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Everything you need to know about the contraceptive FDA approval means US women now have a progestin-only implant among their options

n July 17, the US Food and Drug or even monthly action on the part of the Administration (FDA) approved user, it is well-suited for: Philip D. Darney, MD, MSc what may be the most effective • Women who wish to or need Professor and Chief, Department O of Obstetrics, Gynecology, and hormonal contraceptive ever developed, a to avoid estrogen Reproductive Sciences, University single-rod implant that goes by the trade • Teens who find adherence to a of California-San Francisco, name Implanon. The implant contains 68 contraceptive regimen difficult San Francisco General Hospital ® Dowden Health Media mg of (ENG), the active • Healthy adult women who desire metabolite of desogestrel, in a membrane long-term protection ofCopyright ethylene vinylFor acetate. personal In clinical usetrials only• Women who are breastfeeding involving 20,648 cycles of exposure, only 6 occurred, for a cumulative 1 of 0.38 per 100 woman-years. ❚ IN THIS ARTICLE This article reviews: Pros and cons • the 2 contraceptive mechanisms Advantages include: ❙ How the • indications and patient selection • Cost. A study2 of 15 contraceptive progestin-only • pharmacology, safety, adverse effects methods found the implant cost-effec- implant prevents • patient satisfaction and discontinua- tive compared to short-acting methods, tion rates provided it was used long-term. As of fertilization • insertion and removal press time, the manufacturer had not Page 52 • key points of patient counseling released the price. Unlike Norplant, a multi-rod implant • Short fertility-recovery time. ❙ Take a lesson from which garnered a million American users • No serious cardiovascular effects.3 the Australians before it was removed from the market, Drawbacks. Progestin-only contraceptives Page 63 the single-rod implant is easy to insert and also have disadvantages: remove. Before you can order the implant, • Implants require a minor surgical pro- you must complete a manufacturer-spon- cedure by trained clinicians for inser- sored training program. tion and removal. • Cost-effectiveness depends on duration of use; early discontinuation negates 2 ❚ Which patients this benefit. • The implant does not protect against are suitable candidates? sexually transmitted infections—this is Because the subdermal implant contains a disadvantage of all contraceptive only progestin, provides up to 3 years of methods except and, per- protection, and requires no daily, weekly, haps, other barrier methods.

50 OBG MANAGEMENT • September 2006

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Everything you need to know about the contraceptive implant ▲

A forgettable contraceptive—that’s its allure After Implanon is inserted just below the dermis 6 to 8 cm above the elbow crease on the inner aspect of the arm, it remains effective for up to 3 years. To remove it, make a 2-mm incision at the distal tip of the implant and push on the other end of the rod until it pops out.

Insertion

Implanon implant

40 mm Dermis

Fat

Removal

Muscle

The implant resides beneath the dermis but above the subcutaneous fat. It remains palpable but invisible, releasing about 60 µg of etonogestrel per day

IMAGES: RICH LAROCCO

❚ The Norplant experience ing intrauterine system (Mirena), and FAST TRACK Research and development of progestin- injectable methods (Depo-Provera) are Average insertion only subdermal implants began more than safer than oral contraceptives (OCs) 35 years ago, but early research involving because they lack estrogen, which can pro- time: 1 minute very-low-dose implants found that they voke deep venous thrombosis.6,7 did not prevent ectopic pregnancies. This LNG, the gonane progestin used in Average removal problem ended with Norplant, a 6-capsule Norplant, binds with high affinity to the time: 3 minutes implant using the potent progestin lev- progesterone, , mineralocorti- onorgestrel (LNG). coid, and glucocorticoid receptors, but not Norplant was highly effective. Over 7 to estrogen receptors. ENG, also known as years of use, fewer than 1% of women 3-keto-desogestrel, demonstrates no estro- became pregnant.4 Despite low genic, anti-inflammatory, or mineralocorti- rates and few serious side effects, limita- coid activity, but has shown weak andro- tions in component supplies and negative genic and anabolic activity, as well as media coverage on complications with strong antiestrogenic activity. removal led to its withdrawal in 2002, Unlike LNG, which binds mainly to leaving no implant available in the US.5 sex hormone-binding globulin, ENG binds mainly to albumin, which is not affected by varying endogenous or exogenous estradiol levels. The safety of ENG has been demon- ❚ The antiestrogenic effect strated in studies of combined estrogen- Long-acting, progestin-only contraceptives progestin OCs and progestin-only OCs such as the new implant, the LNG-releas- that use desogestrel as a component.

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▲ Everything you need to know about the contraceptive implant

How the progestin-only implant prevents fertilization

The progestin-only implant has 2 primary to support the production, growth, and mechanisms: maturation of ovarian follicles.11 • Inhibition of • Restriction of sperm penetration of Oocytes are not fertilized, even if follicles cervical mucus28 grow during use of the progestin implant. If the follicle ruptures, abnormalities of the ovu- Ovulation is suppressed. LNG implants latory process prevent release of a viable egg. disrupt follicular growth and inhibit ovulation by exerting negative feedback on the hypo- Sperm cannot penetrate the cervical thalamic–pituitary axis, causing a variety of mucus. The antiestrogenic action of the changes, from anovulation to insufficient luteal progestin renders the cervical mucus vis- function. A few women using LNG implants cous, scanty, and impenetrable by sperm.12 have quiescent , but most begin to ovulate as LNG blood concentrations gradual- Contraceptive effects occur ly fall.29 The ENG implant suppresses ovula- before fertilization tion by altering the hypothalamic–pituitary No signs of embryonic development have –ovarian axis and down-regulating the been found among implant users, indicating luteinizing hormone surge, which is required the implant lacks properties.

Desogestrel in combination with ❚ Pharmacology of Implanon ethinyl estradiol may slightly increase the Implanon is a single nonbiodegradable attributable risk of deep venous thrombo- rod of 40% ethylene vinyl acetate and sis, but this response has not been shown 60% ENG (40 mm x 2 mm) covered with without estrogen. a membrane of rate-controlling ethylene FAST TRACK vinyl acetate 0.06 mm thick. The progestin-only Bioavailability implant suppresses ❚ Design features The 68 mg of ENG contained in the rod are ovulation and The single-rod design means little discom- initially absorbed by the body at a rate of 60 renders the fort for patients at insertion or removal, an µg per day, slowly declining to 30 µg per day cervical mucus unobtrusive implant, and almost no scar- after 2 years. ring. Insertion and removal are predictably Peak serum concentrations (266 impenetrable brief. In US and European trials, which pg/mL) of ENG are achieved within 1 day by sperm began 10 years ago, average insertion time after insertion, effectively suppressing ovu- was 1 minute, and removal time was 3 min- lation (which requires 90 pg/mL ENG or utes. In contrast, Norplant required up to more).11,12 10 minutes to insert and 1 hour to remove.8 The steady release of ENG into the Because only 1 rod is implanted, there circulation avoids first-pass effects on the is no risk of dislocating previously placed liver. capsules.9 Nor is it necessary, as it was with The bioavailability of ENG remains Norplant, to create channels under the nearly 100% throughout 2 years of use. skin, which made implants difficult to pal- The elimination half-life of ENG is 25 pate after insertion. hours, compared with 42 hours for Finally, ethylene vinyl acetate, the plas- Norplant’s LNG. tic from which Implanon is made, is less likely than Norplant’s Silastic to form a Rapid return to ovulation fibrous sheath that can prolong removal.10 After removal, serum ENG concentra-

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Everything you need to know about the contraceptive implant ▲

tions become undetectable within 1 week, ic effects of the ENG implant are unlikely to and ovulation resumes in 94% of women be clinically significant, including its effects within 3 to 6 weeks after the implant is on lipid and carbohydrate metabolism, liver removed.11,12 function, hemostasis, blood pressure, and thyroid and adrenal function.14–17

❚ Efficacy and safety Adverse event rates Overall, implants, including the ENG Liver enzyme-inducing drugs implant, appear to be safe. The rate of lower ENG levels adverse events is comparable to rates in Like other contraceptive steroids, serum nonusers18 (death, neoplastic disease, car- levels of ENG are reduced in women taking diovascular events, anemia, hypertension, liver enzyme-inducing drugs such as bone-density changes, diabetes, gall blad- rifampin, griseofulvin, phenylbutazone, der disease, thrombocytopenia, and pelvic phenytoin, and carbamazepine, as well as inflammatory disease). anti-HIV protease inhibitors. Pregnancies were reported among Australian women Lactation using Implanon along with some of these In a study comparing 42 lactating moth- antiepileptic drugs.13 er–infant pairs using the ENG implant, compared with 38 pairs using intrauterine Equal efficacy in obese women? devices, there were no significant differ- The efficacy of the single-rod implant was ences in milk volume, milk constituents, studied in clinical trials involving 20,648 timing and amount of supplementary cycles of use.1 Only 6 pregnancies occurred food, or infant growth rates.19 in this population—2 each in years 1, 2, Because it contains no estrogen, and 3 of use. None of the women who Implanon is a good choice for immediate weighed 154 lb (70 kg) or more became postpartum contraception. pregnant.12 However, questions remain as to FAST TRACK whether the new implant will maintain its Progestin high efficacy in obese women, as it has not ❚ Insertion and removal been studied in women weighing more Although the ENG implant is designed to implants have than 130% of their ideal body weight. facilitate rapid, simple insertion and no abortifacient Serum levels of ENG are inversely related removal, clinicians require training in properties to body weight and diminish over time, Implanon-specific technique.20 Insertion but increased pregnancy rates in obese takes an average of 1 to 2 minutes.21 women have not been reported. The disposable trocar comes pre- loaded,22 and the needle tip has 2 cutting Potential for ectopic pregancy edges with different slopes. The extreme Suspect ectopic pregnancy in the rare tip has a greater angle and is sharp to event that a woman becomes pregnant or allow penetration through the skin. The experiences lower abdominal pain.1 The second upper angle is smaller, and the reason: Pregnancies in women using con- corresponding edge is unsharpened to traceptive implants are more likely to be reduce the risk of placing the implant in ectopic than are pregnancies in the gener- muscle tissue. al population. Ovulation is possible in the Subdermal placement is imperative for third year of use, but intrauterine preg- efficacy and easy removal. nancies are very rare.1 Insertion technique Limited metabolic effects Have the patient lie on the examination Published studies indicate that the metabol- table with her nondominant arm flexed at

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▲ Everything you need to know about the contraceptive implant

the elbow and her hand next to her ear. ly follows an (in which case, no Identify and mark the insertion site using a additional contraception is needed). sterile marker, and apply any necessary In all cases, exclude pregnancy before local anesthetic. The insertion site should inserting the implant, although there is no be 6 to 8 cm above the elbow crease on the evidence that hormonal contraceptives inner aspect of the arm. Also mark the skin cause birth defects. 6 to 8 cm proximal to the first mark; this serves as a guide during insertion. Removal technique Remove Implanon from its package The ENG implant can be removed at any and, with the shield still on the needle, con- time at the woman’s discretion, but will firm the presence of the implant (a white remain effective for 3 years. cylinder) within the needle tip. Remove the Removal requires a 2-mm incision at needle shield, holding the inserter upright the distal tip of the implant. The other end to prevent the implant from falling out. of the rod is then pushed until the rod pops Apply countertraction to the skin at the out of the incision.9 insertion point and, holding the inserter at Mean removal time is 2.6 to 5.4 an angle no greater than 20 degrees, insert minutes.22 the needle tip into the skin with the beveled In rare cases, the ENG implant can- side up. Lower the inserter to a horizontal not be found when the time comes for position, lifting the skin with the needle tip removal, and special procedures, includ- without removing the tip from the subder- ing sonographic determination of loca- mal connective tissue, and insert the needle tion and sonographically guided removal, to its full length. are required. Next, break the seal of the applicator Pain, swelling, redness, and hematoma by pressing the obturator support, and have been reported during insertion and rotate the obturator 90% (in regard to the removal. needle) in either direction. At this point, Because ovulation resumes rapidly fol- the insertion process is the opposite of an lowing removal, women still desiring con- FAST TRACK injection: Hold the obturator in place and traception should begin another method Implanon retract the cannula. immediately or have a new rod inserted After insertion, the implant may not be through the removal incision. is a safe choice visible but must remain palpable.1 for immediate Timing the insertion. Placement should occur at one of the following times: postpartum ❚ Tell patients to expect contraception • For women who have not been using contraception or who have been using a altered bleeding nonhormonal method, insert the Side effects associated with the ENG implant between days 1 and 5 of menses. implant include menstrual irregularities: • For women changing from a combina- • infrequent bleeding, 26.9% tion or progestin-only OC, insert the • amenorrhea, 18.6% implant any time during pill-taking. • prolonged bleeding, 15.1% • For women changing from injectable • frequent bleeding, 7.4% contraception, insert the implant on Other effects include weight gain, the date the next injection is scheduled. 20.7%; acne, 15.3%; breast pain, 9.1%; • For women using the IUD, insertion and headache, 8.5%.8,18 can take place at any time. These symptoms rarely provoke dis- continuation. Women using any progestin- Additional birth control for 7 days only method will have changed bleeding Advise all women to use an additional bar- patterns; it is estrogen, along with regular rier method of contraception for 7 days progestin withdrawal, that provides pre- following insertion, unless insertion direct- dictable uterine bleeding.23,24

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▲ Everything you need to know about the contraceptive implant

A comparison of bleeding patterns in have been used successfully by millions of ENG implant users and LNG implant women. The benefits are high efficacy, users found a lower mean number of long duration, absence of estrogen, ease of bleeding/spotting days with the former use, reversibility, and safety. ■ (15.9–19.3 vs 19.4–21.6; P=.0169).25 Because total uterine blood loss is reduced, REFERENCES users of progestin-only contraceptives (as 1. Implanon [package insert]. Roseland, NJ: Organon; 2006. well as OCs) are less likely to be anemic. 2. Trussell J, Leveque JA, Koenig JD, et al. The economic The same comparison25 found that value of contraception: a comparison of 15 methods. Am J Public Health. 1995;85:494–503. users of ENG implants had more variable 3. Diaz S, Pavez M, Cardenas H, Croxatto HB. Recovery of bleeding patterns than users of LNG fertility and outcome of planned pregnancies after the implants. Unfortunately, it is impossible to removal of Norplant subdermal implants or copper-T IUDs. Contraception. 1987;35:569–579. predict which patterns a woman is likely to 4. Sivin I, Mishell DR Jr, Darney P, Wan L, Christ M. experience. capsule implants in the United States: a 5- The ENG implant reduced or elimi- year study, Obstet Gynecol. 1998;92:337–344. nated menstrual pain in 88% of women 5. Kuiper H, Miller S, Martinez E, Loeb L, Darney PD. Urban adolescent females' views on the implant and contracep- who previously experienced dysmenor- tive decisionmaking: a double paradox. Fam Plann rhea; pain increased in only 2% of ENG Perspect. 1997;29:167–172. implant users.18 6. Fu H, Darroch JE, Haas T, Ranjit N. Contraceptive failure rates: new estimates from the 1995 National Survey of Family Growth. Fam Plann Perspect. 1999;31:56–63. 7. Meirik O, Farley TMM, Sivin I, for the International Collaborative Post-Marketing Surveillance of Norplant. ❚ Most women Safety and efficacy of levonorgestrel implant, intrauterine liked the implant device, and . Am J Obstet Gynecol. 2001;97:539. 8. Croxatto HB, Urbancsek J, Massai R, Coelingh Bennink H, Despite side effects and the need for a van Beek A. A multicentre efficacy and safety study of the physician to insert and remove the single contraceptive implant Implanon. Implanon Study implants, most women are satisfied with Group. Hum Reprod. 1999;14:976–981. 9. Zieman M, Klaisle C, Walker D, Bahisteri E, Darney P. the method, citing its long duration, con- Fingers versus instruments for removing levonorgestrel FAST TRACK venience, and high efficacy.26,27 contraceptive implants (Norplant). J Gynecol Tech. Advise patients 1997;3:213. Discontinuation rates 10. Meckstroth K, Darney PD. Implantable contraception. to use barrier Obstet Gynecol Clin North Am. 2000;27:781–815. Nevertheless, some women do choose to 11. Markarainen L, van Beek A, Tuomiyaara L, Asplund B, contraception discontinue the method before 3 years are Bennink HC. Ovarian function during the use of a single up. Discontinuation rates range from contraceptive implant (Implanon) compared with Norplant. for 7 days Fertil Steril. 1998;69:714-721. 30.2% in Europe and Canada to 0.9% in 12. Croxatto HB, Mäkäräinen L. The pharmacodynamics and after insertion 18,22 Southeast Asia. Bleeding irregularities efficacy of Implanon. Contraception. 1998;58:91S–97S. are the most commonly cited reason for 13. Harrison-Woolrych M, Hill R. Unintended pregnancies with discontinuation, as they were for Norplant. the etonogestrel implant (Implanon): a case series from post-marketing experience in Australia. Contraception. A meta-analysis of 13 studies pub- 2005;71:306–308. lished between 1989 and 1992 found that, 14. Mascarenhas L, van Beek A, Bennink H, Newton J. among 1,716 women using the ENG Twenty-four month comparison of apolipoproteins A-1,A-II implant, 5.3% discontinued in months 1 and B in contraceptive implant users (Norplant and Implanon) in Birmingham, United Kingdom. Contraception. to 6, 6.4% discontinued in months 7 to 12, 1998;58:215–219. 4.1% discontinued in months 13 to 18, 15. Biswas A, Viegas OA, Bennink HJ, Korver T, Ratnam SS. and 2.8% discontinued in months 19 to Effect of Implanon use on selected parameters of thyroid and adrenal function. Contraception. 2000;62:247–251. 24. Overall, 82% of women continued to 16. Biswas A, Viegas OA, Coeling Bennink JH, Korver T, 8 use the ENG implant for up to 24 months. Ratnam SS. Implanon contraceptive implants: effects on carbohydrate metabolism. Contraception. 2001;63:137–141. Extensive, worldwide experience 17. Biswas A, Viegas OA, Roy AC. Effect of Implanon and Norplant subdermal contraceptive implants on serum Already the 6-capsule and 2-rod LNG lipids-a randomized comparative study. Contraception. implants and the single-rod ENG implant 2003;68:189–193.

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Take a lesson from the Australians

Lack of training, lack of What to advise patients30 counseling, lack of success • Strongly stress the likelihood of When the ENG implant was introduced changes in bleeding patterns in Australia in 2001, an unexpectedly • Lack of inherent protection against high number of unintended pregnancies sexually transmitted infections, and were reported: 100 pregnancies during importance of protective measures the first 18 months.13 Almost universally, (though the implant likely reduces these events were traced to improper the risk of pelvic inflammatory insertion by untrained clinicians, as well disease) as poor patient selection, timing, and • User-specific lifestyle and health counseling. advice, such as the need for supple- In response, the Royal Australian mental contraception in some women College of General Practitioners developed during the first 7 days of use policies for adequate documentation of • Pros and cons of implants compared proper insertion procedures and patient with other methods education. The problems disappeared.13 • The date when removal is indicated1 Preinsertion counseling and postinser- tion follow-up are essential for continued Consent form use of implants because they increase the The patient should sign a consent form, patient’s satisfaction with the method and which should be included in her medical help minimize costly removals. record.

18. Rekers H, Affandi B. Implanon studies conducted in 27. Darney PD, Callegari LS, Swift A. Atkinson ES, Robert Indonesia. Contraception. 2004;70:433. AM. practices of urban teens using Norplant contraceptive implants, oral contraceptives, and con- 19. Reinprayoon D, Taneepanichskul S, Bunyavejchevin S, et al. doms for contraception. Am J Obstet Gynecol. FAST TRACK Effects of the etonogestrel-releasing contraceptive implant 1999;180:929–937. (Implanon) on parameters of breastfeeding compared to those of an . Contraception. 2000;62:239–246. 28. Shaaban MM, Salem HT, Abdullah KA. Influence of lev- Bleeding onorgestrel contraceptive implants, Norplant, initiated early 20. Bromham DR, Davey A, Gaffikin L, Ajello CA. Materials, postpartum, upon lactation and infant growth. irregularities are methods and results of the Norplant training program. Br J Contraception. 1985;32:623–635. the most common Fam Plann. 1995;10:256. 29. Brache V, Faundes A, Johansson E, Alvarez F.Anovulation, 21. Mascarenhas L. Insertion and removal of Implanon: practi- inadequate luteal phase, and poor sperm penetration in reason for cal considerations. Eur J Contracept Reprod Health Care. cervical mucus during prolonged use of Norplant implants. 2000;5(suppl 2):29. Contraception. 1985;31:261–273. discontinuing 22. Smith A, Reuter S. An assessment of the use of Implanon 30. Funk S, Miller MM, Mishell DR Jr, et al. Safety and efficacy in three community services. J Fam Plann Reprod Health of Implanon, a single-rod implantable contraceptive con- the implant taining etonogestrel. Contraception. 2005;71:319–326. Care. 2002;28:193–196. 23. Darney PD, Taylor RN, Klaisle C, Bottles K, Zaloudek C. Serum concentrations of estradiol, progesterone, and lev- Dr. Darney reports that he is a consultant to Organon and a onorgestrel are not determinants of endometrial histology speaker for Barr Laboratories, Berlex, and Organon. or abnormal bleeding in long-term Norplant implant users. Contraception. 1996;53:97–100. 24. Alvarez-Sanchez F, Brache V, Thevenin F, Cochon L, Faundes A. Hormonal treatment for bleeding irregularities EXAMINING in Norplant implant users. Am J Obstet Gynecol. THE EVIDENCE

1996;174:919–922. CLINICAL IMPLICATIONS OF KEY TRIALS 25. Zheng S-R, Zheng H-M, Qian S-Z, Sang G-W, Kaper RF.A randomized multicenter study comparing the efficacy and bleeding pattern of a single-rod (Implanon) and a six-cap- Q Does unopposed estrogen sule (Norplant) hormonal contraceptive implant. increase the risk Contraception. 1999;60:1–8. of breast cancer? 26. Darney PD, Atkinson E, Tanner S, et al. Acceptance and perceptions of Norplant among users in San Francisco, A Turn to page 24 USA. Stud Fam Plann. 1990;21:152–160.

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