Levonelle (ENDOCRINE THERAPY)

Levonelle^® 1500 microgram tablet

Each tablet contains 1500 micrograms of levonorgestrel

Excipient with known effect: 142.5 mg lactose monohydrate.

Tablet

Almost white, flat, rimmed tablet of about 8 mm diameter with an impressed mark of “G00” on one side.

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

For oral administration:

Posology

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

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, i.e. Cu-IUD or take a double dose of levonorgestrel (ie 2 tablets taken together) for those women unable or unwilling to use Cu-IUD.

Levonelle 1500 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 Levonelle 1500 does not contraindicate the continuation of regular hormonal contraception.

Paediatric population:

There is no relevant use of Levonelle 1500 for children of prepubertal age in the indication emergency contraception Levonelle 1500 is not recommended in children.

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If pregnancy occurs after treatment with Levonelle 1500, the possibility of an ectopic pregnancy should be considered. The absolute risk of ectopic pregnancy is likely to be low, as Levonelle 1500 prevents ovulation and fertilisation. Ectopic pregnancy may continue, despite the occurrence of uterine bleeding.

Therefore, Levonelle 1500 is not recommended for patients who are at risk of ectopic pregnancy (previous history of salpingitis or of ectopic pregnancy).

Levonelle 1500 is not recommended in patients with severe hepatic dysfunction.

Severe malabsorption syndromes, such as Crohn's disease, might impair the efficacy of Levonelle 1500.

Levonelle 1500 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 1500 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 1500 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 Levonelle 1500 with increasing body weight or body mass index (BMI). 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 1500 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.

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

The most commonly reported undesirable effect was nausea.

* Bleeding patterns may be temporarily disturbed, but most women will have their next menstrual period within 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 national reporting system listed in Appendix V

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: 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 preovulatory phase, when the likelihood of fertilisation is the highest. Levonelle 1500 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 Levonelle 1500 (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).

Another study conducted in 1997 (Lancet 1998; 352: 428-33) showed that two 750 microgram doses taken 12 hours apart prevents 85% 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)

Table 2: 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.

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.

Distribution

The results of a pharmacokinetic study carried out with 16 healthy women showed that following ingestion of one tablet of Levonelle 1500 maximum drug serum levels of levonorgestrel of 18.5ng/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.

Biotransformation

Levonorgestrel is not excreted in unchanged form but as metabolites.

Elimination

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.

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

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

Potato starch

Maize starch

Colloidal silica anhydrous

Magnesium stearate

Talc

Lactose monohydrate.

Not applicable.

5 years.

Store in original packaging in order to protect from light.

PVC/Aluminium-blister containing one tablet. The blister is packaged in a folded carton.

No special requirements.

Gedeon Richter Plc.

Gyömrői út 19-21.

1103 Budapest,

Hungary

PL 04854/0150

14^th June 2004

21/12/2016