SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Mifegyne Combikit 600 mg / 400 microgram tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One package of Mifegyne Combikit contains one mifepristone tablet and one misoprostol tablet.

Each tablet of mifepristone contains 600 mg mifepristone.

Each tablet of misoprostol contains 400 microgram misoprostol.

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablet.

Mifepristone tablet: Biconvex, light yellow, almond shaped tablet with a length of 19 mm and a width of 11 mm, with y engraved on one side and 600 on the other side.

Misoprostol tablet: White, round, flat tablets, with a diameter of 11 mm, with "M400" engraved on one side.

4 CLINICAL PARTICULARS

For termination of pregnancy, the anti-progesterone mifepristone and the prostaglandin analogue can only be prescribed and administered in accordance with the countries national laws and regulations.

4.1 Therapeutic indications

Mifegyne Combikit is indicated for medical termination of developing intra-uterine pregnancy of up to 49 days of amenorrhea (see section 4.2).

4.2 Posology and method of administration Posology

600 mg of mifepristone (1 tablet) is taken in a single oral dose, followed 36 to 48 hours later, by the administration of misoprostol 400 micrograms (1 tablet) orally in a single dose.

Vomiting within 45 minutes after the intake of the mifepristone tablet or within 30 minutes after the intake of the misoprostol tablet could lead to a decrease in efficacy: oral intake of a new mifepristone respectively misoprostol tablet is recommended in this case.

Paediatric population

Only limited data are available on the use of mifepristone and misoprostol in adolescents.

Method of administration

Mifepristone and misoprostol tablets are for oral use only and should not be taken by any other route of administration.

4.3 Contraindications

-    This product SHOULD NEVER be prescribed in the following situations:

-    hypersensitivity to mifepristone, misoprostol or other prostaglandins, or to any of the excipients listed in section 6.1,

-    pregnancy not confirmed by ultrasound scan or biological tests,

-    suspected extra-uterine pregnancy,

-    pregnancy beyond 49 days of amenorrhea at treatment initiation,

-    chronic adrenal failure,

-    severe asthma uncontrolled by therapy,

-    inherited porphyria.

4.4 Special warnings and precautions for use

Warnings

Because of its abortifacient properties, mifepristone and misoprostol should never be used in a woman with an ongoing pregnancy who wants to complete it.

The age of the pregnancy must be determined from the questioning and the clinical examination of the patient. Uterine ultrasound is recommended.

This method requires an active involvement of the woman who should be informed of the method's requirements:

-    the necessity to combine treatment of mifepristone with misoprostol to be administered at a second visit 36 to 48 hours after administration of this mifepristone,

-    the need for a follow-up visit (3^rd visit) within 14 to 21 days after intake of mifepristone in order to check for complete expulsion,

-    the possible failure of the method, leading to a pregnancy termination by another method.

Because of possible acute effects of misoprostol, women should be fully counselled regarding the likely signs and symptoms they may experience and have direct access to the treatment centre by telephone or local access.

In the case of a pregnancy occurring with an intra-uterine device in situ, this device must be removed before administration of mifepristone.

• Risks related to the method

-    Failures

The non-negligible risk of on-going pregnancy occurs in 1% of the cases where the medical termination of pregnancy was within 49 days of amenorrhea and after administration of 600 mg mifepristone followed by 400 pg oral misoprostol. This makes the control visit mandatory in order to check that the expulsion is completed.

In rare case of non complete expulsion, a termination by another method may be necessary.

The efficacy of the medical termination of pregnancy method decreases:

-    When the labelled regimen is not strictly applied,

-    With parity

-    Bleeding

The patient must be informed of the occurrence of prolonged vaginal bleeding (an average of about 12 days or more after mifepristone intake) which may be heavy. Bleeding occurs in almost all cases and is not in anyway a proof of complete expulsion.

The bleeding can occur very quickly after misoprostol intake, and sometimes later:

-    in 60%, expulsion occurs within 4 hours following misoprostol intake

-    in the remaining 40% of the cases, expulsion occurs within 24 to 72 hours following misoprostol intake.

Rarely the expulsion may occur before administration of the prostaglandin analogue (around 3% of cases). This does not preclude the control visit in order to check for the complete expulsion and the uterine vacuity.

The patient should be informed not to travel far away from the prescribing centre as long as complete expulsion has not been recorded. She will receive precise instructions as to whom she should contact and where to go, in the event of any problems emerging, particularly in the case of very heavy vaginal bleeding. This is bleeding that lasts longer than 12 days and/or that is heavier than the normal menstrual bleeding.

A follow-up visit must take place within a period of 14 to 21 days after the intake of mifepristone to verify by the appropriate means (clinical examination, together with beta-hCG measurement or ultrasound scan) that expulsion has been completed and that vaginal bleeding has stopped. In case of persistent bleeding (even light) beyond the control visit, its disappearance should be checked within a few days.

If an ongoing pregnancy is suspected, a further ultrasound scan may be required.

Persistence of vaginal bleeding at this point could signify incomplete abortion, or an undiagnosed ectopic pregnancy, and appropriate treatment should be considered.

Since heavy bleeding requiring haemostatic curettage occurs in 0 to 1.4% of the cases during the medical method of pregnancy termination, special care should be given to patients with haemostatic disorders with hypocoagulability, or with anaemia. The decision to use the medical or the surgical method should be decided with specialised consultants according to the type of haemostatic disorder and the level of anaemia.

In the event of an ongoing pregnancy diagnosed after the follow-up visit, termination by another method will be proposed to the woman.

-Infection

Serious cases (including fatal cases) of toxic shock and septic shock following infections with atypical pathogens (Clostridium sordellii and perfringens, Klepsiella pneumonia, Escherichia coli, group A Streptococcus), have been reported after medical abortion, with the use of mifepristone 200 mg followed by unauthorised vaginal or buccal administration of misoprostol tablets.

Clinicians should be aware of this potentially fatal complication.

- Teratogenicity

Patients who decide to continue the pregnancy after treatment must be informed of the risk of teratogenicity. This risk is inherent to the mifepristone and misoprostol regimen objective and is enhanced when regimens other than the one mentioned in section 4.2 Posology and method of administration is used. Exposure of the foetus to misoprostol or mifepristone increases the risk of developing Moebius syndrome and/or an amniotic band syndrome. A termination of pregnancy by another method shall be considered. In case of continuation of the pregnancy close monitoring by ultrasound scan must be performed in specialised centres.

Precautions for use

In case of suspected acute adrenal failure, dexamethasone administration is recommended. 1 mg of dexamethasone antagonises a dose of 400 mg of mifepristone.

Due to the antiglucocorticoid activity of mifepristone, the efficacy of long-term corticosteroid therapy, including inhaled corticosteroids in asthmatic patients, may be decreased during the 3 to 4 days following intake of mifepristone. Therapy should be adjusted.

Cardiovascular risk

Rare but serious cardiovascular accidents (myocardial infarction and/or spasm of the coronary arteries and severe hypotension) have been reported following the intra vaginal and intra muscular administration of a high dose of prostaglandin analogue. Misoprostol administered orally could also constitute a potential risk factor of acute cardiovascular events. For this reason, women with risk factors for cardiovascular disease (e.g. age over 35 years with chronic smoking, hyperlipidemia, diabetes) or established cardiovascular disease should be treated with caution.

Rhesus allo-immunisation

The medical termination of pregnancy requires rhesus determination and hence the prevention of rhesus allo-immunisation as well as other general measures taken usually during any termination of pregnancy.

Contraception initiation after medical termination of pregnancy

During clinical trials, new pregnancies occurred between embryo expulsion and the resumption of menses. Therefore, when a termination of pregnancy conducted by medical procedure is medically confirmed, it is recommended to start contraception immediately.

Method of prostaglandin administration

During intake and for three hours following the intake, the patient should, in principle, be monitored in the treatment centre, in order not to miss possible acute effects of prostaglandin administration. The treatment centre must be equipped with adequate medical facilities.

On discharge from the treatment centre all women should be provided with appropriate medications as necessary and be fully counselled regarding the likely signs and symptoms she may experience and have direct access to the treatment centre by telephone or local access.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Mifepristone

On the basis of this drug’s metabolism by CYP3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampicin, dexamethasone, St. John’s Wort and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone).

Based on in vitro inhibition information, co-administration of mifepristone may lead to an increase in serum levels of drugs that are CYP3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP3A4 substrates and have narrow therapeutic range, including some agents used during general anaesthesia.

Misoprostol

Misoprostol is predominantly metabolised via fatty acid oxidising systems and has shown no adverse effect on the hepatic microsomal mixed function oxidase (P450) enzyme system.

A decrease of the efficacy of the method can theoretically occur due to the antiprostaglandin properties of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin (acetyl salicylic acid). Some evidence suggests that coadministration of NSAIDs on the day of prostaglandin administration does not adversely influence the effects of mifepristone or the prostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical termination of pregnancy.

Antacids may decrease the bioavailability of misoprostol.

Antacids containing magnesium may aggravate diarrhoea caused by misoprostol.

4.6 Fertility, pregnancy and lactation

Pregnancy

In animals (see section 5.3 Pre-clinical safety data), the abortifacient effect of mifepristone precludes the proper assessment of any teratogenic effect of the molecule.

With subabortive doses of mifepristone, malformations were observed in rabbits, but not in rats, mice or monkeys.

Use in pregnancy has been associated with birth defects/malformations for ongoing pregnancies exposed to mifepristone and misoprostol or misoprostol alone.

Rare cases of malformations of the extremity of lower limbs (out of them, club-foot) have been reported in case of mifepristone administered alone or associated with prostaglandins. One of the possible mechanisms might be amniotic band syndrome. However, data is too limited to determine whether the mifepristone is a human teratogen.

Prenatal exposure to misoprostol has been associated with Moebius syndrome (congenital facial paralysis, with or without limb defects) and with amniotic band syndrome (limb deformities/ amputations, especially clubfoot, acheiria, olygodactyly, cleft palate inter alia). Women considering medical termination of pregnancy should be precisely counselled on the risks to their foetus if an abortion failure occurs and a termination by another method is not desirable.

Consequently:

-    Women should be informed, that due to the risk of failure of the medical method of pregnancy termination and to the risk to the foetus, the follow-up visit is mandatory (see Section 4.4 special warnings and special precautions for use).

-    Should a failure of the method be diagnosed at the follow-up visit (viable ongoing pregnancy), and should the patient still agree, pregnancy termination should be completed by another method.

-    Should the patient wish to continue with her pregnancy, a careful ultrasound monitoring of the pregnancy, with a special attention to the limbs, must be established in a specialised centre.

Breast-feeding

Mifepristone is excreted in mother’s milk in small amounts. Misoprostol may also be excreted in breast milk and consequently, women should avoid breast-feeding while taking mifepristone and misoprostol.

Fertility

Mifepristone and misoprostol do not affect fertility. It is possible that the woman becomes pregnant again as soon as the termination of pregnancy is completed. Therefore it is important to inform the patient to start contraception immediately after the termination of the pregnancy is confirmed.

4.7 Effects on ability to drive and use machines

No data showing an effect on the ability to drive are known. Dizziness could occur as a side effect inherent of the abortion process. When driving or using machines one should take this possible side effect into account.

4.8 Undesirable effects

The side effects of misoprostol are usually an extension of the pharmacological action and of the drug bioavailability. The most common adverse reactions for the mifepristone - misoprostol combination are gastrointestinal disorders e.g. nausea, vomiting, diarrhoea and abdominal pain.

The frequencies of occurrence of side effects are classified as follows:

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1.000 to <1/100)

Rare (>1/10.000 to <1/1.000)

Very rare (<1/10.000)

Not known (cannot be estimated from the available data)

Infections and infestations

Common:

-Infection following abortion. Suspected or confirmed infections (endometritis, pelvic inflammatory disease) have been reported in less than 5% of women.

Very rare:

-Very rare cases of serious or fatal toxic and septic shocks (caused by Clostridium sordellii or perfringens, Klebsiella pneumonia, Escherichia coli, group A Streptococcus), which can be with or without fever or other obvious symptoms of infection, have been reported after medical abortion with the use of unauthorised vaginal or buccal administration of misoprostol tablets for oral use. Clinicians should be aware of this potentially fatal complication (see section 4.4. - special warnings and special precautions for use).

Immune system disorders Not known:

-Anaphylaxis, hypersensitivity

Nervous system disorders

Rare:

-Headache

Vascular disorders Uncommon:

-Hypotension (0.25%)

Rare but serious cardiovascular accidents (myocardial infarction and/or spasm of the coronary arteries and severe hypotension) have been reported mainly with the use of non-authorised vaginal administration of misoprostol tablets.

Gastrointestinal disorders

Very common:

-Nausea, vomiting, diarrhoea (these gastro intestinal effects related to prostaglandin use are frequently reported).

Common:

-Cramping, light or moderate.

Skin and subcutaneous tissue disorders

Uncommon

-Hypersensitivity: Skin rashes uncommon (0.2%).

Rare

-Single cases of urticaria, erythroderma, erythema nodosum, toxic epidermal necrolysis have also been reported.

Very rare

-Angioedema

Musculoskeletal and connective tissue disorders Not known -Back pain.

Reproductive system and breast disorders

Very common:

-Very common uterine contractions or cramping (10 to 45%) in the hours following prostaglandin intake.

Common:

-Heavy bleeding occurs in about 5% of the cases and may require haemostatic curettage in up to 1.4% of the cases.

Rare:

-During induction of second trimester termination of pregnancy or labour induction for foetal death in utero within the third trimester, uterine rupture has been uncommonly reported after prostaglandin intake. The reports occurred particularly in multiparous women or in women with a caesarean section scar.

Congenital, familial and genetic disorders Rare:

-Foetal death, birth defects

General disorders and administration site conditions

Rare:

-malaise, vagal symptoms (hot flushes, dizziness, chills), fever.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any side effects not listed in this leaflet. You can also report side effects directly via the yellow card scheme at www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this medicine.

4.9 Overdose

Mifepristone

In the event of accidental massive ingestion, signs of adrenal failure might occur. Signs of acute intoxication may require specialist treatment including the administration of dexamethasone.

Misoprostol

In the event of overdosage, symptomatic treatment and appropriate medical care should be done. Gastrointestinal haemorrhage, renal failure, acute rhabdomyolysis, uterine haemorrhage and death have been reported after a massive dose of 12 mg misoprostol.

Symptoms related to an overdose of misoprostol: sedation, tremor, convulsions, dyspnoea, abdominal pain, diarrhoea, fever, haemorrhage, spasm of coronary arteries, hypotension, and bradycardia.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Mifepristone

Pharmacotherapeutic group: OTHER SEX HORMONE AND MODULATOR OF THE REPRODUCTIVE FUNCTION/ ANTIPROGESTOGEN

ATC code : GO3 X B01.

Mifepristone is a synthetic steroid with an antiprogestational action as a result of competition with progesterone at the progesterone receptors.

At doses ranging from 3 to 10 mg/kg orally, it inhibits the action of endogenous or exogenous progesterone in different animal species (rat, mouse, rabbit and monkey). This action is manifested in the form of pregnancy termination in rodents.

In women at doses of greater than or equal to 1mg/kg, mifepristone antagonises the endometrial and myometrial effects of progesterone. During pregnancy it sensitises the myometrium to the contraction- inducing action of prostaglandin. During the first trimester, pre-treatment with mifepristone allows the dilatation and opening of the cervix uteri.

In the event of an early termination of pregnancy, the combination of a prostaglandin analogue used in a sequential regimen after mifepristone leads to an increase in the success rate to about 95 per cent of the cases and accelerates the expulsion of the conceptus.

In clinical trials, according to the prostaglandin used and the time of application, the results vary slightly.

The success rate is around 95 % when 600 mg mifepristone is combined with misoprostol 400 pg orally up to 49 days of amenorrhea.

According to the clinical trials and to the type of prostaglandin used, the failure rate varies. Failures occur in 1.3 to 7.5% of the cases receiving sequentially mifepristone followed by a prostaglandin analogue, of which:

-    0 to 1.5% of ongoing pregnancies

-    1.3 to 4.6% of partial abortion, with incomplete expulsion

-    0 to 1.4% of haemostatic curettage

Mifepristone binds to the glucocorticoid receptor. In animals at doses of 10 to 25 mg/kg it inhibits the action of dexamethasone. In man the antiglucocorticoid action is manifested at a dose equal to or greater than 4.5 mg/kg by a compensatory elevation of ACTH and cortisol. Glucocorticoid bioactivity (GBA) may be depressed for several days following a single administration of 200 mg mifepristone for termination of pregnancy. The clinical implications of this are unclear, however vomiting and nausea may be increased in susceptible women.

Mifepristone has a weak anti-androgenic action which only appears in animals during prolonged administration of very high doses.

Misoprostol

Pharmacotherapeutic class: Other gynaecological drugs, oxytocics - prostaglandins ATC code: G02AD06

Misoprostol (a synthetic analogue of prostaglandin E1) is used in combination with mifepristone for the termination of pregnancies of < 49 days of amenorrhea.

In the event of an early termination of pregnancy, the combination of mifepristone-misoprostol leads to an increase in the success rate to about 95% of the cases and accelerates the expulsion of the conceptus. The success rate is around 95 % when 600 mg mifepristone is combined with misoprostol 400 microgram orally up to 49 days of amenorrhea.

At the recommended dosage, misoprostol induces contractions of smooth muscle fibres of the myometrium and a relaxation of the cervix uteri. The uterotonic properties of misoprostol should facilitate the opening of the cervix uteri and the expulsion of intra-uterine remains.

At the recommended dosage, misoprostol should not involve cardiac, hepatic or renal undesirable effects.

5.2 Pharmacokinetic properties

Mifepristone

Absorption

After oral administration of a single dose of 600 mg, mifepristone is rapidly absorbed. The peak concentration of 1.98 mg/l is reached after 1.30 hours (means of 10 subjects).

After oral administration of low doses of mifepristone (20 mg), the absolute bioavailability is 69%.

Distribution

In plasma mifepristone is 98% bound to plasma proteins: albumin and principally alpha-1-acid glycoprotein (AAG), to which binding is saturable. Due to this specific binding, volume of distribution and plasma clearance of mifepristone are inversely proportional to the plasma concentration of AAG.

Biotransformation

N-Demethylation and terminal hydroxylation of the 17-propynyl chain are primary metabolic pathways of hepatic oxidative metabolism.

Elimination

There is a non-linear dose response. After a distribution phase, elimination is at first slow, the concentration decreasing by a half between about 12 and 72 hours, and then more rapid, giving an elimination half-life of 18 hours. With radio receptor assay techniques, the terminal half-life is of up to 90 hours, including all metabolites of mifepristone able to bind to progesterone receptors.

Mifepristone is mainly excreted in faeces. After administration of a 600 mg labelled dose, 10% of the total radioactivity is eliminated in the urine and 90% in the faeces.

Misoprostol

Absorption

Misoprostol is rapidly absorbed following oral administration, with peak plasma levels of the active metabolite (misoprostol acid) occurring after about 30 minutes. The plasma elimination half-life of misoprostol acid is 20-40 minutes.

Distribution

The free acid of misoprostol is less than 90 % bound to plasma proteins. Misoprostol is metabolised by fatty acids-oxidising systems, present in several organs of the human body.

Elimination

After oral administration of ³H-misoprostol approximately 73 % of the radioactivity is excreted in urine and approximately 15 % in the faeces. Approximately 56 % of total radioactivity is eliminated within 8 hours via urine.

Administration of misoprostol with food does not change the bioavailability of misoprostol acid, but reduces the maximum plasma concentration due to a slower absorption rate.

5.3 Preclinical safety data

Mifepristone

In toxicological studies in rats and monkeys up to a duration of 6 months, mifepristone produced effects related to its antihormonal (antiprogesterone, antiglucocorticoid and antiandrogenic) activity.

In reproduction toxicology studies, mifepristone acts as a potent abortifacient. No teratogenic effect of mifepristone was observed in rats and mice surviving foetal exposure. In rabbits surviving foetal exposure, however, foetal anomalies were observed (cranial vault, brain and spinal cord). The effect was dose-dependent. In monkeys, the number of foetuses surviving the abortifacient action of mifepristone was insufficient for a conclusive assessment. No evidence of teratogenicity was observed in postimplantation rat and monkey embryos exposed to mifepristone in vitro.

Misoprostol

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.

At high repeated doses in rats and rabbits, misoprostol was foeto- and embryotoxic. No teratogenic potential was observed.

In single- and repeat-dose studies in dogs, rats and mice at multiples of the human dose, toxicological findings were consistent with the known pharmacological effects of the E-type prostaglandins, the main symptoms being diarrhoea, vomiting, mydriasis, tremors and hyperpyrexia.

Intra-uterine but not the intragastric delivery of misoprostol to rats significantly worsened mortality from Clostridium sordellii uterine infection, and impaired bacterial clearance in vivo.

Misoprostol has been shown to alter calcium homeostasis in neuro-2a cells and contribute to abnormal cell function in vitro. Imbalances in calcium homeostasis can potentially affect early neuronal development.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Mifepristone tablet:

Silica, colloidal anhydrous (E551)

Maize starch Povidone (E1201)

Magnesium stearate (E572)

Cellulose microcrystalline (E460)

Misoprostol tablet: Microcrystalline cellulose Hypromellose

Sodium starch glycolate (type A) Hydrogenated castor oil

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Misoprostol in PVC-PCTFE/Alu blister: shelf-life for the combination pack 1 year Misoprostol in OPA-Alu-PVC/Alu blister: shelf-life for the combination pack 2 years

6.4 Special precautions for storage

Store below 25°C.

Any tablet stored outside the blister or not used immediately has to be discarded. Store in the original package in order to protect from moisture and light.

6.5    Nature and contents of container

Pack size: a total of 2 tablets i.e.

1 mifepristone 600 mg tablet (PVC/Alu blister strip)

1 misoprostol 400 microgram tablets (OPA-Alu-PVC/Alu or PVC-PCTFE/Alu blister strip)

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

EXELGYN

216, Boulevard Saint-Germain

75007 Paris France

8    MARKETING AUTHORISATION NUMBER(S)

PL 16152/0005

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/07/2014

10    DATE OF REVISION OF THE TEXT

03/07/2014