SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Toomee 1.5 mg Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 1.5 mg levonorgestrel.

Excipients with known effect: each tablet contains 154.00 mg lactose monohydrate For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet

Round, white to off-white, uncoated flat tablets of 8 mm debossed with ‘145’ on one side and the other side plain.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

4.2    Posology and method of administration

Oral use

The treatment necessitates the intake of one tablet. The efficacy of the method is higher the sooner after the unprotected intercourse the treatment is initiated. Therefore, the tablet must be taken as soon as possible, preferably within 12 hours after the unprotected intercourse, and no longer than 72 hours (3 days) after the intercourse.

Toomee can be taken at any moment during the menstrual cycle unless menstrual bleeding is overdue.

If vomiting occurs within three hours of taking the tablet, another tablet should be taken immediately.

After using an emergency contraception, it is recommended to use a local contraceptive method (condom, spermicide, cervical cap) until the next menstrual periods resume. The use of Toomee does not contraindicate the continuation of regular hormonal contraception.

Paediatric population:

There is no relevant use of Toomee for children of prepubertal age in the indication emergency contraception.

4.3    Contraindications

Hypersensitivity to the active substance (levonorgestrel) 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 Toomee 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 Toomee, the possibility of an ectopic pregnancy should be considered. The absolute risk of ectopic pregnancy is likely to be low as Toomee prevents ovulation and fertilisation. Ectopic pregnancy may continue, despite the occurrence of uterine bleeding. Therefore, Toomee is not recommended for patients who are at risk of ectopic pregnancy (previous history of salpingitis or of ectopic pregnancy).

Toomee is not recommended in patients with severe hepatic dysfunction. Severe malabsorption syndromes, such as Crohn's disease, might impair the efficacy of Toomee.

Cases of thromboembolic events have been reported after Toomee intake. The possibility of occurrence of a thromboembolic event should be considered in women with other pre-existing thromboembolic risk factor(s), especially personal or family history suggesting thrombophilia.

After Toomee intake, menstrual periods are usually of normal abundance and occur at the expected date. They can sometimes occur earlier or later than expected by a few days. It is recommended to have a medical visit to initiate or adapt a method of regular contraception. In case no menstrual period occurs in the next pill-free period following the use of Toomee after regular hormonal contraception, pregnancy should be ruled out.

Repeated administration within a menstrual cycle is not advisable, because of an undesirable high load of hormones for the patient and the possibility of severe disturbances of the cycle. Toomee 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 longterm methods of contraception.

The use of emergency contraception does not replace the necessary precautions against sexually transmitted diseases.

Concomitant use of Toomee and drugs containing ulipristal acetate is not recommended (see section 4.5).

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.

4.5 Interaction with other medicinal products and other forms of interaction

Associations to be taken into consideration:

The metabolism of levonorgestrel is enhanced by the concomitant use of liver enzyme inducers: anticonvulsant (phenobarbital, phenytoin, primidone, carbamazepine); rifabutin; rifampicin; griseofulvin; ritonavir; Hypericum perforatum (St. John's wort). The efficacy of Toomee may be decreased in case of concomitant intake of these active substances.

Ulipristal acetate is a progesterone receptor modulator that may interact with the progestational activity of levonorgestrel. Therefore the concomitant use of levonorgestrel and drugs containing ulipristal acetate is not recommended.

Medicines containing levonorgestrel may increase the risk of cyclosporin toxicity due to possible inhibition of cyclosporin metabolism.

4.6 Fertility, pregnancy and lactation

Pregnancy

Toomee should not be given to pregnant women. This medicinal product cannot interrupt an ongoing pregnancy.

In case of failure of this contraceptive meaning continued pregnancy, epidemiological studies indicate no malformative effects of progestins on foetus.

Nothing is known on the consequences for the child if doses higher than 1.5 mg levonorgestrel are taken.

Breastfeeding

Levonorgestrel is excreted into breast milk. Therefore, it is suggested to breastfeed immediately before taking the Toomee tablet and to skip nursing at least 8 hours following Toomee administration.

Fertility

A rapid return to fertility is likely following treatment with Toomee for emergency contraception; therefore, regular contraception should be continued or initiated as soon as possible following the use of Toomee to ensure ongoing prevention of pregnancy.

Clinical experience reveal no effect on fertility in humans after use of levonorgestrel. Similarly nonclinical studies show no evidence of adverse effects in animals (see section 5.3)

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. Nevertheless, if women experience fatigue and dizziness after taking Toomee, they should not drive or use machines.

4.8 Undesirable effects

The following table gives the frequency of undesirable effects after intake of

1.5 mg levonorgestrel reported in clinical trials*.

Body System	Frequency of adverse reactions
	Very common (> 1/10)	Common (> 1/100 to 1/10)
Nervous system disorders	Dizziness Headache
Gastrointestinal disorders	Nausea Abdominal pain	Diarrhoea1 Vomiting
Reproductive system and Breast disorders	Uterine pain Breast tenderness Delay of menses4 Heavy menses2 Bleeding1	Dysmenorrhoea3
General disorders and administration site conditions	Fatigue1

*    Trial 1 (n=544): Contraception, 2002, 66, 269-273

*    Trial 2 (n=1359): Lancet, 2002, 360:1803-10

*    Trial 3 (n=1117): Lancet 2010; 375:555-62

*    Trial 4 (n=840): Obstetrics and Gynecology 2006; 108:1089-1097

Not recorded in Trial 2

3

Not reported in Trial 1 or 2

⁴    Delay defined as more than 7 days.

These undesirable effects usually disappear within 48 hours after the intake of Toomee. Breast tenderness, spotting and irregular bleeding are reported in up to 30 percent of patients and can last until the next menstrual period which can be delayed.

Hypersensitivity reactions such as pharyngeal/face oedema and cutaneous reactions have been reported after the intake of Toomee.

Cases of thromboembolic events have been reported during the postmarketing period (see section 4.4).

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 at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Serious 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 -G03AD01

The primary mechanism of action is blockade and/or delay of ovulation via suppression of the luteinizing hormone (LH) peak. Levonorgestrel interferes with the ovulatory process only if it is administered before the onset of the LH surge. Levonorgestrel has no emergency contraceptive effect when administered later in the cycle.

In clinical trials, the proportion of pregnancies avoided after the use of levonorgestrel varied from 52% (Glasier, 2010) to 85% (Von Hertzen, 2002) of expected pregnancies. Efficacy appears to decline with time after intercourse.

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 used regimen, levonorgestrel is not expected to induce significant modifications of blood clotting factors, and lipid and carbohydrate metabolism.

Adolescent populations:

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

Absorption

Orally administered levonorgestrel is rapidly and almost completely absorbed. Bioavailability of oral levonorgestrel is approximately 100 percent.

After oral administration of 1.5 mg levonorgestrel, the plasma terminal half-life of the product is estimated to 43 hours. The maximal plasma concentration of levonorgestrel (approximately 40 nmol/l) is reached within 3 hours.

Distribution

In the plasma, it is strongly bound to 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

Levonorgestrel is not excreted in unchanged form but as metabolites. No pharmacologically active metabolites are known.

The biotransformation follows the known pathways of steroid metabolism, the levonorgestrel is hydroxylated in the liver.

Elimination

Levonorgestrel metabolites, as glucuronide conjugates, are excreted in about equal proportions with urine and faeces.

Levonorgestrel is eliminated via kidney (60-80%) and liver (40-50%).

5.3    Preclinical safety data

Nonclinical data reveal no special hazard for humans, beyond the information included in other sections of the SPC. Animal experiments with levonorgestrel have shown virilization of female fetuses at high doses.

A preclinical study conducted in mice showed no effect on fertility in the progeny of treated dams. Two studies investigating the consequence of exposure to levonorgestrel on the development of pre-embryos before implantation, showed that levonorgestrel had no adverse effects on fertilisation and the in vitro growth of mouse pre-embryos.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate Maize starch Povidone

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

PVC/PVdC/Aluminum-blister containing one tablet. The blister is packed in a carton.

6.6    Special precautions for disposal

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

7    MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road,

Hampden Park,

Eastbourne,

East Sussex,

BN22 9AG United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/1763

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/08/2014

10 DATE OF REVISION OF THE TEXT

24/10/2016

1

Not recorded in Trial 1