Levonorgestrel

Article Author:
Christina Vrettakos
Article Editor:
Tushar Bajaj
Updated:
4/6/2019 9:11:11 PM
PubMed Link:
Levonorgestrel

Indications

Levonorgestrel, also known as the morning-after pill, is a first line oral emergency contraceptive pill that has approval from the World Health Organization to prevent pregnancy. It is FDA approved to be used within 72 hours of unprotected sexual intercourse or when a presumed contraceptive failure has occurred. There has been off-label efficacy shown for up to 96 hours.[1] A prescription is not needed, and it is available over the counter at local pharmacies. The FDA has also approved levonorgestrel availability for all age groups due to its lack of life-threatening contraindications and side effect profile.[2] Levonorgestrel can be used as an oral combination pill with estradiol as a long-term option for birth control and is available in other forms such as an implant or a transdermal patch. There is a levonorgestrel-releasing intrauterine device considered to be a “low maintenance” birth control option for women that is efficacious for up to five years.[3] It has also been used off-label effects for treatment of endometrial hyperplasia, menorrhagia, endometriosis, and menopausal hormone therapy.  

Mechanism of Action

Levonorgestrel (LNG—17alpha-Ethynyl-18-methylestr-4-en-17beta-ol-3-one) is a second-generation synthetic progestogen, that is the active component of the racemic mixture of norgestrel. It binds to progesterone and androgen receptors where it can delay gonadotropin-releasing hormone from being released from the hypothalamus. This action blunts the luteinizing hormone surge that occurs during the pre-ovulation stage. Ultimately, it can delay or inhibit ovulation by preventing fertilization via inhibiting follicular rupture and release of a viable egg from the ovaries. Optimal efficacy is achievable when it is taken in the pre-ovulation stage as well. Levonorgestrel also induces the thickening of cervical mucus, which helps by interfering with sperm motility and passage. There has been no evidence in recent studies that levonorgestrel has a significant effect on the endometrium to alter it to prevent pregnancy.[4]

Studies have shown that levonorgestrel is not subject to significant first-pass metabolism. Levonorgestrel undergoes metabolism via hydroxylation, conjugation, and reduction in the liver. Its bioavailability varies from 85 to 100%.[5]

Administration

For emergency contraceptive use, the recommended dose is 1.5 mg oral tablet within 72 hours. There is also a 0.75 mg oral tablet that can be given with a second 0.75 mg dose if needed 24 hours later. A 3 mg oral levonorgestrel is for patients who are concomitantly taking a CYP3A4 cytochrome p450 liver enzyme-inducing drug, e.g., rifampicin, St. John’s wort, carbamazepine, or phenobarbital due to these agents increasing hepatic clearance of levonorgestrel. Vomiting can occur within two hours of administration at which case the patient would need to repeat the initial dose taken.[6]

For the long term birth control options, the levonorgestrel intrauterine T-shaped device has 52 mg of levonorgestrel covered by a rate-controlling membrane that regulates the rate of release of hormones.[3] The combined oral contraceptive pill with ethinylestradiol comes in a 21 pill pack per month with 0.1 mg of levonorgestrel and 0.02 mg of ethinylestradiol.

Adverse Effects

For the emergency contraceptive, the timing of when the drug is taken plays a significant role in its efficacy in preventing pregnancy; this means the adverse effect of pregnancy occurring become greater when the patient waits over 48 to 72 hours or longer to take the drug as well as taking the drug during an ovulation cycle. Many studies have shown an efficacy reduction in women whose BMI is greater than 30 kg/m^2, but not significant enough to restrict this subset of patients from using levonorgestrel, which is thought to be due to lower bioavailability of a standard 1.5 mg dose given of levonorgestrel, free plus albumin bound, in these patients. The most common side effects are menstrual abnormalities, amenorrhea, dysmenorrhea, oligomenorrhea, headaches, and acne.  Other side effects that can occur are nausea and vomiting. Importantly, this drug does not protect any patient from sexually transmitted infections, and diseases and patients are advised to use condoms for protection from such.[7][8]

For the intrauterine device, there is 0.1% of pregnancy to occur within the first year of use. The intrauterine device most commonly causes menstrual irregularities including amenorrhea and oligomenorrhea. Other side effects of the intrauterine device are similar to those of the combined oral contraceptive pill route such as ovarian cysts, weight gain, depression, acne, and low libido.[3]

Drug-Drug Interactions: 

The following may diminish the therapeutic effect of progestins: acitretin, anticoagulants, antidiabetic agents, barbiturates, carbamazepine, fosphenytoin, griseofulvin, mifepristone, phenytoin, primidone, retinoic acid derivatives, and St. John's wort.

The following may decrease the serum concentration of progestins: aprepitant, artemether, bexarotene, bile acid sequestrants, bosentan, brigatinib, clobazam, CYP3A4 inducers, dabrafenib, darunavir, efavirenz, encorafenib, eslicarbazepine, exenatide, felbamate, fosaprepitant,  ixazomib, lamotrigine, lesinurad, lixisenatide, lopinavir, lorlatinib, lumacaftor, metreleptin, mycophenolate, nelfinavir, nevirapine, oxcarbazepine, perampanel, rifamycin derivatives, saquinavir, sugammadex, and topiramate.

The following may increase the serum concentration of progestins: atazanavir, cobicistat, tipranavir, and voriconazole. 

The following may enhance the thrombogenic effect of progestins: C1-inhibitors and carfilzomib.

Contraindications

For the emergency contraceptive form, there are several contraindications including allergy, hypersensitivity, severe liver disease, pregnancy, and drug-drug interactions with liver enzyme-inducing drugs.[9]

For the intrauterine device, the contraindications include uterine anomalies (fibroids, cysts), breast carcinoma, active cervicitis/vaginitis, suspected cervical dysplasia, and pregnancy.[3]

Emergency contraceptive form: The medication is not for use in women confirmed to be pregnant; however, there is no proof nor reports of adverse effects on the mother or fetus following inadvertent exposure during pregnancy.[10]

Pregnancy for the IUD: Use during pregnancy or suspected pregnancy is contraindicated. 

Combined ethinylestradiol and levonorgestrel is pregnancy category X. 

Breastfeeding: levonorgestrel is present in breast milk; however, the relative infant dose is 8%. Breastfeeding is acceptable when the relative infant dose of a medication is less than 10%.[11]

Monitoring

Routine examinations with a gynecologist are encouraged for the long-term combined oral pill or intrauterine device birth control options; this is to monitor side effects and possible pregnancy. Levonorgestrel undergoes metabolism by the liver and is subject to impairment in patients with liver dysfunction. Therefore, monitoring liver function tests at the time of administration may be beneficial. Also, drugs containing CYP3A4 cytochrome p450 liver-enzyme inducing properties require close vigilance when a patient takes levonorgestrel. Another emergency contraceptive method may need to be considered to avoid drug-drug interactions.  These liver-enzyme inducing drugs can cause rapid metabolism and decrease the efficacy of levonorgestrel when there is concomitant use.[12]

Toxicity

There is a lack of research regarding the toxic levels and effects in humans. While there could be toxicity seen in patients with liver disease, there is not enough research to support this. More human trial studies will be necessary. There have been studies that show LD50 to be over 5000 mg/kg in rats when given orally, with a significant decrease in white blood cell counts.[13]

Enhancing Healthcare Team Outcomes

While levonorgestrel is a first line emergency contraceptive for unwanted pregnancy, communication and teamwork between primary care physicians, gynecologists, obstetricians, pharmacists, nurse practitioners, physician assistants, and nursing staff working together in an interdisciplinary team approach, can make a tangible difference in a patient’s experience while taking levonorgestrel. There has been controversy about the morning after pill being available without a prescription and sold over the counter at any local pharmacy.  This agent can be deemed as a drug that promotes risky sexual behavior, but can also be a drug of convenience for both perceived and verifiable contraceptive failures. This issue is how healthcare teams can combine patient education with adequate treatment plans to promote levonorgestrel use in the most effective way without compromising patient safety.[14] (Level V)

  • Primary care physicians and gynecologists should ask the patient about pertinent sexual history routinely to help monitor sexual behavior and document any changes.
  • Maintenance of a strong physician-patient relationship so that the patients trust the physicians and can be honest about their sexual practices and potentially risky behavior in a judgment-free atmosphere.
  • Pharmacists should emphasize the side effects of levonorgestrel, its strict timeline to achieve optimal drug efficacy, and how it will not prevent sexually transmitted infections and diseases.

References

[1] Chao YS,Frey N, 2018 Nov 29;     [PubMed PMID: 30883064]
[2] David M,Berends L,Bartley J, Current Opinion of Obstetricians on the Prescription of Emergency Contraception: A German-American Comparison. Geburtshilfe und Frauenheilkunde. 2012 Nov;     [PubMed PMID: 25258456]
[3] Beatty MN,Blumenthal PD, The levonorgestrel-releasing intrauterine system: Safety, efficacy, and patient acceptability. Therapeutics and clinical risk management. 2009 Jun;     [PubMed PMID: 19707273]
[4] Kahlenborn C,Peck R,Severs WB, Mechanism of action of levonorgestrel emergency contraception. The Linacre quarterly. 2015 Feb;     [PubMed PMID: 25698840]
[5] Basaraba CN,Westhoff CL,Pike MC,Nandakumar R,Cremers S, Estimating systemic exposure to levonorgestrel from an oral contraceptive. Contraception. 2017 Apr;     [PubMed PMID: 28041990]
[6] Black KI,Hussainy SY, Emergency contraception: Oral and intrauterine options. Australian family physician. 2017 Oct;     [PubMed PMID: 29036770]
[7] Festin MPR,Peregoudov A,Seuc A,Kiarie J,Temmerman M, Effect of BMI and body weight on pregnancy rates with LNG as emergency contraception: analysis of four WHO HRP studies. Contraception. 2017 Jan;     [PubMed PMID: 27527670]
[8] Shen J,Che Y,Showell E,Chen K,Cheng L, Interventions for emergency contraception. The Cochrane database of systematic reviews. 2019 Jan 20;     [PubMed PMID: 30661244]
[9] Back DJ,Orme ML, Pharmacokinetic drug interactions with oral contraceptives. Clinical pharmacokinetics. 1990 Jun;     [PubMed PMID: 2191822]
[10] Curtis KM,Tepper NK,Jatlaoui TC,Berry-Bibee E,Horton LG,Zapata LB,Simmons KB,Pagano HP,Jamieson DJ,Whiteman MK, U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports. 2016 Jul 29     [PubMed PMID: 27467196]
[11] Ito S, Drug therapy for breast-feeding women. The New England journal of medicine. 2000 Jul 13     [PubMed PMID: 10891521]
[12] Coricovac D,Farcas C,Nica C,Pinzaru I,Simu S,Stoian D,Soica C,Proks M,Avram S,Navolan D,Dumitru C,Popovici RA,Dehelean CA, Ethinylestradiol and Levonorgestrel as Active Agents in Normal Skin, and Pathological Conditions Induced by UVB Exposure: In Vitro and In Ovo Assessments. International journal of molecular sciences. 2018 Nov 14;     [PubMed PMID: 30441863]
[13] Kim SK,Shin SJ,Yoo Y,Kim NH,Kim DS,Zhang D,Park JA,Yi H,Kim JS,Shin HC, Oral toxicity of isotretinoin, misoprostol, methotrexate, mifepristone and levonorgestrel as pregnancy category X medications in female mice. Experimental and therapeutic medicine. 2015 Mar;     [PubMed PMID: 25667641]
[14] Brandão ER, [Long-acting reversible contraception methods in the Brazilian Unified National Health System: the debate on women's (in)discipline]. Ciencia     [PubMed PMID: 30892508]