The Single-Rod Contraceptive Implant – Safety

(Published July 2008)

Single-Rod Implant: Safety and Clinical Management

Health professionals should be familiar with the clinical characteristics associated with the use of the single-rod implant, which include:

• Changes in bleeding patterns without subsequent anemia
• Minor pain at the insertion site
• Mild, often transient, side effects such as breast pain and headache
• Minor weight change
• No reduction in bone mineral density
• Possible drug-drug interactions
• Possible venous thromboembolism (see DVT and Contraindications; next sections)
• Associated non-contraceptive benefits
• Minimal effect on libido

Endometrial Bleeding

Irregular endometrial bleeding, including amenorrhea, is common as with other progestin-only methods. The bleeding patterns observed in women using Implanon in clinical studies include a risk of unscheduled bleeding or irregularly irregular cycles.¹ These irregular cycles included:

• Frequent irregular bleeding
• Heavy menstrual flow
• Prolonged bleeding
• Amenorrhea
• Spotting
• Unpredictability of bleeding pattern over time

It is important for clinicians to understand that bleeding patterns are variable and unpredictable for individual women. The characteristics of one cycle are independent from those of previous cycles; thus, a pattern seen in one 3-month period may be different than the pattern in the next 3-month period. This non-patterned bleeding should be discussed with women prior to insertion to enhance understanding and tolerance of the contraceptive method and to minimize discontinuation.

The mechanism of irregularly irregular cycles of endometrial bleeding are complex and poorly understood and few studies have been conducted on the management of bleeding with the implant.² The National Institutes of Health studied bleeding with progestin-only products in clinical trials of different medical interventions and found there is no simple or direct approach for the management of irregular bleeding. Methods studied for treating bleeding induced by implants have all proved to be ineffective.³ Studies addressing this problem are currently being conducted in Europe. Ethinyl estradiol (not other estrogens) has been found to terminate a bleeding episode and may help women to cope in the early months of implant use until bleeding patterns improve spontaneously with time.^4,5 Implanon™ has demonstrated less bleeding/spotting days and a higher incidence of amenorrhea (2.0 percent to 18 percent) in a comparative study with Norplant^® (1.0 percent to 6.2 percent), and this finding may be seen as an advantage by many women.⁶

Anemia

Anemia is not found with the single-rod implant despite the altered bleeding patterns. The mean hemoglobin level increased slightly from baseline in an integrated analysis of 13 clinical trials examining the bleeding patterns observed in Implanon users.¹

Ovarian Cysts

Ovarian cysts may occur during the first year of use with the single-rod implant. In one study, cysts appeared in 5.2 percent of women at three months, 7.2 percent at six months, and 26.7 percent at 12 months; rates were similar to those occurring in Jadelle^® users and slightly higher than those of intrauterine contraceptive users.⁸ Follicular cysts occur with progestin only and oral contraceptive use. They may not be functional (producing estradiol) but they are apparent with ultrasound. These cysts are follicular and appear to be secondary to delayed follicular atresia. The follicle (ovarian cyst) may continue to grow beyond the size it would attain in a normal cycle. The cysts can be up to 5.0 cm in diameter and last for two to three months. Generally, these enlarged follicular cysts disappear spontaneously (shrink). If they rupture, mild pelvic pain may occur for 24–48 hours.⁸ Follicular cysts rarely require surgery, only follow up using ultrasound at monthly intervals. If a patient presents with abdominal pain, ectopic pregnancy or the presence of ovarian cysts should be ruled out. Depending on the clinical situation, expectant management of simple ovarian cysts should be considered in lieu of surgery.

Adverse Events

Symptoms associated with implant insertion reported in the clinical trials include swelling, redness, pain, hematoma, and expulsion. Among more than 1,400 women, fewer than four percent reported pain, and the other symptoms were extremely rare (Table 3 and 4). Implanon users have also reported headache, weight gain, acne, breast and abdominal pain, mood swings, depression, and decreased libido in addition to pain at the insertion site.⁹

Adverse events that led to discontinuation of treatment in one percent or more of subjects in the clinical trials are shown in Table 3. Adverse events reported in more than five percent of subjects in the clinical trials are shown in Table 4.

Weight gain

The mean weight gain in US Implanon users was 2.8 pounds after one year and 3.7 pounds after 2 years in clinical studies.⁸ How much of the weight gain was related to Implanon is unknown. Weight gain was listed by 2.3 percent of users as the reason for having Implanon removed.

Bone Mineral Density

Progestin-only implants are not associated with decreased bone mineral density (BMD). Bone mineral density at the lumbar spine, proximal femur, and distal radius was measured using dual energy X-ray absorptiometry in an open label, prospective 2-year comparison study of 44 women with single-rod implants and 29 women with a non-hormonal intrauterine device (IUD).¹⁰ Changes in BMD were basically similar between the two groups. The only statistically significant difference between the two treatments was an increase in BMD at the lumbar spine with the single-rod implant.

Drug-drug Interactions

As with all drugs there is the potential for drug interactions. Inhibition of CYP3A4 may increase serum etonogestrel concentrations and the risk of experiencing symptoms of progestin excess (Figure 5). Drugs that induce hepatic CYP3A4 enzymes may substantially decrease the efficacy of etonogestrel and put patients at increased risk for unintended pregnancies.⁹ The medical literature reports several cases of pregnancies occurring while Implanon was in situ, but the women were taking concomitant interfering medications.¹¹

Deep Vein Thrombosis

The overall incidence of deep vein thrombosis (DVT) is about 0.67 per 1,000 among the general public and 800 per 100,000 women years in pregnancy.^12,13 There have been post-marketing reports of thrombosis among Implanon users though it is not known whether Implanon changes a woman’s risk for thrombosis.⁸ Venous thrombosis occurs in non-contracepting women, as well as in those using combined hormonal contraceptives, and women who are pregnant. Because Implanon contains one of the two hormones that are in combined oral contraceptive pills, venous thrombosis may be a side effect of Implanon (see Contraindications). The risk of venous thrombosis is increased in women who smoke and/or are obese. There is also an increased risk of thrombosis after surgery and with prolonged bed rest or sitting.¹⁴

Non-Contraceptive Benefits

Improved Acne

The single-rod implant has associated non-contraceptive benefits including a possible decrease in acne. In a two-year single-arm study (n=84), 61 percent of women who were found to have acne at the start of the study reported improvement in their acne, and 31 percent reported no change.¹⁶ Only eight percent reported that their acne had worsened.

Improved dysmenorrhea

A second associated non-contraceptive benefit is improvement in dysmenorrhea. Dysmenorrhea at study initiation was reported by 187 women. The majority (81 percent) reported improvement in dysmenorrhea during use of the single-rod implant at study end.¹⁵

References:

1. Affandi B. An integrated analysis of vaginal bleeding patterns in clinical trials of Implanon^®. Contraception. 1998;58:99S-107S.
2. Hickey M, Crewe J, Mahoney LA, Doherty DA, Fraser IS, Salamonsen LA. Mechanisms of irregular bleeding with hormone therapy: the role of matrix metalloproteinases and their tissue inhibitors. J Clin Endocrinol Metab. 2006;91(8):3189-98.
3. Abdel-Aleem H, d’Arcangues C, Vogelsong K, Gülmezoglu A. Treatment of vaginal bleeding irregularities induced by progestin only contraceptives. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD003449.
4. Weisberg E, Hickey M, Palmer D, O’Connor V, Salamonsen LA Findlay JK, Fraser IS.A pilot study to assess the effect of three short-term treatments on frequent and/or prolonged bleeding compared to placebo in women using Implanon. Hum Reprod. 2006; 21(1):295-302.
5. Meirik O, Fraser I, d’Arcangues C, WHO Consultation on Implantable Contraceptives for Women. Implantable contraceptives for women. Hum Reproduct Update. 2003;9(1):49-59.
6. Zheng SR, Zheng HM, Qian SZ, Sang GW, Kaper RF. A randomized multicenter study comparing the efficacy and bleeding pattern of a (Implanon^®) and a six-capsule (Norplant^®) hormonal contraceptive implant. Contraception. 1999;60:1-8.
7. Hidalgo MM, Lisondo C, Juliato CT. Espejo-Arce X, Monteiro I, Bahamondes L. Ovarian cysts in users of Implanon and Jadelle subdermal contraceptive implants. Contraception. 2006;73:532-536.
8. Implanon (etonogestrel implant) Physician Insert. Organon USA, Inc. Roseland, NJ. 2006.
9. ACOG. American College of Obstetricians and Gynecologists. A new progestin implant (Implanon) for long-term contraception. Medical Letter. 2007;109(4):990-991.
10. Beerthuizen R, van Beek A, Massai R, Mäkäräinen L, Hout J, Bennink HC. Bone mineral density during long-term use of the progestogen contraceptive implant Implanon compared to a non-hormonal method of contraception. Hum Reprod. 2000;15:118-122.
11. Schindlbeck C, Janni W, Friese K. Failure of Implanon contraception in a patient taking carbamazepine for epilepsia. Arch Gynecol Obstet. 2006 Jan;273(4):255-6.
12. Heineman LA, Dinger J. Safety of a new oral contraceptive containing drospirenone. Drug Saf. 2004;27:1001-18.
13. Scarvelis D, Wells PS. Diagnosis and treatment of deep-vein thrombosis. CMAJ. 2006;147(9):1087-1092.
14. Schwarz T, Siegert G, Oettler W, Halbritter K, Beyer J, Frommhold R, et al. Venous thrombosis after long-haul flights. Arch Intern Med. 2003;163:2759-64.
15. Funk S, Miller MM, Mishell DR Jr, Archer DF, Poindexter A, Schmidt J, Zampaglione E; The Implanon US Study Group. Safety and efficacy of Implanon, a single-rod implantable contraceptive containing etonogestrel. Contraception. 2005 May;71(5):319-26.