1. NAME OF THE MEDICINAL PRODUCT

Levonelle-2^TM 750 microgram tablet.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 750 micrograms of levonorgestrel Excipient with known effect: lactose monohydrate For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Tablet

Each tablet is round and white with an imprinted mark of “INOR” on one side.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

4.2    Posology and method of administration

For oral administration: Two tablets should be taken together, 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 tablets, another two tablets 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, i.e. Cu-IUD or take a double dose of levonorgestrel (i.e. 4 tablets taken together) for those women unable or unwilling to use Cu-IUD (see section 4.5).

Levonelle-2 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 Levonelle-2 does not contraindicate the continuation of regular hormonal contraception.

Paediatric population

There is no relevant use of Levonelle-2 in pre-menarche females. Very limited data are available in 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 Levonelle-2 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.

Levonelle-2 is not recommended in patients with severe hepatic dysfunction.

Severe malabsorption syndromes, such as Crohn’s disease, might impair the efficacy of Levonelle-2.

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 medicine.

After Levonelle-2 intake, 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 initiate or adopt a method of regular contraception. If no withdrawal bleed occurs in the next pill-free period following the use of Levonelle-2 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.

Levonelle-2 is not as effective as a 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.

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) 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 cyclosporin metabolism.

4.6 Fertility, pregnancy and lactation

Pregnancy

Levonelle-2 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 fetus but there are no 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. These changes can result in modified fertility date, however, there are no fertility data in the long term. (See section 4.4.)

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

The most commonly reported undesirable effect was nausea.

System Organ Class MedDRA 17.1.	Frequency of adverse reactions
	Very common (>10%)	Common (>1% to <10%)
Nervous system disorders	Headache	Dizziness
Gastrointestinal disorders	Nausea	Diarrhoea
	Abdominal pain lower	Vomiting
Reproductive system and breast disorders	Bleeding not related to menses	Delay of menses more than 7 days Menstruation irregular 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 time.

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:

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 national reporting system listed in Appendix V.

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.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, Emergency contraceptives, ATC code: G03AD01

The precise mode of action of Levonelle-2 is not known.

At the recommended regimen, levonorgestrel is thought to work mainly by preventing ovulation and fertilisation if intercourse has taken place in the preovulatory phase, when the likelihood of fertilisation is the highest. Levonelle-2 is not effective once the process of implantation has begun.

Efficacy. It was estimated from the results of an earlier clinical study (Lancet, 1998; 352: 428433), that Levonelle-2 (taken as two 750 microgram doses with a 12 hour interval) prevents 85% of expected pregnancies. Efficacy appears to decline with time of start of treatment after intercourse (95% within 24 hours, 85% 24-48 hours, 58% if started between 48 and 72 hours) Results from a recent clinical study (Lancet 2002; 360: 1803-1810) showed that two 750 microgram tablets of levonorgestrel taken at the same time (and within 72 hours of unprotected sex) prevented 84% (CI: 73% - 90.5%) of expected pregnancies.

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

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

Orally administered levonorgestrel is rapidly and almost completely absorbed.

The results of a pharmacokinetic study carried out with 16 healthy women showed that following ingestion of two doses of 0.75 mg levonorgestrel 12 hours apart maximum drug serum levels of 13.8 ng/ml were found at 2 hours.

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 with urine and faeces. The biotransformation follows the known pathways of steroid metabolism, the levonorgestrel is hydroxylated by liver enzymes mainly by CYP3A4 and its metabolites are excreted after glucuronidation by liver glucuronidase enzymes. (See section 4.5).

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

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

Preclinical data reveal no special hazard for humans, beyond the information included in other section of the SPC.

6.    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Potato starch,

Maize starch,

Colloidal silica anhydrous,

Magnesium stearate,

Talc,

Lactose monohydrate.

6.2    Incompatibilities

Not applicable.

6.3    Shelf Life

3 years.

6.4    Special precautions for storage

Do not store above 25 ^oC.

6.5 Nature and Contents of Container

The folded carton of Levonelle-2 contains one blister sheet of two tablets. The blister is made of aluminium/PVC.

6.6 Special precautions for disposal

No special requirements.

7.    MARKETING AUTHORISATION HOLDER

Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

10 DATE OF REVISION OF THE TEXT

22/08/2016