Levonorgestrel

INSTRUCTIONS for medical use of the medicinal product LEVONORGESTREL (LEVONORGESTREL)

Composition:

Active substance: levonorgestrel;

1 tablet contains levonorgestrel (micronized) 0.75 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 «1» 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 the sexual intercourse occurs during the pre-ovulatory phase of the menstrual cycle, that is, when the likelihood 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 to initiation of treatment after sexual intercourse (0.4% [2/450] within 24 hours, 1.2% [4/338] from 25 to 48 hours, 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 when taken within 72 hours after unprotected sexual intercourse, a single 1500 mcg dose of levonorgestrel or two 750 mcg tablets taken simultaneously resulted in a pregnancy rate of 1.34% (16/1,198) (compared to 1.69% [20/1,183] with two 750 mcg tablets taken 12 hours apart). There were no differences in pregnancy rates among women who took the drug on the third or fourth day after unprotected sexual 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 that the pregnancy rate with levonorgestrel use was 1.01% (59/5,863), meaning it prevents pregnancy in 99% of cases (compared to an expected pregnancy rate of approximately 8% in the absence of emergency contraception).

Data on the impact of excessive body weight/high body mass index (BMI) on contraceptive efficacy are limited and inconclusive. 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 a decrease in contraceptive efficacy with increasing body weight or BMI (see Table 2). Both meta-analyses excluded use of levonorgestrel beyond 72 hours after unprotected sexual intercourse (i.e., off-label use) and instances of unprotected sexual 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)

With 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

Levonorgestrel is rapidly and almost completely absorbed after oral administration.

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

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

Distribution

Levonorgestrel binds to serum albumin and sex hormone-binding globulin (SHBG). Only about 1.5% of the total serum level is present 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 unknown.

Elimination

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

Levonorgestrel is excreted in the form of 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 a 50% reduction in Cmax and AUC0–24, compared to women with normal BMI (< 25 kg/m²) (Praditpan et al., 2017). Another study also reported approximately a 50% reduction in levonorgestrel Cmax 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.

Preclinical safety data

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

Results from standard preclinical studies of chronic toxicity, mutagenicity, and carcinogenicity revealed no special hazard to humans other than that already included in other sections of the product information.

Clinical characteristics.

Indications.

Emergency contraception within 72 hours after unprotected sexual intercourse or in cases where the contraceptive method used was 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, primarily inducers of the CYP3A4 enzyme system. A concomitant use with efavirenz has been shown to reduce plasma levels of levonorgestrel (AUC) by approximately 50%.

Medicinal products that are presumed 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 liver enzyme inducers within the past 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 with concomitant use of microsomal liver enzyme inducers) has not been studied.

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

Special precautions for use

Emergency contraception is a method intended for occasional use only. It should never be used as a substitute for regular contraception.

Emergency contraception does not prevent pregnancy in all cases.

If there is uncertainty regarding the timing of unprotected sexual intercourse, or if more than 72 hours have passed since the unprotected act within the same menstrual cycle, there is a possibility that conception may have 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 day 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. The absolute risk of ectopic pregnancy is low, as the medicinal product prevents ovulation and fertilization. However, ectopic pregnancy may develop despite the presence of uterine bleeding.

Therefore, the drug should not be used in patients with an increased 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 affected. However, menstruation may sometimes start several days earlier or later than expected. 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 interval after using the drug and after resuming 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 is limited and inconclusive evidence 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 drug 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. The drug should not be administered to patients with rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding

Pregnancy

The drug should not be used during pregnancy. It does not cause interruption 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 tablet 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; however, there are no data on long-term fertility effects.

Ability to influence reaction rate while driving or operating machinery

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

Method of Administration and Dosage

For oral use.

Two tablets should be taken simultaneously 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 tablets, another two tablets should be taken immediately at once.

Women who have used microsomal enzyme inducers during the past 4 weeks and who 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., 4 tablets at once) 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, it is recommended to use a local barrier method (e.g., condom, diaphragm, spermicide, cervical cap) 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 high doses of levonorgestrel. Overdose may cause nausea and withdrawal bleeding. There is no specific antidote; treatment is symptomatic.

Side effects.

The most common adverse effect associated 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.

Additional adverse reactions reported from post-marketing surveillance include:

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 of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: 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. 2 tablets per blister, 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Steril-Jen Life Sciences (P) Ltd.

Manufacturer's address and site of manufacturing activity.

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