OVERVIEW

Oral means of emergency contraception, colloquially known as “morning after” pills, are used to prevent unwanted pregnancy after unprotected intercourse or suspected contraceptive failure. Two commonly used forms of emergency contraception are levonorgestrel and ulipristal acetate. Both can be administered as a single oral dose, ulipristal within 5 days and levonorgestrel within 2 days of the unprotected intercourse. Both have been shown to be safe and effective, rates of subsequent pregnancy being 0.6% to 3% compared to an expected rate of 5% to 6%. Levonorgestrel is available over-the-counter whereas ulipristal, at least in the United States, is available by prescription only. Neither approach to emergency contraception has been linked to serum enzyme elevations or to clinically apparent liver injury. However, ulipristal when given in daily doses in 3 month courses as therapy for symptomatic uterine fibroids has been linked to several instances of clinically apparent liver injury, some of which have been severe and even fatal.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Levonorgestrel – Generic, Plan B®

Ulipristal Acetate – Ella®

DRUG CLASS

Emergency Contraceptive Agents

COMPLETE LABELING

Levonorgestrel

Ulipristal Acetate

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

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DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Levonorgestrel	797-63-7	C21-H28-O2
Ulipristal	159811-51-5	C28-H35-N-O3
Progesterone	57-83-0	C21-H30-O2

ANNOTATED BIBLIOGRAPHY

References updated: 02 June 2020

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999; does not specifically discuss levonorgestrel or ulipristal).
• Chitturi S, Farrell GC. Estrogen receptor antagonists. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 610-2.

  (Review of hepatotoxicity of hormonal agents; discusses estrogens and progestins, but does not specifically discuss levonorgestrel or ulipristal).
• Schimmer BP, Parker KL. Contraception and pharmacotherapy of obstetrical and gynecological disorders. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1833-52.

  (Textbook of pharmacology and therapeutics).
• Emergency contraception OTC. Med Lett Drugs Ther. 2004;46(1175):10–1. [PubMed: 14749610]

  (Concise review of the efficacy, safety and costs of the over-the-counter form of Plan B that contains two 0.75 mg tablets of levonorgestrel; mentions side effects of nausea and vomiting, headache, abdominal pain and breast tenderness).
• Glasier AF, Cameron ST, Fine PM, Logan SJ, Casale W, Van Horn J, Sogor L, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis. Lancet. 2010;375(9714):555–62. [PubMed: 20116841]

  (Among 1899 women requesting emergency contraception within 5 days of unprotected sexual intercourse who were treated with either ulipristal [30 mg] or levonorgestrel [1.5 mg] and had adequate follow up evaluations, 50 pregnancies occurred and rates were lower with ulipristal [1.8% vs 2.6%] and adverse events were similar in both groups; no mention of ALT elevations or hepatotoxicity).
• Ella: a new emergency contraceptive. Med Lett Drugs Ther. 2011;53(1355):3–4. [PubMed: 21212744]

  (Concise review of the mechanism of action, clinical efficacy, safety, and costs of ulipristal acetate as emergency contraception shortly after its approval for use in the US; mentions its side effects of headache, nausea, abdominal pain, dysmenorrhea, fatigue, and dizziness, but not serious adverse events, ALT elevations or hepatotoxicity).
• Snow SE, Melillo SN, Jarvis CI. Ulipristal acetate for emergency contraception. Ann Pharmacother. 2011;45:780–6. [PubMed: 21666089]

  (Review of the safety and efficacy of ulipristal for emergency contraception; mentions that common adverse events included headache [17%], breast tenderness [16%], nausea [15%] and abdominal pain [13%], and that severe adverse events were rare and none were considered related to ulipristal).
• Chen QJ, Xiang WP, Zhang DK, Wang RP, Luo YF, Kang JZ, Cheng LN. Efficacy and safety of a levonorgestrel enteric-coated tablet as an over-the-counter drug for emergency contraception: a Phase IV clinical trial. Hum Reprod. 2011;26:2316–21. [PMC free article: PMC3157624] [PubMed: 21672924]

  (Among 2445 women requesting emergency contraception treated with levonorgestrel within 72 hours of unprotected intercourse, the pregnancy rate was 0.2% and adverse events included nausea, vomiting, vaginal bleeding, headache, and dizziness, but there was no mention of ALT elevations or liver related adverse events).
• Cheng L, Che Y, Gülmezoglu AM. Interventions for emergency contraception. Cochrane Database Syst Rev. 2012;(8):CD001324. [PubMed: 22895920]

  (Systematic analysis of 100 randomized controlled trials of emergency contraception with 55,666 women using mifepristone, levonorgestrel, copper intrauterine device placement and ulipristal, reported that all regimens were safe; no mention of ALT elevations or hepatotoxicity).
• Donnez J, Tatarchuk TF, Bouchard P, Puscasiu L, Zakharenko NF, Ivanova T, Ugocsai G, et al. PEARL I Study Group. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med. 2012;366:409–20. [PubMed: 22296075]

  (Among 239 women with symptomatic uterine fibroids and excessive bleeding treated with ulipristal [5 vs 10 mg] or placebo daily for up to 13 weeks before surgery, uterine bleeding and fibroid size decreased with ulipristal and adverse events included amenorrhea [73% and 82% vs 6%], headache and breast pain, but “there was no significant difference among the groups in the incidence of abnormal liver-function tests”).
• Richardson AR, Maltz FN. Ulipristal acetate: review of the efficacy and safety of a newly approved agent for emergency contraception. Clin Ther. 2012;34:24–36. [PubMed: 22154199]

  (Systematic review of safety and efficacy of emergency contraception using ulipristal or levonorgestrel reported no “clinically significant changes in biochemical parameters”).
• Plan B one-step OTC. Med Lett Drugs Ther. 2013;55(1419):52. [PubMed: 23797799]

  (Concise review of efficacy and safety of single vs two dose levonorgestrel regimens for emergency contraception; mentions common adverse events of headache, abdominal pain and breast tenderness, but does not mention ALT elevations or hepatotoxicity).
• Turok DK, Jacobson JC, Dermish AI, Simonsen SE, Gurtcheff S, McFadden M, Murphy PA. Emergency contraception with a copper IUD or oral levonorgestrel: an observational study of 1-year pregnancy rates. Contraception. 2014;89:222–8. [PMC free article: PMC4076674] [PubMed: 24332433]

  (Among 542 women requesting emergency contraception who were treated with oral levonorgestrel or implantation of a copper IUD, the one year pregnancy rates were 12% vs 7% and there were no reports of serious adverse events, ALT elevations or hepatotoxicity).
• Levy DP, Jager M, Kapp N, Abitbol JL. Ulipristal acetate for emergency contraception: postmarketing experience after use by more than 1 million women. Contraception. 2014;89:431–3. [PubMed: 24508124]

  (A summary of spontaneous reports of adverse events after use of ulipristal for emergency contraception in more than one million women mentions side effects of nausea, headache, abdominal pain, and dizziness, but not ALT elevations or liver related adverse events).
• Cleland K, Raymond EG, Westley E, Trussell J. Emergency contraception review: evidence-based recommendations for clinicians. Clin Obstet Gynecol. 2014;57:741–50. [PMC free article: PMC4216625] [PubMed: 25254919]

  (Review of emergency contraception mentions that the failure rates of ulipristal range from 0.9-2.1% and of levonorgestrel 0.6-3.1%, although both are less effective when given as an advance supply; in addition, they “have an excellent safety profile, and no deaths or serious complications have been causally linked” to their use).
• Donnez J, Hudecek R, Donnez O, Matule D, Arhendt HJ, Zatik J, Kasilovskiene Z, et al. Efficacy and safety of repeated use of ulipristal acetate in uterine fibroids. Fertil Steril. 2015;103:519–27.e3. [PubMed: 25542821]

  (Among 451 patients with symptomatic uterine fibroids treated with two 12-week courses of ulipristal [5 vs 10 mg daily], more than 80% had control of bleeding, and “laboratory results did not reveal any safety signals, and no patients discontinued treatment due to test abnormalities”).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury in the US collected between 2004 and 2012, no cases were attributed to emergency contraception regimens).
• Festin MP, Bahamondes L, Nguyen TM, Habib N, Thamkhantho M, Singh K, Gosavi A, et al. A prospective, open-label, single arm, multicentre study to evaluate efficacy, safety and acceptability of pericoital oral contraception using levonorgestrel 1.5 mg. Hum Reprod. 2016;31:530–40. [PMC free article: PMC4755445] [PubMed: 26830816]

  (Among 330 women at risk of pregnancy given levonorgestrel tablets [1.5 mg] to use within 24 hours of intercourse, the pregnancy rate was 7.5 per 100 years of use and there were 3 serious adverse events [choledocholithiasis, anemia, and rupture of a corpus luteum cyst]; no mention of ALT elevations or hepatotoxicity).
• Fauser BC, Donnez J, Bouchard P, Barlow DH, Vázquez F, Arriagada P, Skouby SO, et al. Safety after extended repeated use of ulipristal acetate for uterine fibroids. PLoS One. 2017;12:e0173523. [PMC free article: PMC5340384] [PubMed: 28267814]

  (Among 64 women with uterine fibroids treated with 1 to 8 three-month courses of ulipristal [10 mg daily], there were no changes in mean ALT or AST levels or in the “number of laboratory results falling outside of the normal range”).
• Rabe T, Saenger N, Ebert AD, Roemer T, Tinneberg HR, De Wilde RL, Wallwiener M. Selective progesterone receptor modulators for the medical treatment of uterine fibroids with a focus on ulipristal acetate. Biomed Res Int. 2018;2018:1374821. [PMC free article: PMC6261240] [PubMed: 30539001]

  (Review of the efficacy and safety of ulipristal as therapy of uterine fibroids).
• Donnez J. Liver injury and ulipristal acetate: an overstated tragedy? Fertil Steril. 2018;110:593–5. [PubMed: 30196943]

  (Brief summary of the results of liver test monitoring in the preregistration trials of ulipristal which showed no signal for potential hepatotoxicity).
• Ulipristal acetate (Esmya): restrictions on use. Drug Ther Bull. 2018;56:127. [PubMed: 30297449]

  (Summary of a European Union wide review of ulipristal that was initiated after receipt of 8 reports of severe liver injury among an estimated 750,000 women treated with the agent for uterine fibroids, which resulted in recommendations to restrict use of ulipristal [to women with normal liver tests and who have refractory, moderate-to-severe, symptomatic fibroids] and require monitoring of liver tests before, during and after each course of therapy).
• Donnez J, Arriagada P, Marciniak M, Larrey D. Liver safety parameters ofulipristal acetate for the treatment of uterine fibroids: a comprehensive review of the clinical development program. Expert Opin Drug Saf. 2018;17:1225–32. [PubMed: 30460871]

  (Detailed analysis of the changes in serum ALT, AST, Alk P and bilirubin levels in the preregistration trials of ulipristal during which there were no elevations in ALT above 3 times ULN among 422 women who received 5 mg daily and only 7 of 631 who received 10 mg daily, and no instance of clinically apparent liver injury at any dosage).
• Donnez J, Courtoy GE, Dolmans MM. Fibroid management in premenopausal women. Climacteric. 2019;22:27–33. [PubMed: 30601065]

  (Review of clinical features and management of uterine fibroids in premenopausal women mentions that ulipristal “is safe, provides fast control of bleedings, and causes sustained fibroid volume reduction in the vast majority of cases”).
• Del Forno S, Degli Esposti E, Salucci P, Leonardi D, Iodice R, Arena A, Raimondo D, et al. Liver function, tolerability and satisfaction during treatment with ulipristal acetate in women with fibroids: a single center experience. Gynecol Endocrinol. 2020;36:445–7. [PubMed: 31646908]

  (Among 162 women treated with at least one 3-month course of ulipristal [5 mg daily] for uterine fibroids, “no cases of increased serum AST or ALT levels were detected”).
• Meunier L, Meszaros M, Pageaux GP, Delay JM, Herrero A, Pinzani V, Dominique HB. Acute liver failure requiring transplantation caused by ulipristal acetate. Clin Res Hepatol Gastroenterol 2020: S2210-7401(20)30041-3. [PubMed: 32146092]

  (58 year old woman with uterine fibroids developed fatigue 2 months after starting ulipristal followed by jaundice a week after stopping [bilirubin 25.5 mg/dL, ALT 1652 U/L, GGT 252 U/L, INR 2.5], with progressive hepatic failure leading to urgent liver transplantation; publication includes a table summarizing clinical features of 3 other cases of acute liver failure and liver transplantation in women arising 1-6 months after starting ulipristal for uterine fibroids).