Levonorgestrel

Levonorgestrel is a Contraceptive belonging to the pharmacology class of Progestins..

Levonorgestrel can be used in the treatment of emergency contraception.

Levonorgestrel is rapidly and almost completely absorbed (oral). Time to peak plasma concentration: Approx 2 hours (oral) and enters breast milk. Volume of distribution: Approx 1.8 L/kg. Plasma protein binding: 30-56% (albumin); 42-68% (sex hormone-binding globulin) and get metabolised in the liver by the CYP3A4 isoenzyme to inactive metabolites. It Undergoes minimal first-pass metabolism in the liver and get excreted mainly via urine (45%); faeces (32%). Elimination half-life: 30-46 hours (oral); approx 17 hours (IUD).

The common side effects of Levonorgestrel includes: Bleeding pattern alterations (e.g. spotting, irregular bleeding, heavy bleeding, oligomenorrhoea, amenorrhoea), ectopic pregnancy, thromboembolism, hypertension, depression, breast cancer; implant or IUD expulsion, Carbohydrate intolerance, chloasma .

Levonorgestrel is available in the form of Tablets.

The molecule is available in India, Japan, Germany, China.

Levonorgestrel is believed to act as an emergency contraceptive principally by preventing ovulation or fertilization (by altering tubal transport of sperm and/or ova). In addition, it may inhibit implantation (by altering the endometrium). It is not effective once the process of implantation has begun.

Levonorgestrel is believed to act as an emergency contraceptive principally by preventing ovulation or fertilization (by altering tubal transport of sperm and/or ova). In addition, it may inhibit implantation (by altering the endometrium). It is not effective once the process of implantation has begun.

Levonorgestrel is approved for use in the following clinical indications:

Emergency contraception: Prevention of pregnancy following unprotected intercourse or possible contraceptive failure.

Emergency contraception:

Oral: One 1.5 mg tablet as soon as possible within 72 hours of unprotected sexual intercourse or known or suspected contraceptive failure.

Tablets: 1.5 mg

Tablets

Levonorgestrel may be contraindicated in the following conditions:-

Known or suspected sex hormone dependent malignancies (e.g. breast cancer), undiagnosed vaginal bleeding, active or history of thromboembolism (e.g. MI, stroke); acute hepatic disease, hepatic tumours (benign or malignant), severe hepatic disease wherein LFTs have not returned to normal. Oral: Severe diabetes with vascular changes. IUD: Uterine bleeding of unknown aetiology; known or suspected uterine, cervical, or endometrial malignancy; cervical intraepithelial neoplasia (until resolved); untreated acute cervicitis or vaginitis (e.g. bacterial vaginosis, chlamydial or gonococcal cervical infection), other lower genital tract infections (until control of infection), conditions that increase the risk to pelvic infections; congenital or acquired uterine anomaly, including fibroids that impair the uterine activity; history of or active acute pelvic inflammatory disease, postpartum endometriosis or infected abortion (within the past 3 months); postcoital contraception, unremoved IUD. Pregnancy.

Concerns related to adverse effects:

Bleeding irregularities: Spotting may occur following use; the possibility of pregnancy should be considered if menstruation is delayed for >7 days of the expected menstrual period .

Ectopic pregnancy: A history of ectopic pregnancy is not a contraindication for use as an emergency contraceptive. The possibility of ectopic pregnancy should be considered in patients with lower abdominal pain, especially in association with missed periods or vaginal bleeding in patients with prior amenorrhea.

There is no sufficient scientific evidence traceable regarding use and safety of Levonorgestrel in concurrent use with alcohol.

Levonorgestrel is present in breast milk.

Levonorgestrel concentrations in breast milk were evaluated following maternal administration of a single oral dose of levonorgestrel 1.5 mg to 12 women ~11 weeks' postpartum:

Pregnancy Category (FDA): X

Many studies have found no harmful effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted with progestin-only pills have not demonstrated significant adverse effects

The adverse reactions related to Levonorgestrel can be categorized as:

Common Adverse effects:

Bleeding pattern alterations (e.g. spotting, irregular bleeding, heavy bleeding, oligomenorrhoea, amenorrhoea), ectopic pregnancy, thromboembolism, hypertension, depression, breast cancer; implant or IUD expulsion. Oral: Carbohydrate intolerance, chloasma of endometriosis

Less Common Adverse effects:

Hepatic adenoma. Implant: Cholestatic hepatitis or jaundice.

Rare Adverse effects:

Idiopathic intracranial hypertension. IUD: intrauterine pregnancy, ovarian cysts, group A streptococcal sepsis, pelvic inflammatory disease, endometritis, actinomycosis, perforation (total or partial), seizure, bradycardia, syncope.

The clinically relevant drug interactions of Levonorgestrel is briefly summarized here:

• Decreased serum concentration with CYP3A4 enzyme inducers (e.g. rifampicin, phenytoin, carbamazepine, primidone, efavirenz, ritonavir, griseofulvin).
• Increased serum concentration with strong and moderate CYP3A4 inhibitors (e.g. voriconazole, ketoconazole, itraconazole, verapamil, diltiazem, erythromycin, clarithromycin).
• May increase the risk of ciclosporin toxicity. Increased or decreased serum concentration with protease inhibitors.

The most common side effects of Levonorgestrel includes: Bleeding pattern alterations (e.g. spotting, irregular bleeding, heavy bleeding, oligomenorrhoea, amenorrhoea), ectopic pregnancy, thromboembolism, hypertension, depression, breast cancer; implant or IUD expulsion, Carbohydrate intolerance, chloasma.

Pregnancy Category (FDA): X

Many studies have found no harmful effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted with progestin-only pills have not demonstrated significant adverse effects

Labor and Delivery

There is no FDA guidance on use of Levonorgestrel (oral) during labor and delivery.

Nursing Mothers

In general, no adverse effects of progestin-only pills have been found on breastfeeding performance or on the health, growth, or development of the infant. However, isolated post-marketing cases of decreased milk production have been reported. Small amounts of progestins pass into the breast milk of nursing mothers taking progestin-only pills for long-term contraception, resulting in detectable steroid levels in infant plasma.

Pediatric Use

Safety and efficacy of progestin-only pills for long-term contraception have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents less than 17 years and for users 17 years and older. Use of Levonorgestrel emergency contraception before menarche is not indicated.

Geriatic Use

This product is not intended for use in postmenopausal women.

Gender

There is no FDA guidance on the use of Levonorgestrel (oral) with respect to specific gender populations.

Race

No formal studies have evaluated the effect of race. However, clinical trials demonstrated a higher pregnancy rate in Chinese women with both levonorgestrel tablets (2 doses of 0.75 mg levonorgestrel taken 12 hours apart) and the Yuzpe regimen (another form of emergency contraception). There was a non-statistically significant increased rate of pregnancy among Chinese women in the levonorgestrel tablet trial. The reason for this apparent increase in the pregnancy rate with emergency contraceptives in Chinese women is unknown.

Renal Impairment

No formal studies were conducted to evaluate the effect of renal disease on the disposition of levonorgestrel tablet.

Hepatic Impairment

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of levonorgestrel tablet.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Levonorgestrel (oral) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Levonorgestrel (oral) in patients who are immunocompromised.

Pharmacodynamics:

Levonorgestrel prevents pregnancy in several mechanisms. It thickens the cervical mucus which inhibits sperm passage through the uterus and sperm survival. It inhibits ovulation from the negative feedback mechanism on the hypothalamus, resulting in reduced secretion of FSH and LH. It can also alter the endometrium which may affect implantation.

Pharmacokinetics:

Absorption: Rapidly and almost completely absorbed (oral). Time to peak plasma concentration: Approx 2 hours (oral).

Distribution: Enters breast milk. Volume of distribution: Approx 1.8 L/kg. Plasma protein binding: 30-56% (albumin); 42-68% (sex hormone-binding globulin).

Metabolism: Metabolised in the liver by the CYP3A4 isoenzyme to inactive metabolites. Undergoes minimal first-pass metabolism in the liver.

Excretion: Mainly via urine (45%); faeces (32%). Elimination half-life: 30-46 hours (oral); approx 17 hours (IUD).

1. https://www.uptodate.com/contents/ Levonorgestrel -drug-information?search= Levonorgestrel &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Levonorgestrel _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Levonorgestrel ?type=full&mtype=generic#mechanism-of-action