Levonorgestrel

Levonorgestrel 1.5 mg Tablet

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.

Tablet

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

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

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 local barrier method (e.g. condom, diaphragm, spermicide or cervical 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 (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).

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.

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

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

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, total 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.

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.

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.

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.

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

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).

*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:

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.

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.

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)

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

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).

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.

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.

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, the levonorgestrel is hydroxylated in the liver mainly by CP3A4 and its metabolites are excreted as glucuronide conjugates by liver 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 with urine and faeces.

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.

Povidone K-25

Lactose monohydrate

Maize starch

Silica, colloidal anhydrous

Magnesium stearate

Not applicable.

2 years

This medicinal product does not require any special storage conditions.

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

Pack size: 1 tablet

No special requirements.

Generics (UK) Ltd t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

PL 04569/1374

Date of first authorisation: 08/04/2014

Date of latest renewal: 01/09/2018

12/2018