SUMMARY OF PRODUCT CHARACTERISTICS

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.

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

Melkine 1.5 mg tablet is not recommended in children. Melkine 1.5 mg tablet is only intended for postmenarchal women. Limited data are available in postmenarchal women under 16 years of age.

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

Limited and inconclusive data suggest that there may be reduced efficacy of Melkine

1.5 mg with increasing body weight or body mass index (BMI) (see section 5.1). In all women, emergency contraception should be taken as soon as possible after unprotected intercourse, regardless of the woman's body weight or BMI.

If pregnancy occurs after treatment with Melkine 1.5 mg, 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 prevents ovulation and fertilisation. Ectopic pregnancy may continue, despite the occurrence of uterine bleeding.

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

Melkine 1.5 mg 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

After taking Melkine 1.5 mg, menstrual periods are usually normal and occur on the expected date. They can sometimes occur earlier or later than expected. Women should be advised to make an appointment with their doctor to start or adopt a method of regular contraception. If no withdrawal bleeding occurs during the next tablet-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.

Melkine 1.5 mg is not as effective as conventional methods of contraception and is only indicated as an emergency measure. Women who request emergency contraception on repeated occasions should be advised to consider long-term methods of contraception.

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

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

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.

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

Medicinal products containing levonorgestrel may increase the risk of ciclosporin toxicity due to possible inhibition of ciclosporin metabolism.

Fertility, pregnancy and lactation

Pregnancy

Melkine 1.5 mg tablet should not be administered to pregnant women. It will not interrupt a pregnancy. If pregnancy continues, the limited epidemiological data available 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).

Lactation

Levonorgestrel is excreted in human milk. Potential exposure of the infant to levonorgestrel can be reduced if the mother takes the tablet immediately after feeding and avoids nursing following administration of Melkine 1.5 mg tablet

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

The most commonly reported undesirable effect was nausea.

System Organ Class MedDRA 14.1	Frequency of adverse effects
	Very common (> 10%)	Common (> 1/100 to <1/10))
Nervous system disorders	Headache	Dizziness
Gastrointestinal	Nausea	Diarrhoea
disorders	Lower abdominal pain	Vomiting
Reproductive system and breast disorders	Bleeding not related to menstruation*	Delay of menses more than 7 days**

		Irregular menstruation Breast tenderness
General disorders and administration site conditions	Fatigue

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

** If the next menstrual period is more than 5 days late, 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 possible withdrawal bleeding. 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

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 1), 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 2). 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.

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

BMI (kg/m2)	Underweight 0-18.5	Normal 18.5-25	Overweight 25-30	Obese >30
N total	600	3952	1051	256
N pregnancies	11	39	6	3
Pregnancy rate	1.83%	0.99%	0.57%	1.17%
Confidence Interval	0.92-3.26	0.70-1.35	0.21-1.24	0.24-3.39

Table 2: Meta-analysis on studies of Creinin et al., 2006 and Glasier et al., 2010

BMI (kg/m2)	Underweight 0-18.5	Normal 18.5-25	Overweight 25-30	Obese >30
N total	64	933	339	212
N pregnancies	1	9	8	11
Pregnancy rate	1.56%	0.96%	2.36%	5.19%
Confidence Interval	0.04-8.40	0.44-1.82	1.02-4.60	2.62-9.09

Mechanism of action:

The precise mechanism of action of Melkine 1.5 mg is not known. At the recommended dose, levonorgestrel is thought to work mainly by preventing ovulation and fertilisation if intercourse has taken place in the pre-ovulatory phase, when the likelyhood of fertilisation is highest. It may also cause endometrial changes that discourage implantation. Melkine 1.5 mg is not effective once the process of implantation has begun.

Clinical efficacy and safety

Results from a randomised, double-blind clinical study conducted in 2001 (Lancet 2002; 360: 1803-1810) showed that a 1500 microgram single dose of Melkine 1.5 mg (taken within 72 hours of unprotected sex) prevented 84% of expected pregnancies

(compared with 79% when two 750 microgram tablets were taken 12 hours apart).

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

5.2 Pharmacokinetic properties

Absorption

Orally administration of levonorgestrel is rapidly and almost completely absorbed.

Distribution

Following ingestion of one tablet of Melkine 1.5 mg tablet maximum serum levels of levonorgestrel of 18.5 ng/ml were found after 2 hours. After reaching maximum serum levels, the concentration of levonorgestrel decreased with a mean elimination half-life of about 26 hours.

Biotransformation

Levonorgestrel is not excreted in unchanged form but as metabolites.

Elimination

Levonorgestrel metabolites are excreted in approximately equal proportions in urine and faeces. The biotransformation follows the known pathways of steroid metabolism, i.e. levonorgestrel is hydroxylated in the liver and its metabolites are excreted as glucuronide conjugates.

No pharmacologically active metabolites are known.

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.

The absolute bioavailability of levonorgestrel was determined to be almost 100 % of the dose administered.

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

5.3 Preclinical safety data

Experimental studies in animals have shown virilisation of female foetuses at high doses.

Preclinical data from conventional chronic toxicity, mutagenicity and carcinogenicity studies have not revealed any special risk for humans beyond the information included in other sections of this Summary of Product Characteristics.

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.

Special precautions for disposal

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

7    MARKETING AUTHORISATION HOLDER

LABORATORIOS LEON FARMA SA

CALLE LA VALLINA S/N

POLIGONO INDUSTRIAL NAVATEJERA

NAVATEJERA, LEON

E-24008

SPAIN

8    MARKETING AUTHORISATION NUMBER(S)

PL 34518/0020

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/12/2013

10 DATE OF REVISION OF THE TEXT

28/03/2015