SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Levonorgestrel 1.5 mg Tablet

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1.5 mg of levonorgestrel Excipient with known effect:

Each tablet contains 154 mg lactose monohydrate For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

The tablet is a round, white to off-white, uncoated flat tablet debossed ‘145’ on one side and plain on the other 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

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.

Levonorgestrel 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 barrier method (e.g. condom, diaphragm or cap) until the next menstrual period starts. The use of levonorgestrel does not contraindicate the continuation of regular hormonal contraception.

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. 2 tablets taken together) for those women unable or unwilling to use Cu-IUD (see section 4.5).

Paediatric population : There is no relevant use of levonorgestrel for children of prepubertal age in the indication emergency contraception.

Method of administration Levonorgestrel should be taken orally.

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

Levonorgestrel is not recommended in patients with severe hepatic dysfunction.

Severe malabsorption syndromes, such as Crohn's disease, might impair the efficacy of levonorgestrel.

Levonorgestrel 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 Levonorgestrel 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 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.

Levonorgestrel 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.

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

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 ciclosporin toxicity due to possible inhibition of ciclosporin metabolism.

4.6 Fertility, pregnancy and lactation

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; however, there are no fertility data in the long term.

Pregnancy

Levonorgestrel 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 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 tablet immediately after feeding and avoids nursing following levonorgestrel administration.

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 reported.

4.8 Undesirable effects

The most commonly reported undesirable effect was nausea. The following undesirable effects were observed in two different studies.

Very common (> 1/10), Common (> 1/100, <1/10), Uncommon (> 1/1,000, <1/100), Rare (> 1/10,000, <1/1,000) and Very rare (<1/10,000), Not known (cannot be estimated from the available data).

System Organ Class	Frequency of adverse reactions
	Very common (> 1/10)	Common (> 1/100, <1/10)
Nervous system disorders	Headache	Dizziness
Gastrointestinal disorders	Nausea, abdominal pain	Diarrhoea, vomiting
Reproductive system and breast disorders	Bleeding not related to menses1	Delay of menses more than 7 days2 Irregular menstruation Breast tenderness
General disorders and administration site conditions	Fatigue

**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 internet at 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 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Emergency contraceptives, ATC code: G03AD01

Mechanism of action

The precise mode of action of levonorgestrel is not known.

Pharmacodynamic effects

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. It may also cause endometrial changes that discourage implantation. Levonorgestrel is not effective once the process of implantation has begun.

Clinical efficacy and safety

Results from a recent clinical study (Lancet 2002; 360: 1803-1810) showed that a 1500 microgram single dose of levonorgestrel (taken within 72 hours of unprotected sex) prevented 84% of expected pregnancies (compared with 79% when the 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.

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

Paediatric 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

Levonorgestrel: orally administered levonorgestrel is rapidly and almost completely absorbed.

Following ingestion of one tablet of levonorgestrel 1.5 mg maximum drug serum levels of levonorgestrel of 18.5 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 in the liver and the 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

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

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity, mutagenicity and carcinogenicity potential, beyond the information included in other sections of the SmPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Povidone K-25

Lactose monohydrate Maize starch

Silica, colloidal anhydrous Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blister composed of PVC film coated with PVDC and aluminium foil.

Pack size: 1 tablet

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Generics (UK) Ltd t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/1374

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

08/04/2014

DATE OF REVISION OF THE TEXT

11/11/2016

1

Bleeding patterns may be temporarily disturbed, but most women will have their

2

next menstrual period within 7 days of the expected time.