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New Drug Reviews

Levonorgestrel/Ethinyl Estradiol (Lybrel) for Continuous Contraception



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Am Fam Physician. 2008 Jan 15;77(2):222-225.

Each tablet of Lybrel is composed of 90 mcg of levonorgestrel and 20 mcg of ethinyl estradiol. It is labeled for use as a continuous-cycle oral contraceptive. There is no physiologic reason for cyclic use of monophasic oral contraceptives, and research has demonstrated the safety and effectiveness of other estrogen/progestin combinations.1

Name Starting dosage Dose form Approximate monthly cost*

Levonorgestrel/ethinyl estradiol (Lybrel)

1 tablet daily

Tablet containing 90 mcg of levonorgestrel and 20 mcg of ethinyl estradiol

$54


*— Average wholesale cost, based on Red Book, Montvale, N.J.: Medical Economics Data, 2007.

Name Starting dosage Dose form Approximate monthly cost*

Levonorgestrel/ethinyl estradiol (Lybrel)

1 tablet daily

Tablet containing 90 mcg of levonorgestrel and 20 mcg of ethinyl estradiol

$54


*— Average wholesale cost, based on Red Book, Montvale, N.J.: Medical Economics Data, 2007.

SAFETY

Levonorgestrel and ethinyl estradiol are used in several other combination products that have demonstrated long-term safety. Safety of the continuous use of combined hormonal contraceptives has not been followed beyond two years. However, if there are greater safety risks associated with long-term use of extended or continuous-cycle combined hormonal contraceptives than with cyclic contraceptives, they are likely minimal.2

Cautions and contraindications of Lybrel are similar to those of other combined oral contraceptives. It is contraindicated for patients with a history of thromboembolic disorder, undiagnosed vaginal bleeding, active liver disease, or uncontrolled hypertension.3 There also is an increased risk of thrombosis; smoking increases this risk, particularly in women older than 35 years.3 In a 12-month phase 3 study, two cases of deep venous thrombosis and one case of pulmonary embolism were reported in 2,134 patients taking Lybrel.4

As with other oral contraceptives, Lybrel does not protect against sexually transmitted infections,3 and use during pregnancy is contraindicated because the product will be ineffective. Exposure to other combined oral contraceptives has not been shown to increase the risk of fetal malformations.5,6 Use during lactation is not recommended for the first six weeks postpartum; after this time, it is considered safe, but it may affect the quantity of breast milk because of the ethinyl estradiol component.7,8

On cessation of Lybrel, 38.5 percent of women experienced return to menses or pregnancy within 30 days, and 99 percent experienced this within 90 days.9

TOLERABILITY

Studies have found that extended or continuous-cycle combined hormonal oral contraceptive regimens have fewer bleeding days than cyclic regimens; however, there is no difference in the number of spotting days.1,10,11 Patients should be advised that they will likely experience unpredictable bleeding (spotting or more), which will gradually decrease with time. In the largest study to date, after 12 months of continuous use, 60 percent of patients were amenorrheic and 79 percent reported an absence of bleeding (i.e., did not require the use of feminine hygiene products) but may have still experienced spotting. Seventeen percent of patients discontinued therapy because of adverse effects, with one half attributing discontinuation to unexpected uterine bleeding.4

It can be determined from the limited published data that tolerability of Lybrel is similar to that of other combined oral contraceptives. The most common adverse effects include headache, dysmenorrhea, abdominal pain, and back pain.4 Continuous-cycle combined oral contraceptives have also been associated with decreased rates of headache, genital itch, bloating, and menstrual pain compared with cyclic regimens; however, some studies have shown no difference.1

EFFECTIVENESS

The effectiveness of Lybrel is likely similar to that of other continuous-cycle combined oral contraceptives, which are as effective as cyclic regimens in preventing pregnancy.1,1012 Based on North American data, 2.38 per 100 typical women taking Lybrel for one year will become unintentionally pregnant, which is a rate similar to that of other combined oral contraceptives.3,13 Perfect users will have a lower rate of pregnancy (about 1.60 pregnancies per 100 women per year).4 As with all medications, it is reasonable to expect that effectiveness outside a structured clinical trial setting will be less than that observed in studies. Continuous-cycle combined oral contraception is also useful for decreasing dysmenorrhea in patients with endometriosis.14,15

PRICE

Lybrel costs approximately $54 per month. Alesse and Desogen, which are combined oral contraceptives that can be taken continuously, cost approximately $38 and $44 per month, respectively.

SIMPLICITY

Lybrel is taken at the same time each day, continuously without a seven-day break.3 Most women will continue to experience menstrual bleeding for the first several months; however, it may be less predictable than it is with other cyclic combined oral contraceptive regimens. Women should expect menstrual bleeding at any time and need to be counseled about this possibility.

Bottom Line

Lybrel appears to be as safe and effective as other combined oral contraceptives; however, at this time, there is little published data about this specific product. Other combined monophasic oral contraceptives, some of which cost less than Lybrel, can be used continuously and have been shown to produce similar results. Patients who choose to take contraceptives continuously should be advised that they may experience spotting or irregular menses at any time.

Address correspondence to Lisa McCarthy, PharmD, at lmccart@mcmaster.ca. Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

1. Edelman AB, Gallo MF, Jensen JT, Nichols MD, Schulz KF, Grimes DA. Continuous or extended cycle versus cyclic use of combined oral contraceptives for contraception. Cochrane Database Syst Rev. 2005;3:CD004695.

2. Guilbert E, Boroditsky R, Black A, et al., for the Society of Obstetricians and Gynecologists of Canada. Canadian consensus guideline on continuous and extended hormonal contraception, 2007. J Obstet Gynaecol Can. 2007;29(7 suppl 2):S1–32.

3. Lybrel (90 mcg levonorgestrel and 20 mcg ethinyl estradiol) tablets [Product information]. Philadelphia, Pa.: Wyeth Pharmaceuticals, Inc. http://www.wyeth.com/content/showlabeling.asp?id=489. Accessed September 24, 2007.

4. Archer DF, Jensen JT, Johnson JV, Borisute H, Grubb GS, Constantine GD. Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol: phase 3 study results. Contraception. 2006;74(6):439–445.

5. Lammer EJ, Cordero JF. Exogenous sex hormone exposure and the risk for major malformations. JAMA. 1986;255(22):3128–3132.

6. Raman-Wilms L, Tseng AL, Wighardt S, Einarson TR, Koren G. Fetal genital effects of first-trimester sex hormone exposure: a meta-analysis. Obstet Gynecol. 1995;85(1):141–149.

7. Kelsey JJ. Hormonal contraception and lactation. J Hum Lact. 1996;12(4):315–318.

8. Contraceptives, oral, combined. Record No. 422. Bethesda, Md.: U.S. National Library of Medicine. http://toxnet.nlm.nih.gov/. Accessed September 24, 2007.

9. Davis AR, Kroll R, Soltes B, Haudiquet V, Constantine G, Grubb G. Return to menses after continuous use of a low-dose oral contraceptive. Obstet Gynecol. 2006;107(4 suppl):3S.

10. Miller L, Notter KM. Menstrual reduction with extended use of combination oral contraceptive pills: randomized controlled trial. Obstet Gynecol. 2001;98(5 pt 1):771–778.

11. Kwiecien M, Edelman A, Nichols MD, Jensen JT. Bleeding patterns and patient acceptability of standard or continuous dosing regimens of a low dose oral contraceptive: a randomized trial. Contraception. 2003;67(1):9–13.

12. Anderson FD, Hait H. A multicenter, randomized study of an extended cycle oral contraceptive [published correction appears in Contraception. 2004;69(2):175]. Contraception. 2003;68(2):89–96.

13. Seasonale (levonorgestrel/ethinyl estradiol tablets) 0.15 mg/0.03 mg [Product information]. Pomona, N.Y.: Duramed pharmaceuticals, 2003; http://www.seasonale.com/pdf/Seasonale_prescribing_info.pdf. Accessed September 24, 2007.

14. Vercellini P, Frontino G, De Giorgi O, Pietropaolo G, Pasin R, Crosignani PG. Continuous use of oral contraceptive for endometriosis associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen. Fertil Steril. 2003;80(3):560–3.

15. Vercellini P, De Giorgi O, Mosconi P, Stellato G, Vicentini S, Crosignani PG. Cyproterone acetate versus a continuous monophasic oral contraceptive in the treatment of recurrent pelvic pain after conservative sugery for symptomatic endometriosis. Fertil Steril. 2002;77(1):52–61.

STEPS new drug reviews cover Safety, Tolerability, Effectiveness, Price, and Simplicity. Each independent review is provided by authors who have no financial association with the drug manufacturer.

The series coordinator for AFP is Allen F. Shaughnessy, PharmD, Tufts University Family Medicine Residency Program at Cambridge Health Alliance, Malden, Mass.



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