than Norplant-2 users to experience amenorrhea in the first year (RR 2.27, 95% CI 1.03 to 4.99) but the difference was not statistically significant after three years (RR 2.65, 95% CI 0.63 to 13.20) 5. LNG-20 users were statistically significantly more likely than all the copper IUD users to discontinue because of: a) hormonal side effects (one trial, RR 4.24, 95% CI 1.99 to 9.05 for IUD>250mm 2 at 5 years; one trial, RR 5.18, 95% CI 1.32 to for IUD =/<250 mm 2 at 5 years) and b) menstrual disturbance (one trial, RR.1.48, 95% CI 1.23 to 1.79 for IUD>250 mm 2 at 5 years). Summary of available estimates of comparative effectiveness 1. According to the results of the systematic review, LNG-20 IUS is more effective in preventing intrauterine and extrauterine pregnancies compared to IUDs with =/< 250mm 2 copper. 2. LNG-20 IUS has similar effectiveness as IUD>250mm 2 and Norplant-2 in preventing pregnancy. 3. No randomized controlled trial comparing hormonally impregnated IUDs with oral contraceptives, barrier or injectable methods was identified. 9. Summary of comparative evidence on safety: Estimate of total patient exposure to date LNG-20 IUS is available since 10 years in Europe and has been used by approximately two million women worldwide (4). LNG-IUS: used by approximately 1% of women aged years in UK (5). Description of adverse effects/reactions Most common side effects include menstrual changes (reduction of blood loss, amenorrhea, prolonged spotting), lower abdominal pain, acne or other skin problems, back pain, mastalgia, headache, vaginal discharge, mood changes and nausea. Uncommon complications can be: expulsion of the device, perforation during insertion, pregnancy. 3

4 Identification of variation in safety due to health systems and patient factors LNG-20 IUS should not be used with the following conditions: ongoing pregnancy; women being less than four weeks post-partum or immediate post-abortion; cancer of the cervix and uterus; post septic abortion; breast cancer; anatomical abnormalities distorting the uterine cavity; pelvic inflammatory disease current or within the last 3 months; pelvic tuberculosis; unexplained uterine bleeding; postpartum endometritis; acute hepatic affections and liver tumor; severe liver cirrhosis; thromboembolic diseases; coagulation disorders or use of anticoagulant medicines; severe anemia; immunosuppressive therapy; multiple sexual partners; hypersensitivity to levonorgestrel or to another component of the device. Summary of comparative safety against comparators Generally, complications with the LNG-20 IUS are rare. Compared with copper IUDs, there was no difference in complication rates such as ectopic pregnancies, PID, embedded devices. LNG IUS may have a higher expulsion rate compared to > 250 mm 2 IUD; possibly explained by the higher need for training to insert this device. 10. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group LNG-IUS generally is more expensive compared to copper IUDs, but offer some noncontraceptive benefits, especially for women with heavy periods and may offer an alternative to hysterectomy for these women. Range of costs of the proposed medicine The cost of LNG-20 IUS varies and is around 230 USD in Switzerland, 270 USD in Canada, and 160 USD in France. In the public sector, the price of LNG-20 IUS is 40 USD. Comparative cost-effectiveness presented as range of cost per routine outcome LNG-20 IUS is one of the most cost-effective methods of birth control in the USA (7). The cost of the device is however somewhat higher than for copper IUDs: 40 USD for the LNG-20 IUS against 0.1 USD for the copper IUD in the public sector (WHO, personal communication). 11. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as well) LNG-IUS is registered in most European countries and the USA. 12. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia) British Pharmacopoeia: levonorgestrel, not Mirena International Pharmacopoeia: requested United States Pharmacopoeia: requested 4

5 13. Proposed text for the WHO Model Formulary Levonorgestrel releasing intra-uterine system (Mirena ) Uses: contraception, hypermenorrhea, endometrial protection during estrogen substitution Contraindications: ongoing pregnancy; less than four weeks post-partum; immediate post-abortion; cancer of the cervix and uterus; post septic abortion; breast cancer; anatomical abnormalities distorting the uterine cavity; pelvic inflammatory disease current or within the last 3 months; pelvic tuberculosis; unexplained uterine bleeding; postpartum endometritis; acute hepatic affections and liver tumor; severe cirrhosis; thromboembolic diseases; coagulation troubles or use of anticoagulant medicines; severe anemia; immunosuppressive therapy; frequent sexual partner changes; hypersensitivity to levonorgestrel or to another component. Precautions: exclude endometrial pathology; without any uterine bleeding after six weeks of use, a pregnancy test is required; epilepsy; diabetes; ovarian cyst; uterine scars; history of ectopic pregnancy; non steroidal antiinflammatory drug use; Gynecological examination before insertion, 12 weeks after and then annually. Administration: Contraception: LNG-releasing IUS should be inserted at the end of menstrual bleeding and before the calculated time of implantation; endometrial protection during estrogen substitution: insertion can be done at any time when amenorrhea or during the last bleeding days. Adverse effects: menstrual changes (reduction of blood loss, amenorrhea, prolonged spotting), lower abdominal pain, acne or other skin problems, back pain, mastalgia, headache, vaginal discharge, mood changes and nausea. Uncommon complications can be: expulsion of the device, perforation during insertion, pelvic inflammatory disease (PID), pregnancy. 22 October 2004 References 1. WHO (2002). The intrauterine device (IUD) worth singing about. Progress in Reproductive Health Research, n 60. p.3 2. Canadian Coordinating Office for Health Technology Assessment. (2001). Emerging Drug List. Levonorgestrel-Releasing Intrauterine System. n French R, Van Vliet H, Cowan F, Mansour D, Morris S, Hughes D, Robinson A, Proctor T, Summerbell C, Logan S, Helmerhorst F, Guillebaud J. Hormonally impregnated intrauterine systems (IUSs) versus other forms of reversible contraceptives as effective methods of preventing pregnancy (Cochrane Review). In: The Cochrane Library, Issue 3, Chichester, UK: John Wiley & Sons, Ltd. 5

6 4. FDA Approves Mirena (LNG-releasing IUS) contraceptive (2000). 5.Dawe F, Meltzer H. (2002). Contraception and Sexual Health, London, UK: Office for National Statistics, 2003; WHO medical eligibility criteria for contraceptive use (2004). 7.Trussel J, Chiou C.F., Reyes E., Knight K. and Borenstein J. et al. (2001). Intrauterine Contraception: Most Cost-Effective Birth Control Available to Women in the United States. Princeton University. 6

LONG-ACTING REVERSIBLE CONTRACEPTION. Summary Tables

LONG-ACTING REVERSIBLE CONTRACEPTION Summary Tables Bridging the Divide: A Project of the Jacobs Institute of Women s Health June 2016 Table 1. Summary of LARC Methods Available Years Since Effective Copper