Melkine 1.5 mg tablet – Summary of Product Characteristics (SmPC) for healthcare professionals

1. NAME OF THE MEDICINAL PRODUCT

Melkine 1.5 mg tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1.5 mg of levonorgestrel.

Excipient with known effect: 43.3 mg of lactose monohydrate

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablet.

Melkine 1.5 mg tablet is round and white, with approximate 6 mm of diameter and marked “C” on one side and “1” on the other

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Emergency contraception within 72 hours of unprotected sexual intercourse or failure of a contraception method.

4.2 Posology and method of administration

Posology

One tablet should be taken as soon as possible, preferably within 12 hours and no later than 72 hours after unprotected intercourse (see section 5.1).

If vomiting occurs within three hours of taking the tablet, another tablet should be taken immediately.

Women who have used enzyme-inducing drugs during the last 4 weeks and need emergency contraception are recommended to use a non-hormonal EC (emergency contraception) , i.e. Cu-IUD or take a double dose of levonorgestrel (i.e. 2 tablets taken together) for those women unable or unwilling to use Cu-IUD (see section 4.5).

Melkine 1.5 mg tablet can be used at any time during the menstrual cycle unless menstrual bleeding is overdue.

After using emergency contraception, it is recommended to use a local barrier method (e.g. condom, diaphragm, spermicide, cervical cap) until the next menstrual period starts. The use of Melkine 1.5 mg tablet does not contraindicate the continuation of regular hormonal contraception.

Paediatric population

There is no relevant use of Melkine 1.5 mg for children of prepubertal age in the age in the indication emergency contraception.

Method of administration

For oral administration

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Emergency contraception is an occasional method. It should in no instance replace a regular contraceptive method.

Emergency contraception does not prevent pregnancy in every instance. If there is uncertainty about the timing of the unprotected intercourse or if the woman has had unprotected intercourse more than 72 hours earlier in the same menstrual cycle, conception may have occurred. Treatment with Melkine 1.5 mg tablet following the second act of intercourse may therefore be ineffective in preventing pregnancy. If menstrual periods are delayed by more than 5 days or abnormal bleeding occurs at the expected date of menstrual periods or pregnancy is suspected for any other reason, pregnancy should be excluded.

If pregnancy occurs after treatment with Melkine 1.5 mg tablet the possibility of an ectopic pregnancy should be considered. The absolute risk of ectopic pregnancy is likely to be low, as Melkine 1.5 mg tablet prevents ovulation and fertilisation. Ectopic pregnancy may continue, despite the occurrence of uterine bleeding.

Therefore, Melkine 1.5 mg tablet is not recommended for patients who are at risk of ectopic pregnancy (previous history of salpingitis or ectopic pregnancy).

Melkine 1.5 mg tablet is not recommended in patients with severe hepatic dysfunction.

Severe malabsorption syndromes, such as Crohn's disease, might impair the efficacy of Melkine 1.5 mg tablet

After taking Melkine 1.5 mg tablet menstrual periods are usually normal and occur at the expected date. They can sometimes occur earlier or later than expected by a few days. Women should be advised to make a medical appointment to start or adopt a method of regular contraception. If no withdrawal bleed occurs during the next pill-free period following the use of levonorgestrel after regular hormonal contraception, pregnancy should be ruled out.

Repeated administration within a menstrual cycle is not advisable because of the possibility of disturbance of the cycle.

Limited and inconclusive data suggest that there may be reduced efficacy of <invented name> with increasing body weight or body mass index (BMI) (see section 5.1 and 5.2). In all women, emergency contraception should be taken as soon as possible after unprotected intercourse, regardless of the woman´s body weight or BMI

Melkine 1.5 mg is not as a effective as conventional regular method of contraception and is suitable only as an emergency measure. Women who present for repeated courses of emergency contraception should be advised to consider long-term methods of contraception.

Use of emergency contraception does not replace the necessary precautions against sexually transmitted diseases.

Melkine 1.5 mg tablet contains lactose and sodium

4.5 Interaction with other medicinal products and other forms of interaction

The metabolism of levonorgestrel is enhanced by concomitant use of liver enzyme inducers, mainly CYP3A4 enzyme inducers. Concomitant administration of efavirenz has been found to reduce plasma levels of levonorgestrel (AUC) by around 50%.

Drugs suspected of having similar capacity to reduce plasma levels of levonorgestrel include barbiturates (including primidone), phenytoin, carbamazepine, herbal medicines containing Hypericum Perforatum (St. John's Wort), rifampicin, ritonavir, rifabutin and griseofulvin.

For women who have used enzyme-inducing drugs in the past 4 weeks and need emergency contraception, the use of non-hormonal emergency contraception (i.e. a Cu-IUD) should be considered. Taking a double dose of levonorgestrel ( i.e. 3000 mcg within 72 hours after the unprotected intercourse – this is 2 tablets) is an option for women who are unable or unwilling to use a Cu-IUD, although this specific combination (a double dose of levonorgestrel during concomitant use of an enzyme inducer) has not been studied

Medicines containing levonorgestrel may increase the risk of cyclosporin toxicity due to possible inhibition of ciclosporin metabolism.

4.6 Fertility, pregnancy and lactation

Pregnancy

Melkine 1.5 mg tablet should not be given to pregnant women. It will not interrupt a pregnancy. In the case of continued pregnancy, limited epidemiological data indicate no adverse effects on the foetus but there are not clinical data on the potential consequences if doses greater than 1.5 mg of levonorgestrel are taken (see section 5.3).

Breast-feeding

Levonorgestrel is secreted into breast milk. Potential exposure of an infant to levonorgestrel can be reduced if the breast-feeding woman takes the tablets immediately after feeding and avoids nursing at least 8 hours following levonorgestrel administration.

Fertility

Levonorgestrel increases the possibility of cycle disturbances which can sometimes lead to earlier or later ovulation date, resulting in modified fertility date, however. Although there are no fertility data in the long term, after treatment with levonorgestrel a rapid return to fertility is expected and therefore, regular contraception should be continued or initiated as soon as possible after levonorgestrel EC use.

4.7 Effects on ability to drive and use machines

No studies on the effect on the ability to drive or use machines have been performed.

4.8 Undesirable effects

The most commonly reported undesirable effect was nausea.

*Bleeding patterns may be temporarily disturbed, but most women will have their next menstrual period within 5-7 days of the expectedtime.

** If the next menstrual period is more than 5 days overdue, pregnancy should be excluded.

From Post-marketing surveillance additionally, the following adverse events 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, dysmenorrhoea

General disorders and administration site conditions

Very rare (<1/10,000): face oedema

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard).

4.9 Overdose

Serious undesirable effects have not been reported following acute ingestion of large doses of oral contraceptives. Overdose may cause nausea and withdrawal bleeding may occur. There are no specific antidotes and treatment should be symptomatic.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, emergency contraceptives. ATC Code: G03AD01

Mechanism of action

At the recommended regimen, levonorgestrel is thought to work mainly by preventing ovulation and fertilisation if intercourse has taken place in the pre-ovulatory phase, when the likelihood of fertilisation is the highest. Levonorgestrel is not effective once the process of implantation has begun.

Clinical efficacy and safety

Results from the randomised, double-blind clinical study conducted in 1998,2001 and 2010 showed that 1500 microgram levonorgestrel (taken within 72 hours of unprotected sex) prevented 85%, 84%, 97% of expected pregnancies , respectively.

The pregnancy rate (number of observed pregnancies in women taking EC/total number of women taking EC) was 1.1%, 1.34%, and 0.32%, respectively. Prevented fraction appeared to decrease and pregnancy rates appeared to increase with time of start of treatment after unprotected intercourse, highest efficacy is reached when EC is taken within 24 hours after intercourse. Efficacy appears to decrease with increasing time from unprotected intercourse.

Meta-analysis on three WHO studies (Von Hertzen et al., 1998 and 2002; Dada et al., 2010) showed that the pregnancy rate of levonorgestrel is 1.01% (59/5 863) (compared to an expected pregnancy rate of about 8% in the absence of emergency contraception) see Table 1

Table 1: Meta-analysis on three WHO studies (Von Hertzen et al., 1998 and 2002; Dada et al., 2010)

*CI: confidence interval (compared to an expected pregnancy rate of about 8% in the absence of emergency contraception)

There is limited and inconclusive data on the effect of high body weight/high BMI on the contraceptive efficacy. In three WHO studies no trend for a reduced efficacy with increasing body weight/BMI was observed (Table 2), whereas in the two other studies (Creinin et al. 2006 and Glasier et al., 2010) a reduced contraceptive efficacy was observed with increasing body weight or BMI (Table 3). Both meta-analyses excluded intake later than 72 hours after unprotected intercourse (i.e. off-label use of levonorgestrel) and women who had further acts of unprotected intercourse. For pharmacokinetic studies in obese women see section 5.2.

Table 2: Meta-analysis on three WHO studies (Von Hertzen et al., 1998 and 2002; Dada et al., 2010)

Table 3: Meta-analysis on studies of Creinin et al., 2006 and Glasier et al., 2010

At the recommended regimen, levonorgestrel is not expected to induce significant modification of blood clotting factors, and lipid and carbohydrate metabolism.

Paedriatic population

A prospective observational study showed that out of 305 treatments with levonorgestrel emergency contraceptive tablets, seven women became pregnant resulting in an overall failure rate of 2.3%. The failure rate in women under 18 years (2.6% or 4/153) was comparable to the failure rate in women 18 years and over (2.0% or 3/152).

5.2 Pharmacokinetic properties

Absorption

Orally administered levonorgestrel is rapidly and almost completely absorbed. The absolute bioavailability of levonorgestrel was determined to be almost 100 % of the dose administered.

The results of a pharmacokinetic study carried out with 16 healthy women showed that following ingestion of one tablet of Melkine 1.5 mg tablet maximum serum levels of levonorgestrel of 18.5 ng/ml were found at 2 hours.

Distribution

Levonorgestrel is bound to serum albumin and sex hormone binding globulin (SHBG). Only about 1.5% of the total serum levels are present as free steroid, but 65% are specifically bound to SHBG.

About 0.1% of the maternal dose can be transferred via milk to the nursed infant.

Biotransformation

The biotransformation follows the known pathways of steroid metabolism, i.e. levonorgestrel is hydroxylated by the liver enzymes mainly by CYP3A and its metabolites are excreted after glucuronidation by glucuronidase enzymes (See section 4.5).

No pharmacologically active metabolites are known.

Elimination

After reaching maximum serum levels, the concentration of levonorgestrel decreased with a mean elimination half-life of about 26 hours.

Levonorgestrel is not excreted in unchanged form but as metabolites. Levonorgestrel metabolites are excreted in about equal proportions withurine and faeces.

Pharmacokinetics in obese women

A pharmacokinetic study showed that levonorgestrel concentrations are decreased in obese women (BMI ≥ 30 kg/m²) (approximately 50% decrease in Cmax and AUC0-24), compared to women with normal BMI (< 25 kg/m²) (Praditpan et al., 2017). Another study also reported a decrease of levonorgestrel Cmax by approximately 50% between obese and normal BMI women, while doubling the dose (3 mg) in obese women appeared to provide plasma concentration levels similar to those observed in normal women who received 1.5 mg of levonorgestrel (Edelman et al., 2016). The clinical relevance of these data is unclear.

5.3 Preclinical safety data

Animal experiments with levonorgestrel have shown virilisation of female foetuses at high doses.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenicity potencial beyond the information included in other section ofthe SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Cellulose microcrystalline

Lactose monohydrate

Poloxamer 188

Croscarmellose sodium

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage condition.

6.5 Nature and contents of container

Blisters of PVC/PVDC/Aluminium.

Each box contains one blister with one tablet.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

LABORATORIOS LEON FARMA SA CALLE LA VALLINA S/N

POLIGONO INDUSTRIAL NAVATEJERA

24193VILLAQUILAMBRE, LEON

SPAIN

8 MARKETING AUTHORISATION NUMBER(S)

PL 34518/0020

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

29/06/2022

10 DATE OF REVISION OF THE TEXT

10/03/2024