Levonorgestrel

The dosage of levonorgestrel varies significantly based on the intended use and the delivery system chosen by the patient and their healthcare provider.

Emergency Contraception

For emergency contraception, the standard adult dose is a single 1.5 mg tablet taken as soon as possible after unprotected intercourse. Clinical studies show that efficacy is highest when taken within 24 hours, though it remains effective up to 72 hours. Some providers may suggest use up to 120 hours (5 days) off-label, though efficacy drops significantly after 72 hours. Alternatively, a two-dose regimen of 0.75 mg taken 12 hours apart may be used.

Daily Oral Contraception

In combined oral contraceptives, levonorgestrel is typically dosed at 0.1 mg to 0.15 mg daily, often in a 21-day active/7-day placebo cycle. In progestin-only pills ('mini-pills'), a lower dose (e.g., 0.03 mg) is taken every single day at exactly the same time without a break.

Intrauterine Systems (IUS)

These are clinical procedures where a device is inserted into the uterus. The initial release rates vary: Mirena releases approximately 20 mcg/day, while smaller devices like Skyla release about 14 mcg/day. These devices are replaced every 3 to 8 years depending on the specific brand and indication.

Levonorgestrel is generally considered safe and effective for use in post-menarcheal female adolescents (those who have started their periods). The dosage for emergency contraception in adolescents is the same as the adult dose (1.5 mg). For long-term contraception, the use of IUDs in 'nulliparous' adolescents (those who have never given birth) is supported by the American College of Obstetricians and Gynecologists (ACOG). It is not indicated for use before the onset of menses.

Renal Impairment

No specific dosage adjustments are provided in the manufacturer's labeling for patients with renal impairment. Because levonorgestrel is primarily metabolized by the liver, significant accumulation is not typically expected in those with decreased kidney function, though caution is always advised.

Hepatic Impairment

Levonorgestrel is contraindicated in patients with acute liver disease or liver tumors. Because the liver is the primary site of metabolism, impaired hepatic function can lead to increased systemic levels of the hormone, potentially increasing the risk of side effects.

Elderly Patients

Levonorgestrel is not indicated for use in postmenopausal women, except in specific cases of hormone replacement therapy where it is used to prevent endometrial hyperplasia. It is not intended for use in the geriatric population for contraceptive purposes.

• Emergency Tablets: Take the tablet as soon as possible. It can be taken with or without food. If you vomit within two hours of taking the dose, contact your healthcare provider to discuss whether a repeat dose is necessary.
• Daily Pills: Must be taken at the same time every day. For progestin-only pills, a delay of even 3 hours can necessitate backup contraception for the next 48 hours.
• Storage: Store all forms at room temperature (68°F to 77°F). Keep away from excessive moisture and direct sunlight.

If you miss a dose of a daily levonorgestrel-containing pill, take it as soon as you remember. If you are more than 3 hours late for a progestin-only pill, or if you miss an entire day of a combined pill, you must use a backup method of birth control (like condoms) for the next 48 hours to 7 days, depending on the specific product instructions. Consult your patient information leaflet for the 'missed pill' rules specific to your brand.

Symptoms of a levonorgestrel overdose may include severe nausea, vomiting, and unexpected vaginal bleeding (withdrawal bleeding). While levonorgestrel is not associated with life-threatening acute toxicity, you should contact the Poison Control Center or seek emergency medical attention if a large amount is ingested, particularly by a child.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose without medical guidance.

Most patients taking levonorgestrel, particularly for emergency contraception, experience mild to moderate side effects that typically resolve within 48 to 72 hours. Common reactions include:

• Nausea and Vomiting: This is the most frequently reported side effect for the oral 1.5 mg dose. Nausea occurs in approximately 23% of patients.
• Abdominal Pain: Lower abdominal cramping is common as the body processes the hormone.
• Fatigue: A general feeling of tiredness or lethargy shortly after taking the medication.
• Headache: Mild to moderate tension-type headaches.
• Dizziness: Some patients report feeling lightheaded or unsteady.
• Menstrual Changes: Your next period may be earlier, later, heavier, or lighter than usual. Spotting between periods is also very common in the month following use.

• Breast Tenderness: Sensitivity or swelling of the breast tissue due to hormonal fluctuations.
• Diarrhea: Mild gastrointestinal upset.
• Acne: Some patients may notice increased skin oiliness or breakouts, particularly with long-term progestin use.
• Mood Swings: Irritability or mild depressive symptoms may occur as the body adjusts to the progestin levels.

• Hair Loss (Alopecia): Temporary thinning of the hair has been reported with long-term use of IUDs or implants.
• Hirsutism: Unusual hair growth in an androgenic pattern (e.g., face, chest) due to the slight androgenic activity of levonorgestrel.
• Severe Allergic Reactions: Though extremely rare, some individuals may experience hypersensitivity.

> Warning: Stop taking Levonorgestrel and call your doctor immediately if you experience any of these.

• Ectopic Pregnancy: If you experience severe one-sided lower abdominal pain, especially if your period is late, seek emergency care. Levonorgestrel-only contraception (like the IUD) carries a higher relative risk that if a pregnancy does occur, it may be outside the uterus.
• Severe Pelvic Pain: This could indicate Pelvic Inflammatory Disease (PID) or an ovarian cyst rupture, particularly in IUD users.
• Thromboembolism (Blood Clots): While the risk is lower with progestin-only methods than with estrogen-containing pills, symptoms like sudden leg swelling, chest pain, or shortness of breath require immediate evaluation.
• Jaundice: Yellowing of the skin or eyes, which may indicate liver dysfunction.
• Heavy Persistent Bleeding: Bleeding that is significantly heavier than a normal period or lasts for an extended duration.
• IUD Displacement: For IUD users, feeling the hard plastic of the device at the cervix or being unable to find the strings requires a clinical exam.

With prolonged use of levonorgestrel (such as IUDs or daily pills), the most significant long-term effect is a change in menstrual patterns. Many patients experience 'amenorrhea' (the complete absence of periods) after one year of IUD use. While medically harmless, this can be a significant change for patients. There is also ongoing research into the long-term effects of progestins on bone mineral density and mood disorders, though levonorgestrel is generally considered to have a favorable safety profile compared to older progestins.

No FDA black box warnings currently exist for levonorgestrel-only products (like Plan B or Mirena). However, combined oral contraceptives that contain levonorgestrel plus estrogen carry a black box warning regarding Cigarette Smoking and Serious Cardiovascular Events. Smoking increases the risk of serious cardiovascular side effects from combination hormonal contraceptives, including myocardial infarction (heart attack) and stroke. This risk increases with age (especially over 35) and with the number of cigarettes smoked.

Report any unusual symptoms to your healthcare provider.

Levonorgestrel is a highly effective contraceptive, but it is not suitable for everyone. Before using any form of levonorgestrel, it is vital to disclose your full medical history to your healthcare provider. This medication does not protect against HIV infection (AIDS) or other sexually transmitted infections (STIs). Patients should continue to use barrier protection (condoms) if STI protection is required.

There are no specific FDA black box warnings for levonorgestrel when used as a progestin-only medication (e.g., emergency contraception or IUDs). However, when levonorgestrel is combined with estrogen in birth control pills, the following warning applies:

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age and smoke.

• Ectopic Pregnancy Risk: Healthcare providers should consider the possibility of an ectopic pregnancy in women who become pregnant or complain of lower abdominal pain while using levonorgestrel, especially those with a history of fallopian tube surgery or PID.
• Liver Disease: Levonorgestrel should be avoided in patients with active liver disease, hepatitis, or liver tumors (benign or malignant), as the liver is responsible for metabolizing the hormone.
• Undiagnosed Vaginal Bleeding: Before starting levonorgestrel, any abnormal or undiagnosed vaginal bleeding must be evaluated to rule out malignancy or other serious conditions.
• Breast Cancer: Because some breast cancers are hormone-sensitive, levonorgestrel is generally not recommended for patients with current or past breast cancer.
• Depression: Patients with a history of clinical depression should be monitored closely. If the depression recurs to a serious degree, the medication should be discontinued.

For patients using long-term levonorgestrel delivery systems (IUDs or implants), regular clinical follow-ups are necessary. This typically includes:

• Pelvic Exams: To ensure the IUD remains correctly positioned.
• Blood Pressure: Periodic monitoring, as hormonal contraceptives can sometimes cause elevations in BP.
• Glucose Monitoring: Patients with diabetes may experience slight changes in insulin sensitivity while taking progestins and should monitor their blood sugar levels more frequently when starting the drug.

Levonorgestrel is not known to impair the ability to drive or operate heavy machinery. However, if a patient experiences dizziness or fatigue (common after emergency contraception), they should wait until these symptoms subside before engaging in such activities.

There is no direct contraindication between alcohol and levonorgestrel. However, alcohol can increase the likelihood of vomiting. If a patient vomits shortly after taking an emergency contraceptive pill, the drug may not have been absorbed, leading to contraceptive failure.

Levonorgestrel does not require a tapering period. When a daily pill is stopped or an IUD is removed, fertility typically returns to the patient's baseline very quickly, often within the first cycle. Patients should be aware that they can become pregnant immediately after stopping the medication.

> Important: Discuss all your medical conditions with your healthcare provider before starting Levonorgestrel.

While few drugs are strictly contraindicated, the use of Ulipristal acetate (another form of emergency contraception, brand name Ella) alongside levonorgestrel is generally avoided. Because both drugs target the progesterone receptor, they may interfere with each other's efficacy if taken within 5 days of one another. Taking both can potentially reduce the effectiveness of both medications, increasing the risk of unintended pregnancy.

Most serious interactions involve drugs that induce hepatic enzymes, specifically the CYP3A4 system. These 'enzyme inducers' speed up the metabolism of levonorgestrel, significantly lowering its concentration in the blood and potentially leading to contraceptive failure.

• Anticonvulsants: Drugs like Carbamazepine, Phenytoin, Phenobarbital, and Primidone can reduce levonorgestrel levels.
• Antimicrobials: Rifampin and Rifabutin are potent inducers that significantly decrease the effectiveness of hormonal contraceptives.
• Antiretrovirals: Certain HIV medications, such as Efavirenz and Ritonavir-boosted protease inhibitors, can alter the plasma levels of progestins.

• Griseofulvin: This antifungal medication may reduce the effectiveness of oral contraceptives.
• Bosentan: Used for pulmonary hypertension, it can decrease the concentration of levonorgestrel via enzyme induction.

• Grapefruit Juice: Unlike many other drugs, grapefruit juice does not have a clinically significant effect on levonorgestrel that would require avoidance, though it theoretically could slightly increase levels by inhibiting CYP3A4.
• High-Fat Meals: May delay the time to peak concentration (Tmax) of oral levonorgestrel but does not reduce the total absorption (AUC).

• St. John's Wort (Hypericum perforatum): This is a well-documented and serious interaction. St. John's Wort is a potent inducer of CYP3A4 and has been linked to numerous cases of 'breakthrough' ovulation and unintended pregnancy in patients using hormonal contraceptives. Patients on levonorgestrel should avoid this herbal supplement.

Levonorgestrel may affect the results of certain laboratory tests, including:

• Sex Hormone-Binding Globulin (SHBG): Levels are typically decreased.
• Thyroid-Binding Globulin: May be increased, potentially affecting total T4 levels (though free T4 usually remains normal).
• Coagulation Factors: May slightly alter tests for prothrombin and factors VII, VIII, IX, and X.

Management Strategy

If you must take an enzyme-inducing medication (like an anti-seizure drug or Rifampin) while needing contraception, your doctor may recommend a non-hormonal method, such as a copper IUD, or a higher dose of the progestin if appropriate. For emergency contraception, some guidelines suggest doubling the dose of levonorgestrel (to 3 mg) if the patient has used an enzyme inducer in the last 4 weeks, though this is an off-label recommendation.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking.

In clinical practice, absolute contraindications are conditions where the risk of using levonorgestrel clearly outweighs any possible benefit. Levonorgestrel must NEVER be used in the following scenarios:

1. 1Known or Suspected Pregnancy: While levonorgestrel emergency contraception will not harm an existing pregnancy, daily pills and IUDs are contraindicated once pregnancy is confirmed. In the case of IUDs, there is a high risk of septic abortion if the device is left in place during pregnancy.
2. 2Undiagnosed Abnormal Uterine Bleeding: This must be fully investigated before starting hormonal therapy to ensure a malignancy is not being masked.
3. 3Active Liver Disease: This includes acute hepatitis, severe cirrhosis, or liver tumors. The liver's inability to metabolize the hormone could lead to toxic accumulation.
4. 4Current Breast Cancer: Because breast cancer can be sensitive to progestins, levonorgestrel is contraindicated in patients with known or suspected breast malignancy.
5. 5Hypersensitivity: Any known allergy to levonorgestrel or any of the inactive ingredients (such as lactose in some tablet formulations).

These conditions require a careful risk-benefit analysis by a healthcare provider:

• History of Ectopic Pregnancy: Especially relevant for IUD use, as the risk of a repeat ectopic pregnancy is slightly higher if contraception fails.
• Severe Arterial Disease: Patients with a history of stroke or ischemic heart disease should use progestins with caution.
• Active Pelvic Inflammatory Disease (PID): A contraindication for IUD insertion, though not for oral tablets.
• Migraine with Aura: While the risk is primarily associated with estrogen, some providers exercise caution with high-dose progestins in patients with complex migraines.

Patients who have had allergic reactions to other 19-nortestosterone derivatives (such as norethindrone or norgestrel) may be at an increased risk of cross-sensitivity to levonorgestrel. Always inform your allergist of your contraceptive history.

> Important: Your healthcare provider will evaluate your complete medical history before prescribing Levonorgestrel.

Levonorgestrel is not indicated for use during an established pregnancy. However, extensive epidemiological studies have shown that accidental use of levonorgestrel (specifically for emergency contraception) during early pregnancy does not increase the risk of birth defects, miscarriage, or other adverse fetal outcomes. It is not an abortifacient and will not interrupt a pregnancy that has already implanted. If you become pregnant while an IUD is in place, the device should be removed immediately by a professional to reduce the risk of infection and miscarriage.

Levonorgestrel is excreted in breast milk. However, at the doses used for contraception, it is generally considered safe for nursing infants. The World Health Organization (WHO) and ACOG suggest that progestin-only methods (like the 'mini-pill' or IUD) are the preferred hormonal choice for breastfeeding mothers because they do not interfere with milk production as estrogen-containing pills might. Most guidelines recommend waiting 6 weeks postpartum before inserting an IUD to reduce the risk of uterine perforation.

Safety and efficacy have been established in females of reproductive age. Use before the onset of puberty (menarche) is not indicated. In adolescents, levonorgestrel is a first-line recommendation for both emergency and long-term contraception due to its high efficacy rate and the reduction of 'user error' associated with IUDs.

There is no indication for the use of levonorgestrel in the geriatric population (typically defined as those over 65). It is not used for contraception in postmenopausal women. In rare cases, it may be used as part of a hormone replacement therapy (HRT) regimen in younger postmenopausal women to protect the endometrium.

There is limited data on the use of levonorgestrel in patients with significant renal impairment. However, since the drug is primarily cleared by hepatic metabolism, it is generally used without dose adjustment in these populations. Monitoring for fluid retention (a rare side effect of progestins) is advised.

Levonorgestrel is contraindicated in patients with significant hepatic impairment. In patients with mild hepatic issues, the drug should be used with extreme caution, and liver function tests (LFTs) should be monitored. If LFTs worsen, the medication should be discontinued immediately.

There is some clinical evidence suggesting that the efficacy of levonorgestrel emergency contraception may be reduced in patients with a Body Mass Index (BMI) of 30 kg/m² or greater. While the FDA currently maintains that it is safe and effective for all women, some clinical guidelines suggest that a copper IUD or the drug Ulipristal acetate may be more effective choices for individuals with obesity.

> Important: Special populations require individualized medical assessment.

Levonorgestrel is a potent agonist of the progesterone receptor. Once bound, the receptor-ligand complex translocates to the cell nucleus, where it binds to specific DNA sequences known as progesterone response elements. This modulates the transcription of various genes involved in the reproductive cycle. Its primary contraceptive effect is the suppression of the mid-cycle surge of Luteinizing Hormone (LH) from the anterior pituitary, which prevents the rupture of the ovarian follicle and the subsequent release of an egg (ovulation). It also increases the viscosity of cervical mucus by altering the glycoprotein structure, creating a 'sperm-hostile' environment.

The pharmacodynamic effect of levonorgestrel is dose-dependent. At low doses (e.g., in the mini-pill), it may not consistently inhibit ovulation in all women but still prevents pregnancy via mucus changes. At higher doses (e.g., emergency contraception), it is highly effective at blocking the LH surge if taken before it begins. It also has mild androgenic activity, which accounts for some side effects like acne or changes in lipid profiles.

| Parameter | Value |

|---|---|

| Bioavailability | ~90% to 100% |

| Protein Binding | 98% (SHBG and Albumin) |

| Half-life | 24 to 45 hours |

| Tmax | 1.6 to 2.0 hours |

| Metabolism | Hepatic (CYP3A4) |

| Excretion | Renal (45%), Fecal (32%) |

• Molecular Formula: C21H28O2
• Molecular Weight: 312.45 g/mol
• Solubility: Practically insoluble in water; soluble in chloroform and acetone.
• Structure: A synthetic 19-norsteroid with a 13-beta-ethyl group, which increases its progestogenic potency compared to older steroids like norethindrone.

Levonorgestrel is classified as a second-generation progestin. It is more potent than first-generation progestins (like norethindrone) and has a different side effect profile than third-generation (desogestrel) or fourth-generation (drospirenone) progestins, particularly regarding the risk of blood clots, which is generally lower for levonorgestrel-based formulations.