Navela 1.5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NAVELA 1.5 (NAVELA 1.5)

Composition:

Active substance: levonorgestrel;

1 tablet contains 1.5 mg of levonorgestrel;

Excipients: microcrystalline cellulose, monohydrate lactose, poloxamer 188, sodium croscarmellose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, biconvex tablets with the engraving "C" on one side and "1" on the other side.

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

Pharmacological properties.

Pharmacodynamics.

The exact mechanism of action of NAVELA 1.5 is unknown. At recommended doses, levonorgestrel affects ovulation and fertilization if sexual intercourse occurs during the preovulatory phase of the menstrual cycle, i.e. at the time of highest probability of fertilization. The drug is not effective once implantation has begun.

Effectiveness: according to results of a previously conducted clinical study, 750 mcg of levonorgestrel (as two 750 mcg doses taken 12 hours apart) prevents pregnancy in 85% of cases. The effectiveness probably decreases the longer the time interval between sexual intercourse and drug intake (95% within the first 24 hours, 85% between 24 and 48 hours, and 58% between 48 and 72 hours).

According to results of a previously conducted clinical study, two tablets of levonorgestrel 750 mcg taken simultaneously (within 72 hours after unprotected sexual intercourse) prevent pregnancy in 84% of cases. No differences were observed in pregnancy rates among women who took the drug on the third or fourth day after unprotected sexual intercourse (p > 0.2).

There are limited data requiring further confirmation regarding the impact of increased body weight/high body mass index (BMI) on the contraceptive efficacy of the drug. In three World Health Organization (WHO) studies, no trend toward reduced efficacy with increasing body weight/BMI was observed (see Table 1), whereas in two other studies, a reduction in efficacy with increasing body weight/BMI was observed (see Table 2). Both meta-analyses were conducted excluding cases of drug administration later than 72 hours after unprotected sexual intercourse (off-label use) and cases in which women had unprotected sexual intercourse after taking the drug.

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 does not exert a significant effect on blood coagulation factors, lipid and carbohydrate metabolism.

Children

In a prospective non-experimental study, it was shown that out of 305 cases of using levonorgestrel tablets for emergency contraception, pregnancy occurred in 7 cases, 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.

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

According to a study in 16 patients, 2 hours after a single 1.5 mg dose of levonorgestrel, the maximum concentration (Cmax) was 18.5 ng/mL.

After reaching Cmax, the blood level of levonorgestrel declines, with a mean elimination half-life of approximately 26 hours.

It is excreted in the form of metabolites in urine and feces in equal proportions. Biocatalytic transformation of levonorgestrel occurs via metabolic pathways typical for steroids. In the liver, levonorgestrel is hydroxylated and excreted from the body as glucuronide conjugates. Pharmacologically active metabolites of levonorgestrel are unknown.

Levonorgestrel binds to albumin and sex hormone-binding globulin (SHBG). 1.5% of the total amount in blood plasma exists in the free steroid form, 65% is specifically bound to SHBG.

The absolute bioavailability is 100% of the administered dose.

Approximately 0.1% of the dose is transferred into the infant's body via breast milk.

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 (levonorgestrel) 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 containing the following active substances may reduce the efficacy of levonorgestrel-containing preparations: barbiturates (including primidone), phenytoin, carbamazepine, St. John's wort (Hypericum perforatum), rifampicin, ritonavir, rifabutin, griseofulvin.

Women who have been taking drugs that are inducers of hepatic microsomal enzymes during the previous 4 weeks should consider using non-hormonal emergency contraceptives (e.g., copper IUD) if emergency contraception is needed. Taking a double dose of levonorgestrel (e.g., 3000 mcg of levonorgestrel within 72 hours after unprotected sexual intercourse) is an option for women who are unable or unwilling to use a copper IUD, although this specific combination (double dose of levonorgestrel during concomitant use of microsomal enzyme inducers) has not been studied.

Levonorgestrel-containing medicinal products may increase cyclosporine toxicity due to possible inhibition of its metabolism.

Special precautions for use.

Emergency contraception is a method that can be used only occasionally. It should not replace 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 unprotected intercourse within the same menstrual cycle, there is a possibility that conception has already occurred. Therefore, the use of NAVELA 1.5 after repeated sexual intercourse may be ineffective in preventing pregnancy. If menstruation is delayed by more than 5 days, or 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 NAVELA 1.5, ectopic pregnancy should be considered. The absolute probability of ectopic pregnancy is low, as the medicinal product NAVELA 1.5 prevents ovulation and fertilization.

Ectopic pregnancy may develop despite the occurrence of uterine bleeding. Therefore, the drug should be used with increased caution in patients at risk of ectopic pregnancy (e.g., history of salpingitis or ectopic pregnancy).

NAVELA 1.5 is contraindicated in patients with severe hepatic impairment.

Severe malabsorption syndromes, such as Crohn's disease, may negatively affect the efficacy of NAVELA 1.5. Women with such conditions should consult a physician when emergency contraception is needed.

After taking NAVELA 1.5, the regularity and nature of menstruation are usually not disrupted. Sometimes menstruation may start several days earlier or later. Women should be advised to consult a physician to select and initiate one of the methods of regular contraception. If withdrawal bleeding does not occur in the following pill-free interval after taking NAVELA 1.5 and after starting regular hormonal contraception, pregnancy must be excluded.

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

There are limited data, requiring further confirmation, suggesting that the contraceptive efficacy of NAVELA 1.5 may decrease with increasing body weight or BMI (see section "Pharmacodynamics"). All women, regardless of body weight or BMI, should take emergency contraceptive methods as soon as possible after unprotected sexual intercourse.

NAVELA 1.5 is ineffective as a regular contraceptive method and should only be used in emergency situations. Women seeking repeated emergency contraception should be advised to consider long-term contraceptive methods.

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

This medicinal product contains lactose and therefore should not be used in patients with rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy

Administration of NAVELA 1.5 tablets during pregnancy is contraindicated. The drug does not cause interruption of pregnancy.

According to limited epidemiological data, no adverse effects on the fetus have been observed if pregnancy continues. However, there are no clinical data on the potential consequences of using doses exceeding 1.5 mg of levonorgestrel.

Lactation period

Levonorgestrel is excreted in breast milk. The potential effect of levonorgestrel on infants can be minimized if the breastfeeding woman takes the tablet immediately after feeding and avoids breastfeeding for at least 8 hours after each dose of NAVELA 1.5.

Fertility

Levonorgestrel may cause menstrual cycle disturbances, which in some cases may lead to earlier or later ovulation. These changes may affect the timing of the fertile period; however, there are no data on fertility from long-term follow-up studies.

Ability to influence reaction speed when driving or operating machinery.

No studies have been conducted on the potential effect of NAVELA 1.5 on the ability to drive or operate machinery.

Method of Administration and Dosage.

Dosage. 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 "Pharmacological Properties").

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

Women who have used enzyme-inducing drugs during the past 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. 4 tablets at once) if they are unable or unwilling to use a copper IUD (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

The medicinal product NAVELA 1.5 can 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. condoms, diaphragms, spermicides, cervical caps) until the onset of the next menstruation. The use of the medicinal product NAVELA 1.5 is not a contraindication for continuing regular hormonal contraception.

Method of Administration. Tablets for oral use.

Children.

The medicinal product NAVELA 1.5 is not intended for use in prepubertal children for the indication of emergency contraception.

Overdose.

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

Adverse reactions.

The most common adverse effect observed during the use of NAVELA 1.5 was nausea.

Table 3

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

If the next menstruation is delayed by more than 7 days, pregnancy should be considered.

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

Skin and subcutaneous tissue disorders: Very rare (< 1/10000): pruritus, urticaria, rash.

Reproductive system and breast disorders: Very rare (< 1/10000): pelvic pain, dysmenorrhea (menstrual disorder).

Gastrointestinal disorders: Very rare (< 1/10000): abdominal pain.

General disorders: Very rare (< 1/10000): facial swelling.

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging to protect from light. Keep the medicine out of the reach of children.

Packaging. 1 tablet in a blister. 1 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Laboratorios Leon Farma, S.A.

Manufacturer's address and place of business.
C/ La Vallicna s/n, Polígono Industrial Navatejera, Villacilambre, 24193 León, Spain