Levonorgestrel

Mechanism of Action

Levonorgestrel (LNG—17-alpha-ethynyl-18-methylestr-4-en-17beta-ol-3-one) is a second-generation synthetic progestogen, the active component of the racemic mixture of norgestrel. It binds to progesterone and androgen receptors, which can delay the release of gonadotropin-releasing hormone 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, as it inhibits follicular rupture and prevents the release of a viable egg from the ovaries. Optimal efficacy is also achievable when it is taken in the pre-ovulation stage. 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 significantly affects the endometrium to alter it to prevent pregnancy.[12]

Pharmacokinetics

Absorption: Levonorgestrel is rapidly and completely absorbed after oral administration. Studies have shown that levonorgestrel is not subject to significant first-pass metabolism. Its bioavailability varies from 85% to 100%.[13] The mean time to mean plasma concentration (Tmax) is about 1.6 ± 0.7 hours.

Distribution: The apparent volume of distribution (Vd) of levonorgestrel is about 1.8 L/kg, suggesting extensive tissue distribution. It exhibits high plasma protein binding (approximately 97.5% to 99%), primarily to sex hormone-binding globulin (SHBG), and to a lesser extent, serum albumin.

Metabolism: Levonorgestrel undergoes metabolism via hydroxylation, conjugation, and reduction in the liver. Levonorgestrel is metabolized by CYP3A4. It is conjugated mainly at the 17β-hydroxyl group to form sulfate conjugates, and to a lesser degree, glucuronide conjugates. In plasma, significant levels of both conjugated and unconjugated 3α,5β-tetrahydrolevonorgestrel are present, with smaller amounts of 3α,5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are subsequently excreted as glucuronide conjugates. Metabolic clearance can vary several-fold between individuals, contributing to interindividual variability in plasma concentrations.

Excretion: Approximately 45% of levonorgestrel and its metabolites are excreted via urine, while around 32% are excreted in feces, predominantly as glucuronide conjugates. The mean elimination half-life (t½) is 24.4 ± 5.3 hours, and the total clearance is about 7.7 ± 2.7 L/h.

Administration

Dosage Forms & Strengths  

Levonorgestrel is available as a 1.5 mg oral tablet.

Adult Dosage

For emergency contraceptive use, the recommended dose is 1.5 mg oral tablet within 72 hours. If taken within 72 hours after unprotected sex, levonorgestrel can reduce the risk of pregnancy by up to 87%. If taken within 24 hours, the efficacy is higher. 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 recommended for patients concomitantly taking a CYP3A4 cytochrome P450 liver enzyme-inducing drug, such as rifampicin, St. John’s wort, carbamazepine, or phenobarbital, due to these drugs increasing the hepatic clearance of levonorgestrel. Vomiting can occur within two hours of administration, in which case the patient would need to repeat the initial dose taken.[14]

For long-term birth control options, the levonorgestrel intrauterine T-shaped device contains 52 mg of levonorgestrel, covered by a rate-controlling membrane that regulates the rate of hormone release.[5] 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.

Specific Patient Populations

Hepatic impairment: No formal studies have been conducted to evaluate the effect of hepatic disease on the disposition of levonorgestrel

Renal impairment: No formal studies have been conducted to assess the impact of renal disease on the disposition of levonorgestrel tablets.

Pregnancy considerations: Levonorgestrel emergency contraceptive is not approved for use in pregnant patients.[15][16] In a systematic review of 47 articles, most adverse reactions to levonorgestrel were common and non-serious in nature. While a few pregnancy-related events such as ectopic pregnancy and miscarriage were reported, these were uncommon and occurred rarely in the context of emergency contraception use. Importantly, no statistically significant difference in adverse event rates was found between the 0.75 mg two-dose regimen and the 1.5 mg single-dose levonorgestrel regimen (p > 0.05), supporting the safety of both dosing strategies.[17] 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%.[18] Combined ethinylestradiol and levonorgestrel is pregnancy category X. 

Breastfeeding considerations: Progestin-only contraceptives like levonorgestrel are the hormonal contraceptives of choice during breastfeeding, as they minimally affect milk composition, supply, or infant growth. Though nonhormonal methods are preferred, expert consensus deems progestins acceptable postpartum. Some evidence suggests they may help protect against lactation-related bone mineral loss. Progestin-only methods may be associated with higher rates of rapid repeat pregnancies. Postcoital levonorgestrel shows no long-term adverse effects on breastfeeding or the infant.[19]

Pediatric patients: It is used in adolescents as an emergency contraceptive.[20] However, use is not indicated before menarche.

Older patients: The product is not intended for use in postmenopausal women, and pharmacokinetic data are not available for this group.

Adverse Effects

For the emergency contraceptive, the timing of when patients ingest the drug plays a significant role in its efficacy in preventing pregnancy; this means the adverse effect of pregnancy occurring becomes greater when the patient waits over 48 to 72 hours or longer to take the drug, as well as when taking the medication during an ovulation cycle. Many studies have shown a reduction in efficacy in women with a BMI greater than 30 kg/m², but this difference is not significant enough to restrict the use of levonorgestrel in this subset of patients. This appears to be due to the lower bioavailability of a standard 1.5 mg dose of levonorgestrel, which is free plus albumin-bound, in these patients. The most common adverse effects are menstrual abnormalities, amenorrhea, dysmenorrhea, oligomenorrhea, headaches, and acne. Other adverse effects that can occur are nausea and vomiting. Importantly, this drug does not protect any patient from sexually transmitted infections and diseases, and the advice to patients is to use condoms for protection.[21][22]

For the intrauterine device, 0.1% of pregnancies occur within the first year of use. The intrauterine device most commonly causes menstrual irregularities, including amenorrhea and oligomenorrhea. Other adverse 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.[5]

Levonorgestrel oral emergency contraception is generally well tolerated, with most adverse effects being common and non-serious. Rare serious events such as ectopic pregnancy, stroke, and anaphylaxis have been reported, although infrequently.[17][5]

Subdermal implants are associated with higher risks of acne, weight gain, dissatisfaction, and removal due to adverse effects compared to levonorgestrel intrauterine systems in reproductive-aged women. These differences may influence contraceptive choice based on individual tolerance and preferences.[23]

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

There are several contraindications for the emergency contraceptive form, including allergy, hypersensitivity, severe liver disease, pregnancy, and drug-drug interactions with liver enzyme-inducing drugs.[24]

For the intrauterine device, the contraindications include uterine anomalies (fibroids, cysts), breast carcinoma, active cervicitis/vaginitis, suspected cervical dysplasia, and pregnancy.[5]

Emergency contraceptive form is not for use in women confirmed to be pregnant; however, there is no proof or reports of adverse effects on the mother or fetus following inadvertent exposure during pregnancy.[16]

The Use of LNG-IUD during pregnancy or suspected pregnancy is contraindicated.

Warning and Precautions

Levonorgestrel intrauterine devices (LNG-IUDs), while effective contraceptives, have been associated with psychiatric symptoms such as depression and suicidality in some studies. Healthcare providers should counsel patients about these potential risks and ensure that an appropriate psychiatric assessment is conducted before use.[25]

The meta-analysis of FAERS data suggested a potential association between levonorgestrel and specific adverse events, most frequently menstrual irregularities like delayed menstruation, dysmenorrhea, menorrhagia, breakthrough bleeding, breast tenderness, and breast enlargement. These findings require further investigation through well-designed studies.[26]

Monitoring

Routine examinations with a gynecologist are encouraged for the long-term combined oral pill or intrauterine device birth control options to monitor adverse 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. Patients may need to consider another emergency contraceptive method 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.[27] According to the American College of Obstetricians and Gynecologists (ACOG), clinical evaluation is recommended for women who have used emergency contraception if their menses are delayed by one week or more beyond the expected date, or if they experience lower abdominal pain or persistent irregular bleeding. It is advised that the woman be informed that a pregnancy test and clinical assessment should be conducted if her menstrual period is delayed by one week or more.[7]

Toxicity

Signs and Symptoms of Overdose

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.[28] There is a lack of human data regarding acute overdose of levonorgestrel. 

Management of Overdose

The management is supportive. Poison control center should be contacted for levonorgestrel overdose for the latest recommendations.

Enhancing Healthcare Team Outcomes

While levonorgestrel is a first-line emergency contraceptive for preventing unwanted pregnancy, effective communication and teamwork among primary care physicians, gynecologists, obstetricians, pharmacists, nurse practitioners, physician associates, and nursing staff working together in an interprofessional team approach to care 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 a drug that promotes risky sexual behavior and can also be a drug of convenience for both perceived and verifiable contraceptive failures. This issue is how healthcare teams can effectively combine patient education with adequate treatment plans to promote the use of levonorgestrel without compromising patient safety.[29] Some examples of interprofessional strategies that can improve the benefits of therapy with levonorgestrel are as follows.

• Primary care physicians and gynecologists should regularly ask the patient about relevant sexual history to help track sexual behavior and document changes.
• Maintaining a strong physician-patient relationship is essential to ensure patients trust their physicians. They can be open and honest about their sexual practices and potentially risky behavior in a judgment-free atmosphere.
• Pharmacists should emphasize the adverse effects of levonorgestrel, its strict timeline to achieve optimal drug efficacy, and how it will not prevent sexually transmitted infections and diseases.

An interprofessional team approach and effective communication among primary care physicians, gynecologists, nurse practitioners, physician assistants, pharmacists, and nurses are crucial to minimizing potential adverse effects and improving outcomes related to levonorgestrel.