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UPDATE NEW DEVELOPMENTS THAT ARE CHANGING PATIENT CARE

Ram Parvataneni, MD, MPH and Philip Darney, MD, MSc CONTRACEPTION Department of Obstetrics, Gynecology, and Reproductive Sciences, San Francisco General Implanon approved … Why the FDA removed ParaGard’s Hospital, University of California, parity rule … Plan B does not promote high-risk behavior San Francisco

hree new developments this year Half of are unintended stand to make a difference in the high • The has one of the highest Trate of unintended pregnancies in the® Dowdenrates of unintended Health births among Media industri- United States. Increased use of highly effec- alized countries. tive, long-acting, user-independent methods • Of the 6 million pregnancies each year in is an effective way to lowerCopyright the rate of unin-For personalthe US, nearly use3 million only are unintended, tended pregnancies in couples using contra- resulting in 1.4 million unintended births ception. Two such methods are the contra- and 1.3 million . ceptive implant and the intrauterine contra- • Half of these unintended pregnancies are ceptive. is an due to failure or incorrect or inconsistent IN THIS ARTICLE effective way to reduce the risk of unintend- use of a contraceptive method.1 ed after failure of a contraceptive ❙ How to insert and method or unprotected or forced sex. A ran- REFERENCES remove Implanon domized trial showed that direct access to 1. Contraception Counts: Ranking State Efforts. New York: Page 32 EC does not increase high-risk behavior. Guttmacher Institute; February 2006.

Implanon essentials: How it works and what to tell patients ❙ Talking with patients about emergency ❙ The single-rod implant (Implanon) is Implanon is independent of user compli- a new, highly effective, long-acting, ance and is rapidly effective and reversible. contraception rapidly reversible contraceptive, It is in use worldwide in more than 30 coun- Page 38 approved by the FDA, July 17,2006. tries since 1998. The new device is a nonbiodegradable new single-rod implant that provides 40 x 2.0 mm rod of 40% ethylene vinyl A highly effective contraception for up to acetate (EVA) and 60% 3 years is expected to be widely available in (ENG) covered with a rate-controlling EVA the United States in 2007. Once inserted, membrane.

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UPDATE CONTRACEPTION CONTINUED

The rod contains 68 mg of ENG, ini- years. The most common reason was tially absorbed by the body at a rate of 60 bleeding pattern changes (13%).5 The µg/day, slowly declining to 30 µg/day after rate of discontinuation was highest 3 years of use.2 Steady release of ENG into during the first 8 months. the circulation avoids first-pass effects on What to tell patients. To improve continua- the liver. tion, counseling should strongly stress the expected change in bleeding patterns. Manufacturer-sponsored training: Call 1-877-IMPLANON Before clinicians can order the implant, they must undergo training sponsored by ❚ Clinical trials the manufacturer, Organon. To take part Outstanding efficacy. In an international in the training, which is set to begin in multicenter trial, there were no intrauter- August, call 1-877-IMPLANON. ine or ectopic pregnancies in a total of 1,200 woman-years (15,000 cycles of How the implant works exposure, 2,000 of which were in the third Ovarian and cervical mechanisms, which year of use).4 The was 0 (95% function prior to fertilization, provide high CI 0.0–0.2).4 In the US series, after a total contraceptive efficacy. exposure of 474 woman-years (6,186 is suppressed. The ENG cycles), no intrauterine or ectopic pregnan- implant, unlike previous - cies were observed.5 It should be noted that containing implants, works primarily by phase III data from Indonesia were retract- suppressing ovulation.3 ENG alters the ed by the manufacturer in 2004.6 The 2 tri- hypothalamic–pituitary–ovarian axis and als noted above included a total of 965 down-regulates the luteinizing women and were not included in this surge, which is required to support the retraction. production, growth, and maturation of Reasons for failures. Pregnancies were ovarian follicles. noted from postmarketing data in FAST TRACK Ovulation returns rapidly after Australia; most of these pregnancies Before inserting removal of the implant.3 resulted from either incorrect timing at Cervical mechanisms also prevent fertiliza- the initial insertion or failure to insert the Implanon, counsel tion. Anti-estrogenic actions of ENG make implant. Based on the Australian phase the patient— the cervical mucus viscous, scanty, and IV data, with 204,486 devices inserted, strongly emphasize impenetrable by sperm. the failure of the method itself was esti- 7 that she should Cost-effectiveness depends on long-term mated to be 1 per 1,000 insertions. use; early removal negates this benefit. At Implanon may be less effective in obese expect bleeding press time, the manufacturer had not women or, as the Australian experience patterns to change released the price of Implanon. showed, with concomitant use of drugs Lack of protection against sexually trans- that stimulate the liver’s cytochrome mitted infections is a disadvantage of the metabolism of steroids, such as some ENG implant, as well as all nonbarrier antibiotics (eg, rifampin) or anticonvul- contraceptive methods. sants (eg, phenytoin). Discontinuation rates have varied by region, but are usually due to bleeding pattern Side effects changes. Infrequent bleeding. The main side effect is a • In an international multicenter trial, change in bleeding patterns. In the US series, 31% discontinued by 2 years and only amenorrhea occurred in 14% to 20% of 6% discontinued in the third year.4 women. In the same series, women experi- Again, the most common reason was enced infrequent bleeding (<3 episodes in 90 irregular bleeding. days) in 30% to 40% of the 90-day refer- • In a US series, 49% discontinued by 2 ence periods, making it the most common

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UPDATE CONTRACEPTION CONTINUED

How to insert and remove Implanon Although the ENG implant is designed to facilitate rapid and simple insertion and removal, clinicians must first be trained. The manufacturer, Organon, announced last month that it would begin training doctors in August.

Insertion Average time: 1 minute4 Removal Average time: 4 minutes4

Location of Applicator implant

The single-rod implant is preloaded in a disposable applicator. Insertion is done in the office using local anesthesia.

Place the 1.5-inch long implant on the inner aspect of the nondominant arm. Position the applicator needle subdermally and withdraw the cannula, leaving the implant rod in place. After insertion, the implant may not be visible but should be palpable.

Timing the insertion • Between days 1 and 5 of menses, in women who either have not been using a contraceptive Removal requires a 2- to 3-mm incision at the distal tip of the implant. Push the other end of the rod until it pops out. method or have been using a nonhormonal method • During a hormone-free week, in women changing from a combination or progestin-only oral Timing the removal contraceptive, or from intrauterine contraception The ENG implant can be removed at any time, • The day on which the next injection is scheduled, but must be removed after 3 years. in women changing from injectable contraception Return to ovulation is rapid following removal, No backup contraceptive is necessary if timing of so women still desiring contraception should begin insertion occurs as detailed. another method immediately or have a new rod LAROCCO RICH In all cases, exclude pregnancy before insertion. inserted through the removal incision. IMAGES:

CONTINUED

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UPDATE CONTRACEPTION CONTINUED

pattern experienced. Prolonged bleeding Contraindications (>14 days of bleeding in one episode) varied The ENG implant should not be placed in from 14% to 36%, and frequent bleeding women with undiagnosed abnormal geni- (>5 episodes in 90 days) varied from 7% to tal bleeding, known or suspected pregnan- 14%.5 Anemia was not observed in the US cy, or hypersensitivity to any of the compo- series despite the irregular bleeding; in fact, nents in the ENG implant. hemoglobins rise. Unpredictable bleeding pattern. Unlike with REFERENCES Norplant, there was no trend over time 2. Wenzl R, van Beek A, Schnabel P, Huber J. Pharmacokinetics of etonogestrel released from the toward a particular bleeding pattern. Implanon. Contraception. 1998;58:283–288. Implanon patterns are irregular and unpre- 3. Makarainen L, van Beek A, Tuomivaara L, Asplund B, dictable and vary from one 90-day reference Coelingh Bennink H. Ovarian function during the use of a single contraceptive implant: Implanon compared with period to the next. Similar results were noted Norplant. Fertil Steril. 1998;69:714–721. 4 in the multicenter international trial. 4. Croxatto HB, Urbancsek J, Massai R, Coelingh Bennink H, Possible therapies include sup- van Beek A. A multicentre efficacy and safety study of the single contraceptive implant Implanon. Implanon Study plementation, nonsteroidal anti-inflamma- Group. Hum Reprod. 1999;14:976–981. tory drugs, oral contraceptive pills, and 5. Funk S, Miller MM, Mishell DR Jr,et al. Safety and efficacy of observation. Implanon, a single-rod implantable contraceptive containing etonogestrel. Contraception. 2005;71:319–326. Other side effects. In the US series, the most 6. Rekers H, Affandi B. Implanon studies conducted in frequent nonmenstrual adverse effects pos- Indonesia. Contraception. 2004;70:433. sibly related to the ENG implant were acne 7. Harrison-Woolrych M, Hill R. Unintended pregnancies with the etonogestrel implant (Implanon): a case series from (14.5%), headache (12.7%), weight gain postmarketing experience in Australia. Contraception. (12.1%), and emotional lability (14.2%). 2005;71:306–308.

Why the FDA removed

ParaGard’s parity restriction FAST TRACK Pelvic infection ❙ An FDA labeling change for the A woman with at least one child and in ParaGard a mutually monogamous relationship is no is related more confirms what the evidence has long longer listed as the recommended patient to sexual behavior supported: The risk of pelvic infection profile. Nor is ParaGard contraindicated than to age, is more related to sexual behavior for a woman with a history of sexually contraceptive type, transmitted disease or pelvic inflammatory than to age, contraceptive choice, or parity or parity disease (PID), unless she has current acute PID or engages in sexual behavior suggest- ❙ Evidence supports a link between ing a high risk for PID. cervical infection—but not IUD use— and pelvic inflammatory disease and Why was the label infertility restrictive to begin with? Early studies8,9 that showed an increased he Food and Drug Administration has risk of PID and infertility in intrauterine Tapproved a less restrictive label for the contraceptive users have been re-analyzed; ParaGard T380A copper intrauterine contra- most of the increased risk was associated ceptive. Evidence has long supported the con- with a single type of intrauterine contracep- clusion that risk of pelvic infection is related tive that is no longer on the market more to a woman’s and her partner’s sexual (), and with high-risk sexual behavior than to her age, contraceptive behaviors.10–12 In most analyses of these choice, or parity. studies, the increased risk of PID was pres-

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UPDATECONTRACEPTION

ent only in the first 20 days after insertion, month rate of PID was lower in users of a indicating undiagnosed cervical infection at LNG-IUS contraceptive than in users of a the time of insertion. copper IUD (Nova-T) (0.5 and 2.0, respec- Furthermore, many studies had tively; P < 0.013), in both parous and nulli- methodological flaws that introduced bias parous women.16 This finding was more into the results, such as comparing marked in women under the age of 25. intrauterine contraceptive users with users of combination oral contraceptives (who Prescribing IUDs in young women have a decreased risk of PID compared When considering an intrauterine contra- with nonusers).13 ceptive for a young woman, it is therefore These early studies also equated nulli- important to assess her risk of a STI, based parity with high-risk sexual behavior. As on her and her partner’s sexual behavior, young women are more likely to acquire and not on parity or age. It is important to sexually transmitted cervical infections, screen for STIs at the time of or prior to and because young age is associated with insertion of an intrauterine contraceptive, nulliparity, many studies erroneously con- and to treat cervicitis prior to insertion. cluded that the increased risk of PID and Nulliparous women who are at low infertility was attributed to nulliparity. risk of STIs can be offered the intrauterine A case-control study in nulliparous contraceptive as an effective, long-term, Mexican women who were seeking treat- user-independent contraception. ment for primary infertility found no associ- The labeling for levonorgestrel ation between tubal infertility and past cop- intrauterine contraceptives should also per IUD use. In this study, 358 women with reflect the evidence that the risk of pelvic primary infertility and documented tubal infection is more related to a patient’s occlusion (cases) were compared with two and/or her partner’s sexual behavior than to sets of controls: 953 nulliparous women her age, contraceptive choice, or parity. with primary infertility and no tubal occlu- sion, and 584 primigravid women. Past use REFERENCES FAST TRACK of a copper IUD was not associated with 8. Lee NC, Rubin GL, Ory HW, Burkman RT. Type of intrauter- tubal occlusion, compared with either infer- ine device and the risk of pelvic inflammatory disease. Screen for STIs Obstet Gynecol. 1983;62:1–6. tile women without tubal occlusion or pri- 9. WHO. PID associated with fertility regulation agents. Task at the time of migravid controls (P values 1.0 and 0.9, Force on Intrauterine Devices, Special Programme of or before inserting respectively).14 However, tubal infertility was Research, Development and Research Training in Human Reproduction. Contraception. 1984:1–21. associated with a past infection with an IUD 10. Lee NC, Rubin GL, Borucki R. The intrauterine device and (as evidenced by Chlamydia pelvic inflammatory disease revisited: new results from the antibodies). This study further supports an Women’s Health Study. Obstet Gynecol. 1988;72:1–6. association between PID and infertility and 11. Gareen IF,Greenland S, Morgenstern H. Intrauterine devices and pelvic inflammatory disease: meta-analyses of pub- cervical infection—not IUD use. lished studies, 1974–1990. Epidemiology. 2000; 11:589–597. 12. Farley TM, Rosenberg MJ, Rowe PJ, Chen JH, Meirik O. Protective effect of progestin Intrauterine devices and pelvic inflammatory disease: an The levonorgestrel-releasing intrauterine international perspective. Lancet. 1992;339:785–788. 13. Grimes DA. Intrauterine device and upper-genital-tract system (LNG-IUS) may even protect against infection. Lancet. 2000;356:1013–1019. PID. One of the primary physiologic effects 14. Hubacher D, Lara-Ricalde R, Taylor DJ, Guerra-Infante F, of progestin contraception is thickening of Guzman-Rodriguez R. Use of copper intrauterine devices the cervical mucus, which protects against and the risk of tubal infertility among nulligravid women. N Engl J Med. 2001;345:561–567. ascending genital tract infection. This pro- 15. Speroff L, Darney PD. A Clinical Guide for Contraception. tective effect results in a decreased incidence 4th ed. Philadelphia: Lippincott, Williams & Wilkins; 2005. of PID in women who use combination oral 16. Toivonen J, Luukkainen T, Allonen H. Protective effect of contraceptive pills, progestin implants, and intrauterine release of levonorgestrel on pelvic infection: 15 three years’ comparative experience of levonorgestrel- and progestin injectables. A randomized con- copper-releasing intrauterine devices. Obstet Gynecol. trolled trial found that the cumulative 36- 1991;77:261–264. CONTINUED

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UPDATE CONTRACEPTION CONTINUED Direct access to Plan B does not promote high-risk behavior

Raine TR, Harper CC, Rocca CH, et al. Direct access to emergency contraception through pharmacies and effect on unintended pregnancy and STIs: a randomized controlled trial. JAMA. 2005;293:54–62.

❙ Advance provision of emergency than 72 hours after unprotected inter- contraception results in increased course. 18–20 No data are available on the usage of emergency contraception efficacy of emergency contraception pills without an associated change in taken more than 120 hours (5 days) after risky sexual behavior, sexually unprotected intercourse. transmitted diseases, or use of long-term contraception Randomized trial ❙ Clinicians should provide emergency contraception in advance of need “It seems unreasonable to ensure timely and appropriate to restrict access” emergency contraceptive use Raine et al21 added significantly to our knowledge of emergency contraception. mergency contraception could This is the first randomized trial address- Esignificantly reduce the risk of ing the question of the effect of access on unintended pregnancy after contra- emergency contraceptive usage. A total of ceptive method failure, or unpro- 2,117 young women (age 15 to 24 years) tected or forced sex. The newer were randomly assigned to these 3 groups: progestin-only emergency contracep- • Pharmacy access (without consulting a tive pills have now largely replaced the physician) older combined (estrogen and progestin) • Advance provision of 3 packs of Plan B ACOG pills because they are more effective and • Clinic access (ie, usual care, which have fewer side effects. required a clinic visit to obtain emer- has launched gency contraception) a campaign Various emergency contraception The study concluded: “While removing regimens are effective the requirement to go through to promote dialogue between The only dedicated progestin-only emer- or clinics to obtain emergency contracep- a woman and her ObGyn about gency contraception pill product in the tion increases use, the public health impact emergency contraception, and United States is Plan B, which contains 2 may be negligible because of high rates of to encourage women to get an tablets of 0.75 mg of levonorgestrel. unprotected intercourse and relative under- advance prescription. When Although the recommended treatment utilization of the method. Given that there they see their doctors wearing schedule is an initial dose within 72 hours is clear evidence that neither pharmacy the “Ask Me” lapel button, of unprotected intercourse and a second access nor advance provision compromises patients may be prompted to dose 12 hours later, a single dose of 1.5 mg contraceptive or sexual behavior, it seems ask about it, thus opening the of levonorgestrel is as effective as and caus- unreasonable to restrict access to emer- door for discussion es no more side effects than 2 tablets of gency contraception to clinics.” The con- 17, 18 FOR MORE INFORMATION: 0.75-mg doses 12 hours apart. clusion reflected the following several out- [email protected] comes, which were assessed after 6 months. 202-484-3321 The sooner the better? Emergency contraception pills are more effective the sooner after sex that they are 4 key outcomes initiated. Both combination oral contracep- 1 Use of emergency contraception tive pills and progestin-only regimens are • The advance provision group used moderately effective even if initiated more emergency contraception at nearly

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twice the rate (37.4%) of the clinic • That women with increased access access group (21.0%). to emergency contraceptives use their • Usage rates were similar in the routine contraception with the same pharmacy access (24.2%) and the consistency as women without clinic access group (21.0%). increased access.

2 New sexually transmitted infection No downside to easier, rates were similar in all groups wider access to Plan B Levels of STIs, such as Chlamydia, were sim- This trial adds to the argument for wider ilar across all groups, and changes in HSV-2 and easier access to emergency contracep- serology were similar across all groups. tion for women. There is no apparent downside from wide access to the current 3 Many did not use the EC, progestin-only emergency contraception even with advance provision regimen. The latest World Health In this study, advance provision of emer- Organization medical eligibility criteria gency contraceptives did not lower preg- describe no situation in which the risks of nancy rates. This finding is disappointing; emergency contraception outweigh the ben- the likely explanation is that women at efits.23 The study by Raine et al21 provides highest risk do not use emergency contra- evidence against concerns about the poten- ception often enough or at all. Thus, the tial for increased high-risk sexual behavior. overall pregnancy rate is unchanged. Eight states (Alaska, California, Nearly half (45%) of the women in the Hawaii, Maine, Massachusetts, New study who reported having unprotected Hampshire, New Mexico, Washington) sex did not use emergency contraception have passed legislation allowing pharma- during the study period, even when they cists to prescribe emergency contracep- received it in advance. tives without a prescription. Norway, Sweden, India, and the Netherlands 4 High-risk sexual behavior allow emergency contraceptive availabil- did not increase in any group ity over-the-counter. ■ FAST TRACK Women who had increased access to This trial adds emergency contraception did not have REFERENCES sex more frequently. Receiving emer- 17. Arowojolu AO, Okewole IA, Adekunle AO. Comparative eval- evidence that uation of the effectiveness and safety of two regimens of gency contraceptives in advance did not levonorgestrel for emergency contraception in Nigerians. wide access affect the number of sex partners, with Contraception. 2002;66:269–273. to Plan B has no most women having only one partner. 18. von Hertzen H, Piaggio G, Ding J, et al. Low dose mifepris- tone and two regimens of levonorgestrel for emergency apparent downside Data on teens in the same study found contraception: a WHO multicentre randomised trial. Lancet that teens did not take more sexual risks .2002;360:1803–1810. than women aged 20 to 24.22 19. Ellertson C, Evans M, Ferden S, et al. Extending the time limit for starting the of emergency contra- A concern with placing emergency con- ception to 120 hours. Obstet Gynecol. 2003;101:1168–1171. traception directly in the hands of women 20. Rodrigues I, Grou F, Joly J. Effectiveness of emergency contraceptive pills between 72 and 120 hours after unpro- has been the theory that it would result in tected . Am J Obstet Gynecol. 2001; increased high-risk behavior and lower use 184:531–537. of regular contraception. 21. Raine TR, Harper CC, Rocca CH, et al. Direct access to emergency contraception through pharmacies and effect This trial found: on unintended pregnancy and STIs: a randomized con- • That women with pharmacy access trolled trial. JAMA .2005;293:54–62. and women given 3 packs of emer- 22. Harper CC, Cheong M, Rocca CH, Darney PD, Raine TR. The effect of increased access to emergency contracep- gency contraceptives in advance were tion among young adolescents. Obstet Gynecol. no more likely to change their regular 2005;106:483–491. 23. Medical Eligibilty Criteria for Contraceptive Use. Geneva: contraceptive method than women World Health Organisation; 2004. who could obtain emergency contra- Dr. Parvataneni is a consultant to Organon. Dr. Darney is a consultant to ception only via a clinic visit. Organon and is a speaker for Berlex and Organon.

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