1. Attia AM et al. Role of the levonorgestrel intrauterine system in effective contraception. Patient Prefer Adherence 2013; 7:

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3 1. Attia AM et al. Role of the levonorgestrel intrauterine system in effective contraception. Patient Prefer Adherence 2013; 7:

4 1. Wu JP et al. Extended use of the intrauterine device: a literature review and recommendations for clinical practice. Contraception 2014; 89: A literature review identified four studies regarding extended use of the LNG- IUS, which is approved for 5 years of use. Based on cumulative, international data, the LNG-IUS appears to be highly effective for pregnancy prevention for up to 7 years among parous women whose mean age is greater than 25 at the time of insertion; no pregnancies were reported between years 5 and 7 in all four studies. 4

5 1. Jones RL et al. Morphological and functional changes in human endometrium following intrauterine levonorgestrel delivery. Hum Reprod 2000; 15 (suppl 3): S Nilsson CJ et al. Endometrial morphology of women using a D-norgestrelreleasing intrauterine device. Fertil Steril 1978; 29: Barbosa I et al. Ovarian function during use of a levonorgestrel-releasing IUD. Contraception 1990; 42:

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7 1. Suhonen S et al. Clinical performance of a levonorgestrel-releasing intrauterine system and oral contraceptives in young nulliparous women: a comparative study. Contraception 2004; 69: Grunloh DS et al. Characteristics associated with discontinuation of longacting reversible contraception within the first 6 months of use. Obstet Gynecol 2013; 122: Enzlin P et al. Sexual functioning in women using levonorgestrel-releasing intrauterine systems as compared to copper intrauterine devices. J Sex Med 2012; 9: Hall KS et al. Contraception and mental health: a commentary on the evidence and principles for practice. Am J Obstet Gynecol 2015; 212: Paterson H et al. Hair loss with use of the levonorgestrel intrauterine device. Contraception 2007; 76: Skovlund CW et al. Association of hormonal contraception with depression. JAMA Psychiatry 2016; 73: Aoun J et al. Effects of Age, Parity, and Device Type on Complications and Discontinuation of Intrauterine Devices. Obstetrics and Gynecology 2014; 123: Rowe, P et al. Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A. Contraception 2016;

8 1. Andersson K et al. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception 1994; 49: Rönnerdag M et al. Health effects of long-term use of the intrauterine levonorgestrel-releasing system. Acta Obstet Gynecol Scand 1999; 78: Suvisaari J et al. Detailed analysis of menstrual bleeding patterns after postmenstrual and postabortal insertion of a copper IUD or a levonorgestrelreleasing intrauterine system. Contraception 1996; 54: Ref 3: Menstrual diaries collected during the first year of a multicentre study were analysed to compare a copper IUD (Nova-T) with an LNG-IUS releasing 20 μg LNG/24 h. The diaries of 193 LNG-IUS users were included in analysis. Patterns reflecting a reduction in bleeding were clearly more common among the LNG-IUS users. During the last trimester, more than half of the women in the LNG-IUS group had infrequent bleeding and 11 16% were amenorrhoeic. The substitution of spotting in place of bleeding accounts for about half of the reduction in the frequency of bleeding in this group. This was confirmed when the patterns were constructed counting spotting as bleeding. When the patterns were analysed this way, only 19 20% of LNG-IUS users had infrequent bleeding. 8

9 1. Sordal T et al. Management of initial bleeding or spotting after levonorgestrel-releasing intrauterine system placement: a randomized controlled trial. Obstet Gynecol 2013; 121: Warner P et al. Randomized placebo-controlled trial of CDB-2914 in new users of a levonorgestrel-releasing intrauterine system shows only shortlived amelioration of unscheduled bleeding. Hum Reprod 2010; 25:

10 1. Aoun J et al. Effects of age, parity, and device type on complications and discontinuation of intrauterine devices. Obstet Gynecol 2014; 123: French RS et al. Levonorgestrel-releasing (20 μg/day) intrauterine systems (Mirena) compared with other methods of reversible contraceptives. BJOG 2000; 107: Heinemann K, et al. Comparative contraceptive effectiveness of levonorgestrelreleasing and copper intrauterine devices: the European Active Surveillance Study for Intrauterine Devices. Contraception 2015; 91: Reference 3: A total of 61,448 women with a newly inserted IUD were enrolled in six European countries between 2006 and The copper IUD cohort contained more than 30 different types. Validated 1-year follow-up information for 58,324 users between 18 and 50 years of age (70% using LNG IUS, 30% using copper IUDs) was collected. Seven women with LNG IUS and 14 women with copper IUDs had an ectopic pregnancy, resulting in incidence rates of 0.02 per 100 WY (95% CI: ) and 0.08 per 100 WY (95% CI: ), respectively. The proportion of ectopic pregnancies among all contraceptive failure pregnancies was higher in LNG IUS users compared to copper IUD users (27% vs. 15%, p =.16), but due to the substantially lower risk of contraceptive failure in LNG IUS users, the overall risk for ectopic pregnancies was significantly lower in LNG IUS users compared to copper IUD users [HR 0.20 (95% CI: )]. 10

11 1. Mørch LS et al. Contemporary Hormonal Contraception and the Risk of Breast Cancer. NEJM 2017; 377:

12 1. Suhonen S et al. Clinical performance of a levonorgestrel-releasing intrauterine system and oral contraceptives in young nulliparous women: a comparative study. Contraception 2004; 69: Aoun J et al. Effects of Age, Parity, and Device Type on Complications and Discontinuation of Intrauterine Devices. Obstetrics and Gynecology 2014; 123: Rowe, P et al. Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A. Contraception 2016;

13 1. Lyytinen HK, Dyba T, Ylikorkala O, Pukkala EI. A case-control study on hormone therapy as a risk factor for breast cancer in Finland: intrauterine system carries a risk as well. Int J Cancer 2010;126: (In the case-control study to evaluate the association between postmenopausal hormone therapy (HT) and the risk for breast cancer in recently postmenopausal Finnish women was found that LNG-IUS used alone was associated with an elevated risk for breast cancer (1.45; ), or as a complement to estradiol (2.15; ) was also associated with an increased risk.) 2. Bahamondes MV, Monteiro I, Castro S, et al. Prospective study of the forearm bone mineral density of long-term users of the levonorgestrelreleasing intrauterine system. Hum Reprod. 2010;25(5): Morin-Papunen L, Martikainen H, McCarthy MI, et al. Comparison of metabolic and inflammatory outcomes in women who used oral contraceptives and the levonorgestrel-releasing intrauterine device in a general population. Am J Obstet Gynecol. 2008;199(5):529. e1 e529. e Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copperreleasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception. 1994;49(1):

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15 1. Sayed GH et al. A randomized clinical trial of a levonorgestrel-releasing intrauterine system and a low-dose combined oral contraceptive for fibroid-related menorrhagia. Int J Gynaecol Obstet 2011; 112: Shabaan MM et al. Levonorgestrel-releasing intrauterine system compared to low dose combined oral contraceptive pills for idiopathic menorrhagia: a randomized clinical trial. Contraception 2011; 83: Reid R et al. Trends in number of hysterectomies performed in England for menorrhagia: examination of health episode statistics 1989 to Br Med J 2005; 330: Gupta J et al. Levonorgestrel intrauterine system versus medical therapy for menorrhagia. N Engl J Med 2013; 368: Irvine GA et al. Randomised comparative trial of the levonorgestrel intrauterine system and norethisterone for treatment of idiopathic menorrhagia. Br J Obstet Gynaecol 1998; 105: Kaunitz AM et al. Levonorgestrel-releasing intrauterine system for heavy menstrual bleeding improves hemoglobin and ferritin levels. Contraception 2012; 86: Crosignani PG et al. Levonorgestrel-releasing intrauterine device versus hysteroscopic endometrial resection in treatment of dysfunctional uterine bleeding. Obstet Gynecol Clin North Am 1997; 90: Kittelsen N et al. A randomized study comparing levonorgestrel intrauterine system (LNG-IUS) and transcervical resection of the endometrium (TCRE) in the treatment of menorrhagia: preliminary results. Gynecol Endocrinol 1998; 7: Malak KA et al. Management of menorrhagia with the levonorgestrel intrauterine system versus endometrial resection. Gynecol Surg 2006; 3: Barrington JW et al. Comparison between the levonorgestrel intrauterine system (LNG-IUS) and thermal balloon ablation in the treatment of menorrhagia. Eur J Obstet Gynecol Reprod Biol 2003; 108: de Souza SS et al. A randomised prospective trial comparing the levonorgestrel-releasing intrauterine system with thermal balloon ablation for the treatment of heavy menstrual bleeding. Contraception 2010; 81: Shaw RW et al. Randomised comparative trial of thermal balloon ablation and levonorgestrel intrauterine system in patients with idiopathic menorrhagia. Aust N Z J Obstet Gynaecol 2007; 47: Brown PM et al. Cost-effectiveness analysis of levonorgestrel intrauterine system and thermal balloon ablation for heavy menstrual bleeding. BJOG 2006; 113: Heliovaara-Peippo S et al. Quality of life and costs of levonorgestrel-releasing intrauterine system or hysterectomy in the treatment of menorrhagia: a 10-year randomised controlled trial. Am J Obstet Gynecol 2013; 209: 535.e Lethaby A et al. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev 2015; 4: CD Louie M, et al. Comparison of the levonorgestrel-releasing intrauterine system, hysterectomy, and endometrial ablation for heavy menstrual bleeding in a decision analysis model. Int J Gynecol Obstet 2017; 139: In order to provide comparative estimates of clinical outcomes after placement of levonorgestrel-releasing intrauterine system (LNG-IUS), ablation, or hysterectomy for AUB, full articles published in available in English comparing at least two treatment modalities of interest among women of reproductive age with AUB were included. A decision tree was generated to compare clinical outcomes in a hypothetical cohort of premenopausal women with nonmalignant AUB. Authors evaluated complications, mortality, and treatment outcomes over a 5-year period, calculated cumulative quality-adjusted life years (QALYs), and conducted probabilistic sensitivity analysis. Levonorgestrel-releasing intrauterine system had the highest number of QALYs ( ), followed by hysterectomy ( ), non-resectoscopic ablation ( ), and resectoscopic ablation ( ). Ablation had more treatment failures and complications than LNG-IUS and hysterectomy. Findings were robust in probabilistic sensitivity analysis. 15

16 1. Heikinheimo O, Gemzell-Danielsson K. Emerging indications for the levonorgestrel-releasing intrauterine system (LNG-IUS). Acta Obstet Gynecol Scand 2012; 91: Magalhães J, Aldrighi JM, de Lima GR. Uterine volume and menstrual patterns in users of the levonorgestrel-releasing intrauterine system with idiopathic menorrhagia or menorrhagia due to leiomyomas. Contraception 2007; 75: Murat Naki M, Tekcan C, Ozcan N, Cebi M. Levonorgestrel-releasing intrauterine device insertion ameliorates leiomyoma-dependent menorrhagia among women of reproductive age without a significant regression in the uterine and leiomyoma volumes. Fertil Steril 2010;94: Sayed GH, Zakherah MS, El-Nashar SA, Shaaban MM. A randomized clinical trial of a levonorgestrel-releasing intrauterine system and a lowdose combined oral contraceptive for fibroid-related menorrhagia. Int J Gynaecol Obstet 2011; 112: Sivin I, Stern J. Health during prolonged use of levonorgestrel 20 micrograms/d and the copper TCu 380Ag intrauterine contraceptive devices: a multicenter study. International Committee for Contraception Research (ICCR). Fertil Steril 1994;61:

17 1. Lindh I et al. The influence of intrauterine contraception on the prevalence and severity of dysmenorrhea: a longitudinal population study. Hum Reprod 2013; 28: The prevalence and severity of dysmenorrhoea were compared in a longitudinal analysis of variance performed in the same women using either intrauterine contraception (copper IUD or LNG-IUS) or COCs with other methods of contraception or no contraception. Random samples of 19- year-old women born in 1962 (n=656), 1972 (n=780) and 1982 (n=666) were assessed at 5 year intervals between 1981 and The current severity of dysmenorrhoea was assessed on each occasion using a VMS and a VAS. The VMS is a scoring system which grades pain as none, mild, moderate or severe using grades 0, 1, 2 and 3, respectively. This scoring system also takes into account the effect on daily activity, systemic symptoms and whether analgesics are required. VAS is a technique where a 100 mm line on a paper represents the continuum of the woman s opinion of the degree of pain. Use of the LNG-IUS (p<0.01) and COC (p<0.0001) were associated with a reduced severity of dysmenorrhoea compared with non-hormonal methods/no contraception. 17

18 1. Vercellini P et al. A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study. Fertil Steril 1999; 72: Vercellini P et al. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril 2003; 80: Tanmahasamut P et al. Postoperative levonorgestrel-releasing intrauterine system for pelvic endometriosis-related pain: a randomized controlled trial. Obstet Gynecol 2012; 119: Petta CA et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod 2005; 20:

19 1. Fedele L et al. Treatment of adenomyosis-associated menorrhagia with a levonorgestrel-releasing intrauterine device. Fertil Steril 1997; 68: Bragheto AM et al. Effectiveness of the levonorgestrel-releasing intrauterine system in the treatment of adenomyosis diagnosed and monitored by magnetic resonance imaging. Contraception 2007; 76: Cho S et al. Clinical effects of the levonorgestrel-releasing intrauterine device in patients with adenomyosis. Am J Obstet Gynecol 2008; 198: 373.e Sheng J et al. The LNG-IUS study on adenomyosis: a 3-year follow-up study on the efficacy and side effects of the use of levonorgestrel intrauterine system for the treatment of dysmenorrhea associated with adenomyosis. Contraception 2009; 79: Ozdegirmenci O et al. Comparison of levonorgestrel intrauterine system versus hysterectomy on efficacy and quality of life in patients with adenomyosis. Fertil Steril 2011; 95: Park DS et al. Clinical experiences of the levonorgestrel-releasing intrauterine system in patients with large symptomatic adenomyosis. Taiwan J Obstet Gynecol 2015; 54: Shaaban OM et al. Levonorgestrel-releasing intrauterine system versus a low-dose combined oral contraceptive for treatment of adenomyotic uteri: a randomised clinical trial. Contraception 2015; 92:

20 1. Gallos ID et al. Oral progestogens vs levonorgestrel-releasing intrauterine system for endometrial hyperplasia: a systematic review and meta-analysis. Am J Obstet Gynecol 2010; 203: 547.e Kim ML et al. Clinical applications of levonorgestrel-releasing intrauterine system to gynecologic diseases. Obstet Gynecol Sci 2013; 56: Scarselli G et al. Levonorgestrel-releasing intrauterine system (LNG-IUS) as an effective treatment option for endometrial hyperplasia: a 15-year follow-up study. Fertil Steril 2011; 95: Gallos ID et al. Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 2012; 207: 266.e Abu Hashim H et al. Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and meta-analysis of randomized trials. Am J Obstet Gynecol 2015; 213(4): Ref 1: This systematic review and meta-analysis of 24 studies compared endometrial hyperplasia regression rates between an oral progestin and the LNG-IUS in 1001 patients. The LNG-IUS was superior in the treatment of simple hyperplasia (nine studies), complex hyperplasia (nine studies) and atypical hyperplasia (14 studies). Hormonal therapy is regarded as the standard management plan for endometrial hyperplasia without atypia or benign endometrial hyperplasia. However, hormonal therapy can be selected in patients with atypical endometrial hyperplasia who desire to preserve their fertility or in patients who are poor surgical candidates due to severe medical comorbidities. Ref. 5: Seven randomized controlled trials (n = 766 women) were included. Main outcome measures were the therapeutic effect rate (histological response) after 3, 6, 12, and 24 months of treatment; rate of irregular vaginal bleeding; and the hysterectomy rate per woman randomized. Meta-analysis was performed with fixed effects model. For treatment of non-atypical endometrial hyperplasia, LNG-IUS achieves higher therapeutic effect rates and lower hysterectomy rates than oral progestins and should be offered as an alternative to oral progestins in these cases. 20

21 1. Apter D, et al. Pharmacokinetics of two low-dose levonorgestrel-releasing intrauterine systems and effects on ovulation rate and cervical function: pooled analyses of phase II and III studies. Fertil Steril 2014;101:

22 1. Gemzell-Danielsson K, Schellschmidt I, Apter. A randomized, phase II study describing the efficacy, bleeding profile, and safety of two low-dose levonorgestrel-releasing intrauterine contraceptive systems and Mirena. Fertil Steril 2012; 97: Gemzell-Danielsson K, Schellschmidt I, Apter. A randomized, phase II study describing the efficacy, bleeding profile, and safety of two low-dose levonorgestrel-releasing intrauterine contraceptive systems and Mirena. Fertil Steril 2012; 97: Nelson A, Apter D, Hauck B, Schmelter T, Rybowski S, Rosen K, Gemzell-Danielsson K. Two low-dose levonorgestrel intrauterine contraceptive systems - a randomized controlled trial. Obstet Gynecol 2013; 122: Gemzell-Danielsson K, Apter D, Dermout S, Faustmann T, Rosen K, Schmelter T, Merz M, Nelson A. Evaluation of a new, lose-dose levonorgestrel intrauterine contraceptive system over 5 years of use. Eur J Obstet Gynecol Reprod Biol 2017; 210: Gemzell-Danielson et al. (2012) reported on a multicentre, open-label, randomised three-arm phase II study, which included a total of 738 women successfully fitted with 19.5 mg LNG-IUS (Kyleena) (n=245), 13.5 mg LNG-IUS (Jaydess) (n=239) or 52 mg LNG-IUS (Mirena) (n=254). The study period was 3 years. This study was not powered to determine whether there was a significant difference in contraceptive effectiveness between the devices. A large multicentre, open-label, randomised two-arm phase III study which included a total of 2,884 women. Nelson et al. (2013) compared women fitted with 19.5 mg LNG-IUS (n=1,452) or 13.5 mg LNG-IUS (1,432) over a study period of 3 years. 870 women using 19.5 mg LNG-IUS and 819 using 13.5 mg LNG-IUS completed the 3 year study. 707 women in the trial who were using 19.5 mg LNG-IUS then entered an optional 2 year trial extension period and the resulting 5 years of data for 19.5 mg LNG-IUS were reported by Gemzell-Danielson et al. (2017). Over the 3-year study period, 0.33 pregnancies per 100 women years (95% confidence interval [CI] ) were observed with the 13.5 mg intrauterine contraceptive system compared with 0.31 per 100 women-years (95% CI ) with the 19.5 mg intrauterine contraceptive system. The phase III trial reported an unadjusted Pearl Index of 0.29 (95% confidence interval [CI] ) for 19.5 mg LNG-IUS over the 5-year duration of use. Both the phase II and phase III studies report that the mean number of bleeding spotting days decrease over time with 19.5 mg LNG-IUS and 13.5 mg LNG-IUS as is observed with 52 mg LNG-IUS. The phase II and III study authors graphical representation of the data suggests that the mean number of bleeding days over the course of 3 years is lower with 52 mg LNG-IUS than with 19.5 mg LNG-IUS and lower with 19.5 mg LNG-IUS than with 13.5 mg LNG-IUS. However statistical significance is not reported. Thus, limited evidence suggests the possibility that higher doses of LNG in the LNG-IUS could be associated with fewer bleeding/spotting days. Amenorrhoea - The phase II trial reported that, at 3 years amenorrhoic were 12.7% of women using 13.5mg LNG- IUS, 18.9% of women using 19.5 mg LNG-IUS and 23.6% using 52mg LNG-IUS (difference not statistically significant). In the phase III trial the incidence of amenorrhoea with 19.5 mg LNG-IUS was 12.7% at 1 year and 22.6% at 5 years. 22

23 1. Gemzell-Danielsson K, Schellschmidt I, Apter. A randomized, phase II study describing the efficacy, bleeding profile, and safety of two low-dose levonorgestrel-releasing intrauterine contraceptive systems and Mirena. Fertil Steril 2012; 97: Gemzell-Danielsson K, Schellschmidt I, Apter. A randomized, phase II study describing the efficacy, bleeding profile, and safety of two low-dose levonorgestrel-releasing intrauterine contraceptive systems and Mirena. Fertil Steril 2012; 97: Nelson A, Apter D, Hauck B, Schmelter T, Rybowski S, Rosen K, Gemzell-Danielsson K. Two low-dose levonorgestrel intrauterine contraceptive systems - a randomized controlled trial. Obstet Gynecol 2013; 122: Gemzell-Danielsson K, Apter D, Dermout S, Faustmann T, Rosen K, Schmelter T, Merz M, Nelson A. Evaluation of a new, lose-dose levonorgestrel intrauterine contraceptive system over 5 years of use. Eur J Obstet Gynecol Reprod Biol 2017; 210: Gemzell-Danielson et al. (2012) reported on a multicentre, open-label, randomised three-arm phase II study, which included a total of 738 women successfully fitted with 19.5 mg LNG-IUS (Kyleena) (n=245), 13.5 mg LNG-IUS (Jaydess) (n=239) or 52 mg LNG-IUS (Mirena) (n=254). The study period was 3 years. This study was not powered to determine whether there was a significant difference in contraceptive effectiveness between the devices. A large multicentre, open-label, randomised two-arm phase III study which included a total of 2,884 women. Nelson et al. (2013) compared women fitted with 19.5 mg LNG-IUS (n=1,452) or 13.5 mg LNG-IUS (1,432) over a study period of 3 years. 870 women using 19.5 mg LNG-IUS and 819 using 13.5 mg LNG-IUS completed the 3 year study. 707 women in the trial who were using 19.5 mg LNG-IUS then entered an optional 2 year trial extension period and the resulting 5 years of data for 19.5 mg LNG-IUS were reported by Gemzell-Danielson et al. (2017). The effect of both 13.5 mg LNG-IUS and 19.5 mg LNG-IUS on the endometrium is weaker compared to 52 mg LNG- IUS, and therefore these new devices are not licenced for the treatment of heavy uterine bleeding and endometrial protection. Side-effects are similar as with 52 mg LNG-IUS. Commonly-reported side effects include acne, pelvic pain, breast discomfort and weight gain. The cumulative risk of at least partial expulsion over 3 years was 4.56% for the 13.5 mg system group and 3.58% for the 19.5 mg system group. The absolute rate of ectopic pregnancies is low per 100 W-Y (13.5 mg LNG-IUS); 0.18 over 5 years (19.5 mg LNG-IUS). However, should a pregnancy occur with an IUC in situ then the likelihood of it being ectopic is greater than if a pregnancy were to occur without an IUC in situ. Over the course of the 3-year study, three and seven ectopic pregnancies occurred in the 13.5 mg and 19.5 mg system groups. With the extension for 19.5 mg LNG-IUS for additional two years in total, five intrauterine pregnancies (two of which resulted in healthy term births, and three in spontaneous abortions), and eight ectopic pregnancies were reported. 23