Levonorgestrel | Pharmacology Mentor

Generic Name

Levonorgestrel

Mechanism

Levonorgestrel is a synthetic progestin that functions through multiple pathways:
• Prevents follicular maturation by down‑regulating LH and FSH release.
• Induces endometrial decidualization and thickening, rendering the endometrium less receptive to implantation.
• Slows cervical mucus secretion, forming a barrier to sperm penetration.
• In emergency contraception, a high single dose suppresses or delays ovulation and may impede implantation if ovulation has already occurred.

Pharmacokinetics

Absorption: Rapid oral uptake; peak plasma concentration (Cmax) at ~2–3 h post‑dose.
Bioavailability: ~60 %, largely unchanged by food.
Distribution: High protein binding (~90 % to albumin/bound globulins).
Metabolism: Hepatic via CYP3A4 → multiple metabolites, some active.
Half‑life: ~24 h (oral), ~33–35 h (IUD‑releasing system).
Excretion: Primarily biliary (fecal) with minimal renal elimination.
Drug interactions: Inducers (rifampin, carbamazepine) lower systemic levels; inhibitors (ketoconazole, itraconazole) may increase exposure.

Indications

Combined oral contraceptives (≤30 μg estrogen + 0.15 mg levonorgestrel).
Single‑dose emergency contraception (0.75 mg × 1 within 24 h; 1.5 mg × 1 within 120 h).
Levonorgestrel‑releasing intrauterine system (LNG‑IUD) in >99 % effective, 6‑year progestin‑only contraception.
Treatment of endometriosis‑related pain in low‑dose formulations.
Amenorrhea or dysfunctional uterine bleeding (low‑dose progestin therapy).

Contraindications

Known or suspected pregnancy – contraindicated.
History of thromboembolic disease (deep vein thrombosis, pulmonary embolism, stroke) or significant thrombophilia.
Unexplained abnormal uterine bleeding or pregnancy.
Breast, uterine, ovarian, cervical, or liver cancer (hormone‑sensitive tumors).
Severe hepatic disease (Child‑Pugh C).
Uncontrolled hypertension, migraine with aura, or smoking >35 pack‑years in women >35 yr – increased cardiovascular risk.

> Warning: Monitor for signs of VTE; advise patients to seek immediate care if leg swelling, shortness of breath, or chest pain occurs.

Dosing

Formulation	Dose	Schedule	Notes
Combined oral contraceptive	0.3 µg ethinyl estradiol + 0.15 mg levonorgestrel	21 days on, 7 days off (or 24/4‑day regimen)	Take at same time daily; rescue contraceptive not needed.
Emergency contraception (tablets)	0.75 mg levonorgestrel (single dose)	Within 24 h of unprotected sex	For ≤2 days of menstrual cycle.
	1.5 mg levonorgestrel (single dose)	Within 120 h of unprotected sex	Most effective within 24 h; dosing error may reduce efficacy.
LNG‑IUD	52 µg/day release	Insertion → lifelong (up to 6 yrs)	Insert after cervical exam; removal within <24 h if side effects.
Low‑dose progestin	200–300 µg/day	Oral	For endometriosis or irregular bleeding.

Administration tips:
• Swallow tablets whole with water; no need to chew.
• Avoid concurrent use of potent CYP3A4 inducers unless a backup contraceptive method is arranged.

Adverse Effects

Common (≤10 %):
Menstrual irregularities (spotting, breakthrough bleeding)
Nausea/vomiting, headache, dizziness
Breast tenderness, weight gain, mood change
Acne/skin changes (rare, high‑dose).
Serious (≤0.1 %):
Venous thromboembolism (VTE)
Myocardial infarction / stroke (especially in >35 yr smoking women)
Hepatic adenoma or carcinoma (rare)
Severe allergic reactions (anaphylaxis).

Monitoring

Parameter	Frequency	Rationale
Body weight, BMI	Every 3–6 mo	Significant weight gain correlates with side‑effects.
Blood pressure	Every visit	Hypertension ↑ VTE risk.
Vascular risk assessment	At initiation, then annually	Screen for diabetes, smoking, family history.
Pregnancy test	After missed menstrual cycle or if contraception failure is suspected	Avoid misuse.
Menstrual pattern	At first visit and 1‑month post‑initiation	Detect breakthrough bleeding early.
Liver function tests	Baseline and if symptoms arise	Hepatotoxicity possible with high‑dose or hepatic disease.

Clinical Pearls

Quick‑Start LRC: Initiating a levonorgestrel‑releasing IUD within 5 days post‑insertion requires no additional backup contraception; the device itself provides >99 % efficacy.
Emergency Contraception Window: The 0.75 mg dose is most effective when given ≤12 h after intercourse; delayed dosing shifts efficacy dramatically (≈20 % decline per hour).
Smoking and Age: In women >35 yr who smoke >10 cig/day, the cardiovascular risk exceeds the benefits of combination therapy; a progestin‑only approach is advised.
Metabolic Caution: Levonorgestrel can mask symptoms of diabetes (e.g., polyuria, polydipsia); check glucose if risk factors present.
Post‑Surgical Contraception: In patients undergoing uterine surgery (e.g., myomectomy), the LNG‑IUD should be inserted within 5–10 days to provide rapid, effective contraception and reduce uterine bleeding.
Drug‑Drug Interaction Alerts: If a patient is prescribed rifampin or carbamazepine, the systemic levonorgestrel level falls <50 %, necessitating a backup method or a higher‑dose progestin form (e.g., LNG‑IUD).

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• Levonorgestrel remains one of the most widely used progestins, offering versatile options—from short‑term emergency contraception to long‑term intrauterine delivery—while maintaining a favorable safety profile when patient risk factors are appropriately considered.