Levonorgestrel

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVONORGESTREL (LEVONORGESTREL)

Composition:

Active substance: levonorgestrel;

1 tablet contains levonorgestrel (micronized) 1.5 mg;

Excipients: lactose monohydrate, corn starch, potato starch, purified talc, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, flat, white or almost white tablets with bevelled edges, engraved with "LN" on one side and "2" on the other side.

Pharmacotherapeutic group. Sex hormones and modulators of the genital system. Emergency contraceptives. ATC code G03A D01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The exact mechanism of action of levonorgestrel is not known. It is believed that, when administered according to the recommended regimen, levonorgestrel acts primarily by preventing ovulation and fertilization, if sexual intercourse occurs during the preovulatory phase of the menstrual cycle—that is, when the probability of fertilization is highest. Levonorgestrel is not effective if the process of implantation has already begun.

Clinical efficacy and safety

In an earlier clinical study (Lancet 1998; 352: 428–433), in which levonorgestrel was administered as two 750 mcg doses 12 hours apart, the pregnancy rate was 1.1% (11/976).

The pregnancy rate increased with increasing time from unprotected intercourse to initiation of treatment (0.4% [2/450] within 24 hours, 1.2% [4/338] from 25 to 48 hours, and 2.7% [5/187] from 49 to 72 hours).

Results from a randomized, double-blind clinical trial conducted in 2001 (Lancet 2002; 360: 1803–1810) demonstrated that administration of a single 1500 mcg levonorgestrel tablet or two 750 mcg tablets taken simultaneously within 72 hours after unprotected intercourse resulted in a pregnancy rate of 1.34% (16/1,198), compared with 1.69% (20/1,183) when two 750 mcg tablets were administered 12 hours apart. No differences in pregnancy rates were observed among women who initiated treatment on the third or fourth day after unprotected intercourse (p > 0.2).

A meta-analysis of three World Health Organization (WHO) studies (Von Hertzen et al., 1998 and 2002; Dada et al., 2010) showed a pregnancy rate of 1.01% (59/5,863) with levonorgestrel use, indicating that it prevents pregnancy in 99% of expected cases (compared to an expected pregnancy rate of approximately 8% in the absence of emergency contraception).

Data on the impact of increased body weight/high body mass index (BMI) on contraceptive efficacy are limited and inconsistent. In the three WHO studies, no trend toward reduced efficacy with increasing body weight/BMI was observed (see Table 1), whereas two other studies (Creinin et al., 2006 and Glasier et al., 2010) reported decreased contraceptive efficacy with increasing body weight or BMI (see Table 2). Both meta-analyses excluded use of levonorgestrel beyond 72 hours after unprotected intercourse (i.e., off-label use) and instances of unprotected intercourse occurring after levonorgestrel intake (for pharmacokinetic studies in women with obesity, see section "Pharmacokinetics").

Table 1

Meta-analysis of three WHO studies (Von Hertzen et al., 1998 and 2002; Dada et al., 2010)

Table 2

Meta-analysis of studies (Creinin et al., 2006 and Glasier et al., 2010)

At the recommended dosage regimen, levonorgestrel has no significant effect on blood coagulation factors, lipid and carbohydrate metabolism.

Pediatric population

In a prospective observational study, pregnancy occurred in 7 out of 305 cases of levonorgestrel tablet use for emergency contraception, resulting in an overall failure rate of 2.3%. The failure rate in women under 18 years of age (2.6% or 4/153) was comparable to the failure rate in women aged 18 years and older (2.0% or 3/152).

Pharmacokinetics

Absorption

After oral administration, levonorgestrel is rapidly and almost completely absorbed.

The absolute bioavailability of levonorgestrel is nearly 100% of the administered dose.

Results from a pharmacokinetic study involving 16 healthy women showed that after a single 1.5 mg dose of levonorgestrel, the maximum serum concentration (Cmax) was 18.5 ng/mL, reached within 2 hours.

Distribution

Levonorgestrel binds to serum albumin and sex hormone-binding globulin (SHBG). Only about 1.5% of the total serum level exists as free steroid, while 65% is specifically bound to SHBG.

Approximately 0.1% of the dose taken by the mother may be excreted into breast milk and transferred to the infant.

Metabolism

Levonorgestrel is metabolized via metabolic pathways typical for steroids—hydroxylation in the liver and excretion as glucuronide conjugates.

Pharmacologically active metabolites are not known.

Elimination

After reaching peak serum levels, levonorgestrel concentrations decline with a mean elimination half-life of approximately 26 hours.

Levonorgestrel is excreted as metabolites and is not excreted unchanged.

Metabolites of levonorgestrel are excreted in approximately equal proportions in urine and feces.

Pharmacokinetics in women with obesity

A pharmacokinetic study showed that levonorgestrel concentrations are reduced in women with obesity (BMI ≥ 30 kg/m²), with approximately 50% lower Cmax and AUC0–24, compared to women with normal BMI (< 25 kg/m²) (Praditpan et al., 2017). Another study also reported approximately 50% lower Cmax of levonorgestrel in women with obesity compared to those with normal BMI, while doubling the dose (3 mg) in women with obesity achieved plasma concentrations similar to those observed in women with normal BMI receiving 1.5 mg levonorgestrel (Edelman et al., 2016). The clinical significance of these findings is unclear.

Non-clinical safety data

Animal experiments with levonorgestrel have shown virilization of female fetuses at high doses.

Standard non-clinical studies of chronic toxicity, mutagenicity, and carcinogenicity revealed no special hazard to humans other than the information included in other sections of this medicinal product information.

Clinical characteristics.

Indications.

Emergency contraception within 72 hours after unprotected sexual intercourse or when the contraceptive method used has proven unreliable.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

The metabolism of levonorgestrel is enhanced when co-administered with drugs that are hepatic enzyme inducers, particularly inducers of the CYP3A4 enzyme system. A decrease in plasma levels of levonorgestrel (AUC) by approximately 50% has been observed when co-administered with efavirenz.

Medicinal products that are expected to have a similar ability to reduce levonorgestrel plasma levels include barbiturates (including primidone), phenytoin, carbamazepine, St. John's wort (Hypericum perforatum), rifampicin, ritonavir, rifabutin, and griseofulvin.

Women who have taken microsomal hepatic enzyme inducers during the previous 4 weeks should consider using non-hormonal emergency contraceptives (e.g., copper IUD) if emergency contraception is needed. Administration of a double dose of levonorgestrel (e.g., 3 mg levonorgestrel within 72 hours after unprotected sexual intercourse) may be acceptable for women who are unable or unwilling to use a copper IUD, although this specific combination (double dose of levonorgestrel co-administered with microsomal hepatic enzyme inducers) has not been studied.

Medicinal products containing levonorgestrel may increase cyclosporine toxicity due to a possible inhibition of its metabolism.

Special precautions for use.

Emergency contraception is a method that can be used only occasionally. It should never be used as a substitute for regular contraception.

Emergency contraception does not prevent pregnancy in all cases.

If there is any uncertainty regarding the timing of unprotected sexual intercourse, or if more than 72 hours have passed since unprotected intercourse within the same menstrual cycle, there is a possibility that conception has already occurred. In such cases, using the drug after subsequent intercourse may be ineffective in preventing pregnancy. If menstruation is delayed by more than 5 days, if unusual bleeding occurs on the expected date of menstruation, or if there are other reasons to suspect pregnancy, pregnancy must be ruled out.

If pregnancy occurs after taking the drug, ectopic pregnancy should be considered as a possibility. The absolute risk of ectopic pregnancy is low, since the medicinal product prevents ovulation and fertilization. However, ectopic pregnancy may develop even in the presence of uterine bleeding.

Therefore, the drug should not be used in patients at risk of ectopic pregnancy (e.g., history of salpingitis or previous ectopic pregnancy).

The drug is not recommended for patients with severe hepatic impairment.

The effectiveness of the drug may be reduced in severe malabsorption syndromes, such as Crohn's disease.

After taking the drug, the regularity and nature of menstruation are usually not disrupted. However, menstruation may sometimes begin several days earlier or later than usual. Women are advised to consult a physician to select and initiate a regular contraceptive method. If withdrawal bleeding does not occur during the next tablet-free period after using the drug and after starting regular hormonal contraception, pregnancy should be ruled out.

Repeated use of the drug within the same menstrual cycle is not recommended due to the potential for menstrual cycle disturbances.

There are limited and inconclusive data suggesting that the contraceptive efficacy of levonorgestrel may decrease with increasing body weight or BMI (see sections "Pharmacodynamics" and "Pharmacokinetics"). All women, regardless of body weight or BMI, should take emergency contraceptive measures as soon as possible after unprotected intercourse.

The medicinal product is less effective than regular contraceptive methods and should only be used in emergency situations. Women seeking repeated emergency contraception should be advised to consider using long-term contraceptive methods.

Emergency contraception does not replace the need for protective measures against sexually transmitted infections.

This medicinal product contains lactose. Patients with rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Use during pregnancy or breastfeeding.

Pregnancy

The drug should not be used during pregnancy. It does not cause termination of pregnancy.

In case of ongoing pregnancy, limited epidemiological data suggest no adverse effects on the fetus. However, there are no clinical data on potential effects on the fetus following doses exceeding 1.5 mg of levonorgestrel.

Breastfeeding

Levonorgestrel is excreted in breast milk. The potential exposure of the infant to levonorgestrel can be minimized if the breastfeeding woman takes the tablets immediately after breastfeeding and avoids breastfeeding for at least 8 hours after each dose.

Fertility

Levonorgestrel may increase the likelihood of menstrual cycle disturbances, which in some cases may lead to earlier or delayed ovulation. These changes may affect the timing of conception, but there are no data on long-term fertility effects.

Ability to affect reaction speed when driving or operating machinery.

No studies have been conducted on the potential impact of the drug on the ability to drive or operate machinery.

Method of Administration and Dosage

For oral use.

One tablet should be taken as soon as possible, preferably within 12 hours and no later than 72 hours after unprotected sexual intercourse (see section "Pharmacodynamics").

If vomiting occurs within 3 hours after taking the tablet, another tablet should be taken immediately.

Women who have used microsomal liver enzyme inducers during the previous 4 weeks and require emergency contraception are advised to use non-hormonal methods of emergency contraception, i.e., copper IUD, or to take a double dose of levonorgestrel (i.e., 2 tablets simultaneously) for women who cannot or do not wish to use a copper IUD (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

The medicinal product may be used at any phase of the menstrual cycle provided there is no menstrual delay.

After using emergency contraception, a local barrier method (e.g., condom, diaphragm, spermicide, cervical cap) is recommended until the onset of the next menstruation. Use of the medicinal product is not a contraindication for continuing regular hormonal contraception.

Children

The medicinal product is not intended for use in prepubertal children for the indication of emergency contraception.

Overdose

There are no data on serious adverse reactions following ingestion of large doses of levonorgestrel. Overdose may cause nausea and withdrawal bleeding. There is no specific antidote; treatment is symptomatic.

Adverse reactions.

The most common adverse effect observed with the use of levonorgestrel was nausea.

Table 3

*The nature of bleeding may vary slightly; however, in most women, the next menstrual period begins within 5–7 days of the expected date.

**If the next menstrual period is delayed by more than 5 days, pregnancy should be ruled out.

According to post-marketing surveillance, the following additional adverse reactions have been reported:

Gastrointestinal disorders:

Very rare (< 1/10,000): abdominal pain.

Skin and subcutaneous tissue disorders:

Very rare (< 1/10,000): rash, urticaria, pruritus.

Reproductive system and breast disorders:

Very rare (< 1/10,000): pelvic pain, dysmenorrhea.

General disorders and administration site conditions:

Very rare (< 1/10,000): facial swelling.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. 1 tablet per blister, 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Steril-Gen Life Sciences (P) Ltd.

Manufacturer's address and location of operations.

No. 45, Mangalam Main Road, Villianur Commune, Puducherry, 605110, India.