Slid e 1. This slide should be shown at each presentation. This slide should be shown at each presentation. Slid e 2. Slid e 3

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1 e 1 New Developments in Contraception This slide should be shown at each presentation. Counseling and Insertion Training Featuring the Levonorgestrel Intrauterine System Sponsored by Association of Reproductive Health Professionals Made possible by an unrestricted educational grant from Berlex Laboratories, Inc. e 2 Learning Objectives This slide should be shown at each presentation. e 3 1. Identify four contraceptive methods approved by the FDA in the U.S. since State the five-year cumulative failure rate with levonorgestrel intrauterine contraception (LNG IUS) 3. Describe the bleeding patterns with during the first year of use 4. Name two non-contraceptive benefits of Why the Need for New Contraceptives Endemic rate of unintended pregnancies 43 % of all U.S. women will have had an induced abortion by age 45 2 % of women selecting sterilization at age 3 years or younger later express regret Henshaw. Fam Plann Perspect 1998;3:24 Hillis et al. Obstet Gynecol 1999;93:889 If current rates were to continue, the U.S. would have the highest abortion rate in the developed world. These are by definition unintended pregnancies that could have been prevented with effective contraception. Many of the women who opt for sterilization at a young age do so because they don t know that equally effective reversible options exist. Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect 1998 Jan-Feb;3(1):24. Hillis SD, Marchbanks PA, Tylor LR, Peterson HB. Poststerilization regret: findings from the United States Collaborative Review of Sterilization. Obstet Gynecol 1999 Jun;93(6):889. e 4 New Era in Contraception The family planning landscape is rapidly changing in the U.S. New methods emerging New information resources Internet Direct-to-consumer advertising

2 e 5 Outline Review these new methods Description Advantages/disadvantages Effectiveness Emphasis on the e 6 New Methods Single-rod Implant Monthly Injectable e 7 Vaginal Ring Patch Reversible Methods of Contraception Cervical cap, diaphragm, sponge Male and female condom DMPA Implants Intrauterine methods Combined and progestin-only OCs Spermicides e 8 e 9 Future Methods Extended regimen oral contraception Extended regimen of other hormonal contraceptive delivery systems Microbicides Male hormonal contraception New barrier methods Standard Days natural family planning method Usage of Different Contraceptive Methods by Age Groups 1% 8% Pill Implant Gallup Survey, % 4% 2% % Age Injectable Other IUD M/F Steril. None Gallup Survey '98-'99

3 e 1 International Patterns of Contraceptive Use % of Contraceptive Users Female Sterilization U.S. Germany Denmark IUD Spinelli et al. Am J Public Health 2;9:143 Abma et al. Vital Health Stat ;19:1 IUDs are used far less often than sterilization despite the fact that this method is effective, convenient, allows a rapid return to fertility, and is not adherence-dependent. The legacy of the Dalkon Shield and persistent myths about IUDs have contributed to lack of use, along with patient concerns about safety, mechanism of action, and comfort. Among all contraceptive users in the U.S., IUDs are used far less often than sterilization. The opposite is true in other countries. Of course, this chart does not include experience with LNG IUS from early clinical trials in the U.S.. Abma JC, Chandra A, Mosher WD, Peterson LS, Piccinino LJ. Fertility, family planning, and women's health: new data from the 1995 National Survey of Family Growth. Vital Health Stat May;(19):1. Spinelli A, Talamanca IF, Lauria L. Patterns of contraceptive use in 5 European countries. European Study Group on Infertility and Subfecundity. Am J Public Health 2 Sep;9(9):143. e 11 e 12 Monthly Injectable.5 cc aqueous suspension contains estradiol cypionate (E 2 C) 5 mg medroxyprogesterone acetate (MPA) 25 mg Approved by the FDA October 2 Monthly Injectable: Characteristics High efficacy Monthly administration Physiologic levels of estradiol Initial irregular bleeding Hormonal side effects Need for monthly injection Medroxyprogesterone estradiol cypionate (MPA E 2 C) is the first monthly combination contraceptive to be licensed for routine use in the U.S. It is administered intramuscularly and contains 5 mg of estradiol cypionate and 25 mg of medroxyprogesterone acetate. In dose-ranging studies, the 5 mg/25 mg combination was found to provide the best balance of efficacy and safety. Higher doses of medroxyprogesterone, although no more effective in suppressing ovulation, produced significantly higher rates of amenorrhea. Lower doses of the progesterone produced inadequate ovulation suppression. Higher doses of estrogen were associated with menstrual irregularities. The greatest advantage of monthly injectables is their high efficacy.

4 e 13 Monthly Injectable: Efficacy Number of women 785 Woman-months of use 8,92 Hall PE. New once-a-month injectable contraceptives, with particular reference to Cyclofem/Cyclo-Provera. Int J Gynaecol Obstet 1998 Aug;62 Suppl 1:S43. First-year cumulative pregnancy rate.2 % e 14 Subdermal Implant Hall. Int J Gynaecol Obstet 1998;62:S43 Single-rod system with disposable inserter Releases etonogestrel (3-ketodesogestrel) for three years As of July 22 not approved by the FDA The subdermal implant is a new contraceptive implant system consisting of a non-biodegradable, single rod. The product is supplied in a pre-loaded, sterile and disposable applicator which facilitates insertion. The active component in a single-rod implant is etonogestrel; it does not contain an estrogen. The core of the implant contains 68 mg of crystalline etonogestrel, dispersed in a matrix of ethylenevinylacetate (EVA) copolymer surrounded by a.6 EVA membrane. e 15 Implant: Characteristics High efficacy Long-term reversible method Hormonal side effects Requires insertion/removal Irregular bleeding Can be felt under skin e 16 Implant: Efficacy Number of women Woman-years of use 2-year cumulative pregnancy rate % Zheng SR, Zheng HM, Qian SZ, Sang GW, Kaper RF. A longterm study of the efficacy and acceptability of a single-rod hormonal contraceptive implant (Implanon) in healthy women in China. Eur J Contracept Reprod Health Care 1999 Jun;4(2):85. e 17 Vaginal Ring Zheng et al. Eur J Contracept Reprod Health Care 1999;4:85 Steroid release Progestin: Etonogestrel: 12 mcg/day (~15 pg/ml) Estrogen: Ethinyl estradiol: 15 mcg/day (~2 pg/ml) Worn for three weeks out of four Approved by the FDA in October 21 The vaginal ring is a low-dose sustained release contraceptive system. Daily doses are less than those of OCPs. The peak serum concentrations reached are much less than with OCPs (less than a fifth of OCPs) One size of the ring fits everyone.

5 e 18 Vaginal Ring: Characteristics Self administered Insertion every four weeks Foreign body in vagina Expulsions Limited published data on efficacy e 19 Vaginal Ring: Efficacy Number of women 16 Timmer CJ, Mulders TM. Pharmacokinetics of etonogestrel and ethinylestradiol released from a combined contraceptive vaginal ring. Clin Pharmacokinet 2 Sep;39(3):233. Woman-cycles of use 16 cycles Cumulative pregnancy rate Limited published data e 2 Timmer and Mulders. Clin Pharmacokinet 2;39:233 Contraceptive Patch Steroid release Progestin: norelgestromin 15 mcg/day Estrogen: ethinyl estradiol 2 mcg/day Worn for three weeks out of four Approved by the FDA in November 21 The patch provides daily steroid doses equivalent to the lowest dose OCPs. Maximum serum concentrations are lower with the patch than with OCPs because the patch is a sustained release system. The size of the patch determines daily dose and maximum concentrations. e 21 Contraceptive Patch: Characteristics Self administered Once-a-week administration Hormonal side effects Efficacy similar to combined oral contraceptives Audet MC, Moreau M, Koltun WD, Waldbaum AS, Shangold G, Fisher AC, Creasy GW. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: a randomized controlled trial. JAMA. 21 May 9;285(18):2347. e 22 Patch: Efficacy Number of women Audet et al. Jama 21;258:2347 1,417 Shangold G, Fisher AC, Rubin A. Pharmacodynamics of the contraceptive patch. Obstet Gynecol 2 Apr 1;95(4 Suppl 1):S36. Woman-cycles of use 2,44 Cumulative pregnancy rate 1% Shangold et al. Obstet Gynecol 2;95:S36

6 e 23 e 24 e 25 Levonorgestrel Intrauterine System () 32 mm : Characteristics Steroid reservoir levonorgestrel 2 mcg/day Approved December 2 High efficacy Long-term reversible method Reduction in menstrual blood loss Low systemic levels of LNG Early spotting common Foreign body in the uterus Expulsions Requires professional insertion : Mechanism of Action Fertilization inhibition: Cervical mucus thickened Sperm motility and function inhibited Endometrium suppressed Weak foreign body reaction induced Ovulation inhibited (in some cycles) Jonsson et al. Contraception 1991;43:447 Videla-Rivero et al. Contraception 1987;36:217 The product is as wide (32mm) as it is long with its arms fully extended. Small T-shaped frame with a LNG-containing cylinder. Potent progestin found in many combination oral contraceptive, progestin-only pills, and implants. The LNG system releases LNG from the cylinder at 2 mcg per day into the uterine cavity for at least 5 years. Highly effective contraceptive protection. Published studies provide data on 12, women years of use. Two million women have used this method world-wide to date. The picture on the slide is just a schematic, so it is not anatomically proportional. The mechanism of action of the levonorgestrel intrauterine system is similar to that of LNG implants or LNG-containing mini-pills. As with other methods, thickening of the cervical mucus (1) and inhibition of sperm motility and function are the primary role (2). The LNG intrauterine system does not usually inhibit ovulation (3), but the pregnancy rate and the ectopic rate are extremely low, suggesting that a primary endometrial effect as the mechanism of action is unlikely. The endometrial atrophy which is a consequence of the high endometrial levels of LNG leads to the substantial decrease in menstrual flow and absence of bleeding in some women noted in users of this form of intrauterine contraception. A weak foreign-body effect is also noted. It is important to some patients that the mechanisms of action are all pre-conception. They prevent fertilization rather than disrupt implantation (a common misconception). Jonsson B, Landgren B-M, Eneroth P. Effects of various IUDs on the composition of cervical mucus. Contraception 1991;43:447. Nilsson CG, Lahteenmaki PLA, Luukkainen T, et al. Ovarian function in amenorrheic and menstruating users of a levonorgestrel-releasing intrauterine device. Fertil Steril 1984;41:52. Videla-Rivero L, Etchepareborda J, Desseru E. Early chorionic activity in women bearing inert IUD, copper IUD and levonorgestrel-releasing IUD. Contraception 1987;36:217.

7 e 26 : Efficacy Overall failure rate.14 per 1 woman-years Gross cumulative five-year rate is.71 per 1 women Andersson et al. Contraception 1994;49:56 Luukkainen et al. Contraception 1987;36:169 According to Luukkainen et al., the 12-month net pregnancy rate with the is.1 per hundred women. Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception 1994;49(1):56. Luukkainen T, Allonen H, Haukkamaa M, Holma P, Pyorala T, Terho J, Toivonen J, Batar I, Lampe L, Andersson K, et al. Effective contraception with the levonorgestrel-releasing intrauterine device: 12-month report of a European multicenter study. Contraception 1987 Aug;36(2):169. e 27 e 28 : Efficacy Five-Year Cumulative Pregnancy Rates per 1 Women by Age and IUD Type Nova T <= Age (Years) Luukkainen and Toivonen. Contraception 1995;52:269 : Comparison to Sterilization year gross cumulative failure rate per 1 women Nova T All Sterilization Post Partum Salpingectomy.6 Andersson et al. Contraception 1994;49:56 Peterson et al. Am J Obstet Gynecol 1996;174:1161 Luukkainen T, Toivonen J. Levonorgestrel-releasing IUD as a method of contraception with therapeutic properties. Contraception 1995 Nov;52(5):269. Because the failure rate is comparable to that of sterilization, it could be viewed in this context as reversible sterilization, not just reversible contraception. Even though this schematic depicts a difference, there is no significant statistical difference between the Nova T and LNG IUS. These data are from the largest study. Other studies have even lower failure rates. Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception 1994;49(1):56. Peterson HB, Xia Z, Hughes JM, Wilcox LS, Tylor LR, Trussell J. The risk of pregnancy after tubal sterilization: findings from the U.S. Collaborative Review of Sterilization. Am J Obstet Gynecol 1996 Apr;174(4):1161. e 29 : Return to Fertility Cumulative pregnancy rate (%) Copper IUD Months Andersson et al. Contraception 1992;46:575 Belhadj et al. Contraception 1986;34:261 The return to fertility with the is rapid, essentially equal to that of the copper IUD and much more rapid than that of methods such as contraceptive implants. Andersson K, Batar I, Rybo G. Return to fertility after removal of a levonorgestrel releasing intrauterine device and Nova-T. Contraception 1992;46:575. Belhadj H, Sivin I, Diaz S, et al. Recovery of fertility after use of the levonorgestrel 2 mcg/d o copper T 38 Ag intrauterine device. Contraception 1986;34(3):261. Vessey MP, Lawless M, McPherson K, Yeates D. Fertility

8 after stopping use of intrauterine contraceptive device. Br Med J (Clin Res Ed) 1983 Jan 8;286(6359):16. e 3 e 31 e 32 Plasma Concentrations of Levonorgestrel Plasma concentrations (pg/ml) Implant Mini-pill Combined OCs : Persistent Follicles As with other progestin-only methods, persistent follicles can occur (in less than 8 % of women). They do not require treatment. : Endometrial Effect Months Days of cycle Ovulation Nilsson et al. Acta Endocrinol 198;93:38 Diaz et al. Contraception 1987;35:551 Pakarinen et al. Fertil Steril 1997;68:59 Changes in the endometrium during normal menstrual cycle The graph on the slide is a schematic that contrasts the plasma concentrations of bolus administration of oral mini-pills and combined OCs with the sustained release of LNG that occurs in the IUS and the LNG implant. At this level of plasma concentration, ovarian hormonal function is maintained. About 85% of cycles are ovulatory at the end of one year, and estrogen levels are normal. As noted earlier, although plasma concentrations are low, endometrial concentrations are high. The effects of the hormone are thus targeted to where they are needed, not spread systemically. With the low-dose, LNG is detected in the serum 15 minutes after insertion. After an initial higher concentration, LNG reaches a steady state in several weeks. has a lower plasma concentration than implants. For short periods, combined OCs produce serum concentrations 5 times those of the low-dose products. Diaz S, Pavez M, Miranda P, Johansson ED, Croxatto HB. Long-term follow-up of women treated with Norplant implants. Contraception 1987 Jun;35(6):551. Kuhnz W, al-yacoub G, Fuhrmeister A. Pharmacokinetics of levonorgestrel and ethinylestradiol in 9 women who received a low-dose oral contraceptive over a treatment period of 3 months and, after a wash-out phase, a single oral administration of the same contraceptive formulation. Contraception 1992 Nov;46(5):455. Luukkainen T, Lahteenmaki P, Toivonen J. Levonorgestrel-releasing intrauterine device. Ann Med 199;22:85-9. Nilsson C G, Lahteenmaki P, Robertson D N, Luukkainen T. Plasma concentrations of levonorgestrel as a function of the release rate of levonorgestrel from medicated intra-uterine devices. Acta Endocrinol 198;93:38. Frequency of follicular cysts is no reason for removal of the IUS. Follow-up by ultrasound is recommended until the cysts disappearance. Although persistent follicles are not a cause for practitioner concern, they may be a concern for patients. Some can reach 3 cm in size, and counseling may need to explain that they are not dangerous and ultimately will go away. Pakarinen P I, Suvisaari J, Luukkainen T, Lahteenmaki P. Intracervical and fundal administration of levonorgestrel for contraception: endometrial thickness, patterns of bleeding, and persisting ovarian follicles. Fertil Steril 1997;68(1):59. LNG is concentrated locally in the endometrium, targeting the effects where they are desired and minimizing systemic side effects. Suppression is complete in three months. Returns to normal stage one month after removal. Pakarinen PI, Suvisaari J, Luukkainen T, Lahteenmaki P. Intracervical and fundal administration of levonorgestrel for

9 e 33 : Endometrial Effect Months Ovulation contraception: endometrial thickness, patterns of bleeding, and persisting ovarian follicles. Fertil Steril 1997 Jul;68(1):59. Silverberg SG, Haukkamaa M, Arko H, Nilsson CG, Luukkainen T. Endometrial morphology during long-term use of levonorgestrel-releasing intrauterine devices. Int J Gynecol Pathol 1986;5(3):235. Pakarinen PI, Suvisaari J, Luukkainen T, Lahteenmaki P. Intracervical and fundal administration of levonorgestrel for contraception: endometrial thickness, patterns of bleeding, and persisting ovarian follicles. Fertil Steril 1997 Jul;68(1):59. Days of cycle Endometrium in resting state with e 34 : Early Spotting Pakarinen et al. Fertil Steril 1997;68:59 Endometrial suppression effect is not immediate Takes three months for full effect on the endometrium Spotting is common during this time Silverberg et al. Int J Gynecol Pathol 1986;5:235 The effects of on menstrual bleeding are comparable to climbing a mountain. The spotting can be rough going for the first three months, but once the patient gets past that time, the bleeding patterns are very acceptable. Silverberg SG, Haukkamaa M, Arko H, Nilsson CG, Luukkainen T. Endometrial morphology during long-term use of levonorgestrel-releasing intrauterine devices. Int J Gynecol Pathol 1986;5(3):235. e 35 e 36 : Number of Bleeding Days Days Months : Bleeding Patterns Copper IUD Luukkainen and Toivonen. 1992;9 2 % of women will have no bleeding at all after 12 months Pekonen et al. J Clin Endocrinol Metab 1992;75:66 Luukkainen et al. Contraception 1987;36:169 Note the dramatic reduction in bleeding days that occurs with over time vis-à-vis the copper IUD. This is a substantial benefit for many women. Luukkainen T, Toivonen J. Progestin IUD - its benefit for women s health. In Sitruk R, Bardin CW, eds. Contraception: Newer Pharmacological Agents, Devices, and Delivery Systems. New York: Marcel Dekker 1992;9. Mechanism on bleeding Anti-proliferative action decreases menstrual blood loss Absence of bleeding is due to local effect Pituitary and ovarian function are normal Pekonen F, Nyman T, Lahteenmaki P, Haukkamaa M, Rutanen EM. Intrauterine progestin induces continuous insulin-like growth factor-binding protein-1 production in the human endometrium. J Clin Endocrinol Metab 1992 Aug;75(2):66. Luukkainen T, Allonen H, Haukkamaa M, Holma P, Pyorala T, Terho J, Toivonen J, Batar I, Lampe L, Andersson K, et al. Effective contraception with the levonorgestrel-releasing intrauterine device: 12-month report of a European multicenter

10 study. Contraception 1987 Aug;36(2):169. e 37 : Non-contraceptive Therapeutic Uses Alternative to hysterectomy Cancelled hysterectomy: 8 % vs. 9 % normal care Treatment of menorraghia 97 % decrease in menstrual blood loss (MBL) Hurskainen et al. Lancet. 21 Jan 27;357:273 Andersson and Rybo. Br J Obstet Gynaecol. 199 Aug;97:69 Both the alternative to hysterectomy and treatment of menorraghia statements are based on data from the cited before-after case studies Andersson JK, Rybo G. Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia. Br J Obstet Gynaecol. 199 Aug;97:69-4. Hurskainen R, Teperi J, Rissanen P, Aalto AM, Grenman S, Kivela A, Kujansuu E, Vuorma S, Yliskoski M, Paavonen J. Quality of life and cost-effectiveness of levonorgestrelreleasing intrauterine system versus hysterectomy for treatment of menorrhagia: a randomised trial. Lancet. 21 Jan 27;357: e 38 : Non-contraceptive Therapeutic Uses (cont) Hormone replacement therapy (HRT) Days of bleeding/spotting at 12 months: 2 vs. 6 oral LNG Adjuvant therapy for tamoxifen users Decidual change in endometrium of all women with Barrington and Bowen-Simpkins. Br J Obstet Gynaecol May;14:614 Gardner et al. Lancet. 2 Nov 18;356:1711 Both statements based on the cited randomized controlled clinical trials. Barrington JW, Bowen-Simpkins P. The levonorgestrel intrauterine system in the management of menorrhagia. Br J Obstet Gynaecol May;14(5):614- Gardner FJ, Konje JC, Abrams KR, Brown LJ, Khanna S, Al- Azzawi F, Bell SC, Taylor DJ. Endometrial protection from tamoxifen-stimulated changes by a levonorgestrel-releasing intrauterine system: a randomised controlled trial. Lancet. 2 Nov 18;356: e 39 US Preventive Services Task Force Ratings Finding Increases concentration of hemoglobin Effective treatment for menorraghia Well-accepted alternative to hysterectomy Strength of conclusion Hubacher and Grimes. Obstet Gynecol Surv 22 Feb;57:12 A A B The US Preventive Services Task Force analyzed the body of medical research relating to various possible benefits of the to determine the level of scientific support for these assertions. They concluded the research provides fair to good supporting evidence about the benefits listed on this slide and the next slide. Only ratings of B or higher are shown in this table. A = good evidence to support the finding B = Fair evidence to support the finding Hubacher D, Grimes DA. Noncontraceptive health benefits of intrauterine devices: a systematic review. Obstet Gynecol Surv 22 Feb;57:12-8

11 e 4 US Preventive Services Task Force Ratings (cont) Finding Prevents anemia Strength of conclusion A Hubacher D, Grimes DA. Noncontraceptive health benefits of intrauterine devices: a systematic review. Obstet Gynecol Surv 22 Feb;57(2):12-8 Can be used as a vehicle for hormone replacement therapy (HRT) Mitigates tamoxifen-induced endometrial effects A B e Hubacher and Grimes. Obstet Gynecol Surv 22 Feb;57:12 Cumulative Termination Rates Per 1 women Expulsion Bleeding Problems 2 15 Hormonal Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception 1994;49(1): e N= Nova T N=937 Five-Year Cumulative Rates of Discontinuation for PID Randomized trial comparing the to CuT 38A Andersson et al. Contraception 1994;49:56 CuT38A Sivin et al. Contraception 199;42:361 Multi-national trial: Egypt, Singapore, United States, Dominican Republic, Brazil, and Chile 1,121 women radomly assigned to CuT38A, 1,124 to LNG IUS Five-year follow-up Insertion training may have varied from site to site (expulsion rates varied from site to site) No predetermined criteria for pelvic inflammatory disease (PID) The removal rates for PID after five years were low, and there were no differences in rates of discontinuation between the two intrauterine contraceptives Sivin I, el Mahgoub S, McCarthy T, Mishell DR Jr, Shoupe D, Alvarez F, Brache V, Jimenez E, Diaz J, Faundes A, et al. Long-term contraception with the levonorgestrel 2 mcg/day (LNg 2) and the copper T 38Ag intrauterine devices: a fiveyear randomized study. Contraception 199 Oct;42(4): e 43 Five-Year Cumulative Rates of Discontinuation for PID Randomized trial comparing the to Nova T Nova T Andersson et al. Contraception 1994;49:56 European study centers: Finland, Sweden, Denmark, Hungary, and Norway 937 women received Nova T (Copper IUD); 1,821 received LNG IUS Highly trained and supervised study locations Prospective uniform criteria for diagnosis and treatment of side effects and problems were established. Definition of PID determined at the outset in the event of a problem, patients were seen immediately by the investigators for evaluation. The may lower the risk of pelvic inflammatory disease compared to other IUDs. There is the suggestion that the effect of levonorgestrel on cervical mucus may make the introduction of pathogens into the upper genital tract less likely. The cumulative

12 e 44 e : Five-Year Cumulative Gross Removal Rate for PID Per 1 women P=.19 Nova-T Ordinal Month Andersson et al. Contraception 1994;49:56 : Possible Complications Symptoms Return of menstruation Consider Expulsion removal rate for PID at 36 months was.5/1 women versus 2/1 women, a significant difference. At 6 months, the cumulative removal rates for PID were.8/1 women for the and 2.2/1 women for the Nova T. Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception 1994;49:56. Note that there was no increase in PID seen in relation to the insertion. This may be due to protocol and training criteria. These include the requirement that cervicitis be excluded before insertion and aseptic technique was used at insertion. Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception 1994;49:56. Fever/chills Continuous bleeding and/or pain after first month post-insertion Infection Perforation, infection, or partial expulsion e 46 : Possible Complications (cont) It is also important to evaluate the patients for missing strings, which may be a sign of expulsion or dislocation. Symptoms Irregular bleeding and/or pain in every cycle Missing string Consider Dislocation or perforation Dislocation or perforation e 47 : Potential Contraindications Pregnancy or suspicion of pregnancy Active cervical or endometrial infections Uterine anomaly Complete list included in the package labeling Pregnancy is a contraindication whether it is known or suspected. The uterine abnormality may be a distorted uterine cavity, either congenital or acquired. Infected abortion is a contraindication only if it occurred within the last three months. Any bleeding of unknown etiology is included.

13 e 48 e 49 : Potential Complications Expulsions Most occur during the first six months after insertion The five-year cumulative expulsion rate is 4.9 per 1 women Perforations Occur at the time of insertion Rare events, fewer than one per thousand : The Inserter Andersson et al. Contraception 1994;49:56 Expulsion rate higher immediate post-abortion than interval insertion No data on immediate post-partum insertion Recommend insertion six weeks post-partum Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception 1994;49(1):56. e 5 e 51 e 52 : Insertion Different insertion technique than other intrauterine contraception New, one-handed insertion Requires hands-on training Efficacy and user continuation dependent on skillful insertion : Counseling Efficacy Return to fertility Side effects Changes in bleeding patterns Non-contraceptive health benefits Safety Insertion and follow-up Counseling: Efficacy High efficacy In clinical studies failure rate about that of female and male sterilization Continuous contraception for up to five years The principal difference in insertion between the and other is the IUS inserted through the cervix with T arms folded upward, and copper devices are inserted with the T arms folded down. The two types of intrauterine contraception have very different insertion techniques and devices. Well-trained providers will have lower expulsion rates and fewer complications. Counseling for the should include discussion about non-contraceptive health benefits such as reduction in bleeding, prevention of anemia, benefits of hormone therapy, mitigation of tamoxifen-induced endometrial affects Reduction in bleeding is more than a side effect of this product. It may be considered a health benefit to many women and it is useful to present it to the patient in this context.

14 e 53 Counseling: Side Effects Possible hormonal side effects Mood changes Acne Headache Breast tenderness Nausea No reported weight gain Possible side effects are more common in the initial months. They occur less often over time. Breast tenderness and nausea are quite uncommon, and patients should understand this. e 54 e 55 e 56 e 57 Mean Weight Change After Five Years Weight gain in kg Nova T 2.4 Andersson et al. Contraception 1994;49:56 Counseling: Changes in Bleeding Bleeding characteristics: 1 4 mo frequent spotting 1 6 mo reduced duration and amount of bleeding Reduction in menstrual blood loss After 12 mo, about 2 % have no bleeding Pakarinen et al. Fertil Steril 1997;68:59 Counseling: Absence of Bleeding Local effect No proliferation of endometrium This is expected. It is not a sign of: Pregnancy Ovarian or pituitary dysfunction Menopause Rapid return to menstruation after removal Counseling: Health Benefits Reduction of Duration and amount of bleeding Ectopic pregnancies Menstrual pain Increase of Hemoglobin Iron storage Luukkainen et al. Contraception 1987;36:169 Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception 1994;49(1):56. Absence of bleeding may be considered a benefit by many women. Pakarinen P I, Suvisaari J, Luukkainen T, Lahteenmaki P. Intracervical and fundal administration of levonorgestrel for contraception: endometrial thickness, patterns of bleeding, and persisting ovarian follicles. Fertil Steril 1997;68(1):59. Patients should understand that no individual can be guaranteed a 9% reduction in blood loss; that is a group figure. However, marked reduction is likely for all women. Differentiate between bleeding and spotting. Many patients may be confused and perceive spotting as bleeding. Understanding what spotting is and that it is a short-term problem can help motivate continuation of use. Note that a lack of bleeding is an expected effect, neither unusual nor harmful. Luukkainen T, Allonen H, Haukkamaa M, Holma P, Pyorala T, Terho J, Toivonen J, Batar I, Lampe L, Andersson K, et al. Effective contraception with the levonorgestrel-releasing intrauterine device: 12-month report of a European multicenter study. Contraception 1987 Aug;36(2):169.

15 e 58 Counseling: Safety > Ten years experience in Europe > Two million users world wide Few serious side effects Highly effective Does not prevent acquisition of STDs Condoms advised for women at risk e 59 Counseling: Insertion Steps in the insertion process Pelvic and speculum exam Sensations produced by tenaculum Paracervical anesthesia, if needed Sensations of IUS as it is inserted Measures you will take for her comfort Briefly describe the steps during the insertion process, including sensations she might experience. The clinician can provide an overview of these before the insertion as well as keep her informed of the process along the way. Letting the patient know she has permission to ask the clinician to slow down or stop may give her a degree of comfort for having some control during the insertion procedure. If there are other comfort measures that the clinician uses such as offering paracervical anesthesia describe these to the patient as well. e 6 e 61 e 62 Counseling: Post-Insertion Schedule a follow-up visit at 1 3 months post-insertion Check for partial or complete expulsion Address any questions or concerns : Therapeutic Possibilities Range of non-contraceptive benefits, including: Treatment of heavy menstrual bleeding Endometrial protection for women receiving estrogen replacement therapy : Treatment of Heavy Bleeding Menstrual blood loss (ml) Before treatment Months of use Andersson and Rybo. Br J Obstet Gynaecol 199;97:69 A follow-up visit can be scheduled from one to three months to check the placement of the device. Most importantly to determine if she has questions or concerns about her method. If she is unhappy with the system or experiencing side effects, provide appropriate counseling. Reassure her when side effects will diminish and let her know she can discontinue the method if she continues to be unhappy with it. We are now transitioning to a discussion of potential noncontraceptive benefits of. Luukkainen T. The levonorgestrel intrauterine system: therapeutic aspects. Steroids 2 Oct-Nov;65(1-11):699. Overall reduction in menstrual blood loss is 9 97% Before-after study of 25 women Decrease menorrhagia in women with adenomyosis Significant increase in hemoglobin and decrease in uterine volume at 12 months Andersson JK, Rybo G. Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia. Br J Obstet Gynaecol 199 Aug;97(8):69-4. Fedele L, Bianchi S, Raffaelli R, Portuese A, Dorta M. Treatment of adenomyosis-associated menorrhagia with a levonorgestrel-releasing intrauterine device. Fertil Steril

16 e 63 e 64 e 65 : Percentage Reduction of Menstrual Blood Loss Placebo Prostaglandin Synthetase Inhibitor Combination OCs Milsom et al. Am J Obstet Gynecol 1991;164:879 vs. Endometrial Resection Pictorial blood loss assessment chart score Baseline 6 months 12 months Levonorgestrel intrauterine system Endometrial resection Crosignani et al. Obstet Gynecol 1997;9:257 as Alternative to Hysterectomy Percent Women Canceling Hysterectomy Medical Therapies Lahteenmaki et al. BMJ 1998;316: ;68(3):426. This slide represents the reduction over a 12-month period for all methods, although the patterns/timeframes of reduction differ among the methods. As this slide shows, the reduces menstrual bleeding substantially more than other contraceptive methods. Milsom I, Andersson K, Andersch B, Rybo G. A comparison of flurbiprofen, tranexamic acid and a levonorgestrel-releasing intrauterine device in the treatment of idiopathic menorrhagia. Am J Obstet Gynecol 1991;164:879. IUS provides contraception Reversible Preserves fertility Crosignani PG, Vercellini P, Mosconi P, Oldani S, Cortesi I, De Giorgi O. Levonorgestrel -releasing intrauterine device versus hysteroscopic endometrial resection in the treatment of dysfunctional uterine bleeding. Obstet Gynecol 1997;9(2): women ages 33-49, scheduled to have hysterectomy for heavy uterine bleeding, three hospitals in Finland Randomly assigned to or current medical treatment At an average follow-up of three years (range months), 13 of 27 women (48%) were still using the The system may provide a long-term alternative to hysterectomy A case-series report of 5 women in Britain shows similar results. Of 5 women scheduled for hysterectomy due to heavy bleeding, 41 who received were taken off the list after nine months, with four developing complete amenorrhea. Lahteenmaki P, Haukkamaa M, Puolakka J, Riikonen U, Sainio S, Suvisaari J, Nilsson CG. Open randomized study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy. BMJ 1998 Apr 11;316(7138):1122.

17 e 66 e 67 e 68 : Hormone Replacement Prevention of endometrial hyperplasia from estrogen therapy Local is logical Oral progestins can cause depression avoids systemic side effects of oral progestins Girdler et al. J Womens Health Gend Based Med 1999;8:637 : Hormone Replacement Bleeding is the most common reason why women discontinue HRT suppresses endometrium % have no bleeding/ spotting at 12 months 82 % continuation rate at three years General Discussion Ettinger. Menopause 1999;6:273 Suhonen et al. Acta Obstet Gynecol Scand 1997;76:145 New methods are coming to U.S. market This should translate into more contraceptive choices, fewer unintended pregnancies These new methods share the common advantage of not requiring daily attention U.S. labeling does not include this use at this time. Girdler SS, O'Briant C, Steege J, Grewen K, Light KC. A comparison of the effect of estrogen with or without progesterone on mood and physical symptoms in postmenopausal women. J Womens Health Gend Based Med 1999 Jun;8(5):637. U.S. labeling does not include this use at this time. Andersson K, Mattson L-A, Rybo G, Stadberg E. Intrauterine release of levonorgestrel - a new way of adding progestogen in hormonal replacement therapy. Obstet Gynecol 1992;79(6):963. Ettinger B. Personal perspective on low-dosage estrogen therapy for postmenopausal women. Menopause 1999 Fall;6(3):273. Suhonen S, Holmstrom T, Lahteenmaki P. Three-year followup of the use of a levonorgestrel releasing intrauterine system in hormone replacement therapy. Acta Obstet Gynecol Scand 1997;76(2):145. e 69 Intrauterine Contraception in the U.S. 2 mcg levonorgestrel/day Approved for 5 years Approved 2 Copper IUD copper ions Approved for 1 years Approved 1988 e 7 PID Incidence Rate for All IUDs by Time Since Insertion Combined WHO clinical trial data for all IUDs - 22,98 IUD insertions (per 1, woman-years) Month (first year) Year Time Since Insertion Farley et al. Lancet 1992;339:785 22,98 IUD insertions, 51,399 woman-years of use Overall rate of PID was 1.6 cases per 1 woman years of use This graph shows an exponential decrease in risk after the first month. Even during the first month, the PID rate is only about one in 1, This is no different from the baseline of all women using no method of contraception An increased risk of PID with IUDs associated with insertion

18 was not seen in the European /Nova T comparative trial Farley TM, Rosenberg MJ, Rowe PJ, Chen JH, Meirik O. Intrauterine devices and pelvic inflammatory disease: an international perspective. Lancet 1992 Mar 28;339(8796):785. e 71 Dispelling Myths: Intrauterine Contraception Infections are a frequent problem Prevents implantation Women are not interested in intrauterine contraception e 72 Prophylactic Antibiotics? Any risk of infection associated with the IUD relates to insertion One woman in 1, will develop PID in the first three months Meta-analysis has not shown any overall benefit of prophylactic antibiotics Grimes and Schulz. Contraception 1999;6:57 Walsh et al. Lancet 1998;351:15 Asymptomatic IUS users with documented GC or chlamydia infections need treatment not IUD removal. Grimes DA, Schulz KF. Prophylactic antibiotics for intrauterine device insertion: a metaanalysis of the randomized controlled trials. Contraception 1999 Aug;6(2):57. Walsh T, Grimes D, Frezieres R, Nelson A, Bernstein L, Coulson A, Bernstein G. Randomised controlled trial of prophylactic antibiotics before insertion of intrauterine devices. IUD Study Group. Lancet 1998 Apr 4;351(918):15. e 73 Myth: IUD Prevents Implantation Most evidence now suggests that all IUDs induce a foreign body reaction that is spermicidal, preventing fertilization Today s intrauterine contraceptives have other mechanisms of action that prevent fertilization Alvarez et al. Fertil Steril 1988;49:768 Studies found an absence of any detectable hcg in the sera of 3 users of non-medicated IUDs over a thirty-month period, which suggests that disruption of implantation is not a major mechanism Other mechanisms of action that prevent fertilization include thickening the cervical mucus and creating a barrier to sperm penetration. Alvarez F, Brache V, Fernandez E, Guerrero B, Guiloff E, Hess R, Salvatierra AM, Zacharias S. New insights on the mode of action of intrauterine contraceptive devices in women. Fertil Steril 1988 May;49(5):768. Segal SJ, Alvarez-Sanchez F, Adejuwon CA, Brache de Mejia V, Leon P, Faundes A. Absence of chorionic gonadotropin in sera of women who use intrauterine devices. Fertil Steril 1985 Aug;44(2):214.

19 e 74 e 75 Use of Contraception by U.S. Women Physicians % of Women Using Method 4 2 Women MDs General Population Sterilization IUD Pills Frank. Obstet Gynecol 1999;94:666 Incidence* of Ectopic Pregnancy Copper IUD No method All U.S. women Recent survey shows that physicians are more likely to use IUD themselves IUD is a very popular method of contraception in Europe Erica Frank, MD MPH. Contraceptive use by female physicians in the United States. Obstet Gynecol 1999;94:666. Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception 1994;49(1):56. Sivin I. IUDs and ectopic pregnancy. Stud Fam Plann 1983 Feb;14(2):57. ACOG, 2. e 76 * Per 1, woman-years Andersson et al. Contraception 1994;49:56 Sivin. Stud Fam Plann 1983;14:57 Summary 1. Several new contraceptive methods are available in the U.S. 2. was approved by the FDA in 2 3. Fewer than one in 1 women will get pregnant in five years with e 77 Summary bleeding patterns: 1 4 mo frequent spotting 1 6 mo reduced duration and amount of bleeding > 12 mo, about 2 % have no bleeding Treatment of heavy menstrual bleeding and endometrial protection with HRT