SUMMARY OF PRODUCT CHARACTERISTICS
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1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule, hard contains 100 mg racecadotril.
Excipient(s) with known effect: Each capsule, hard contains 41 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Capsule, hard
Ivory-coloured capsules, hard, capsule size no. 2, containing a white powder with a sulphurous odour.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
4.2 Posology and method of administration
Posology Adults 1 capsule 3 times daily, preferably before main meals. On the first day of treatment, one additional capsule should be taken initially, regardless of the time of day. Treatment should be continued until 2 normal stools have been passed; however, the duration of treatment should not exceed 3 days. Long-term treatment with racecadotril is not recommended.
Paediatric population Special formulations of racecadotril are available for infants, children and adolescents.
Elderly population No dose adjustment is necessary in elderly patients.
Caution is required in patients with renal or hepatic impairment (see section 5.2).
Method of administration Oral use.
4.3 Contraindications
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Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Precautions for use The use of
Medical advice should be sought in the event of an acute episode of ulcerative colitis.
There are limited data in patients with renal or hepatic impairment. Special care is required when treating these patients and
The availability of the active substance may be reduced in patients with persistent vomiting.
In case of chronic diarrhoea, a medical doctor should be consulted.
Warning This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Occurrence of skin reactions has been reported with the use of the product. These are in most cases mild and do not require treatment but in some cases they can be severe, even life- threatening (Stevens-Johnson syndrome, toxic epidermal necrolysis, skin exfoliation, DRESS). Association with racecadotril cannot be fully excluded. When experiencing severe skin reactions (e.g. progressive skin rash often with blisters or mucosal lesions), the treatment has to be stopped immediately. Patients should be advised of the signs and symptoms and monitored closely for skin reactions.
4.5 Interaction with other medicinal products and other forms of interaction
ACE inhibitors (e.g. captopril, enalapril, lisinopril, perindopril, ramipril) are known to cause angioedema. This risk may be elevated when used concomitantly with
Co-administration of racecadotril with loperamide or nifuroxazide does not modify the kinetics of racecadotril in man.
4.6 Fertility, pregnancy and lactation
Pregnancy There are no adequate data from the use of racecadotril in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, fertility, embryonal/foetal development, childbirth/delivery or postnatal development (see section 5.3). As
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Breastfeeding This medicinal product should not be used in breast-feeding women because of a lack of information regarding passage of the active substance into breast milk.
Fertility No effects on fertility were observed in fertility studies carried out with racecadotril in rats.
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
Data from clinical studies in acute diarrhoea patients are available for 2193 adults treated with racecadotril and 282 treated with placebo. The undesirable effects listed below have occurred more frequently with racecadotril than with placebo or have been reported during postmarketing surveillance. The frequency of undesirable effects is defined using the following convention:
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
Nervous system disorders Common: Headache
Skin and subcutaneous tissue disorders (see section 4.4) Uncommon: Rash, erythema Not known: Erythema multiforme, tongue oedema, facial oedema, lip oedema, eyelid oedema, angioedema, urticaria, erythema nodosum, papular rash, prurigo, pruritus, toxic skin eruption
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.
4.9 Overdose
No cases of overdose have been reported. In adults, single doses above 2 g (equivalent to 20 times the therapeutic dose) have not had any harmful effects.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties 4
Pharmacotherapeutic group: Other antidiarrheals ATC code: A07XA04
Racecadotril is a prodrug which is hydrolysed to its active metabolite thiorphan. Thiorphan is an inhibitor of enkephalinase, a cell membrane peptidase located in various tissues, notably the epithelium of the small intestine. This enzyme contributes both to the hydrolysis of exogenous peptides and to the breakdown of endogenous peptides such as enkephalins. Racecadotril protects enkephalins from enzymatic breakdown (which is increased in acute diarrhoea), prolonging their action at enkephalinergic synapses in the small intestine and reducing hypersecretion without affecting basal secretion.
Racecadotril is a pure intestinal antisecretory active substance. It reduces intestinal hypersecretion of water and electrolytes induced by cholera toxins or inflammation and does not affect basal secretory activity. By potentiating the action of enkephalins on delta-opioid receptors, it exerts a rapid antidiarrhoeal effect without modifying intestinal transit.
Racecadotril does not produce abdominal distension or increased abdominal wall tension. During clinical development, the incidence of secondary constipation was comparable in patients treated with racecadotril and patients treated with placebo. Following oral administration, racecadotril has exclusively peripheral activity, with no effects on the central nervous system.
In randomised, double-blind active comparator studies carried out in patients with acute diarrhoea, the antisecretory agent racecadotril and the antimotility agent loperamide were found to be equally effective with respect to onset of action, reduction of stool frequency and duration of diarrhoea.
A randomised crossover study showed that, when given at therapeutic doses (1 capsule) or supratherapeutic doses (4 capsules), racecadotril 100 mg capsules (
5.2 Pharmacokinetic properties
Absorption Following oral administration, racecadotril is rapidly absorbed. The bioavailability of racecadotril is not modified by food but peak activity is delayed by about 1½ hours.
Distribution Following oral administration of 14C-labelled racecadotril in healthy subjects, levels of racecadotril in plasma were more than 200 times higher than in blood cells and 3 times higher than in whole blood. The drug therefore did not bind to blood cells to any significant extent. Distribution of radioactivity in other tissues was moderate, as indicated by a mean apparent volume of distribution in plasma of 66.4 kg.
90% of the active metabolite of racecadotril, thiorphan ((RS)-N-(1-oxo-2-(mercaptomethyl)-3- phenylpropyl)glycine), is bound to plasma proteins, mainly to albumin.
Biotransformation The half-life of racecadotril, measured as plasma enkephalinase inhibition, is about 3 hours.
Racecadotril is rapidly hydrolysed to its active metabolite, thiorphan ((RS)-N-(1-oxo-2- (mercaptomethyl)-3-phenylpropyl)glycine), which is in turn transformed into inactive
5 metabolites, identified as S-methylthiorphan sulphoxide, S-methylthiorphan, 2- methanesulphinylmethyl propionic acid and 2-methylsulphanylmethyl propionic acid. Each of these metabolites exceeds 10% of the systemic exposure to the parent drug. Additional minor metabolites were also detected and quantified in the urine and faeces.
Pharmacokinetic/pharmacodynamic relationships The duration and extent of the effect of racecadotril are dose-dependent. Plasma enkephalinase activity is significantly inhibited within the first 30 minutes after administration. Peak plasma enkephalinase inhibition is reached after about 2 hours and corresponds to 75% inhibition after a dose of 100 mg. The duration of plasma enkephalinase inhibition at this dose is about 8 hours.
Repeated administration of racecadotril does not lead to accumulation. In-vitro data show that racecadotril/thiorphan and the four inactive major metabolites do not inhibit the major CYP isoforms (3A4, 2D6, 2C9, 1A2 and 2C19) to any clinically relevant extent. In-vitro data show that racecadotril/thiorphan and the four inactive major metabolites do not induce the CYP 3A or 1A families, the CYP isoforms 2A6, 2B6, 2C9/2C19 or 2E1 or UGT enzymes to any clinically relevant extent.
Racecadotril does not modify protein binding of active substances strongly bound to proteins, such as tolbutamide, warfarin, niflumic acid, digoxin or phenytoin.
In patients with liver failure (Child-Pugh grade B cirrhosis), the kinetic profile of the active metabolite of racecadotril showed similar Tmax and T½ and lower Cmax (-65%) and AUC (-29%) compared to healthy subjects.
In patients with severe renal impairment (creatinine clearance 11 - 39 ml/min), the kinetic profile of the active metabolite of racecadotril showed lower Cmax (-49%) and higher AUC (+16%) and T½ than in healthy subjects (creatinine clearance > 70 ml/min).
In the paediatric population, the pharmacokinetic profile is similar to that in the adult population. Peak levels are reached 2½ hours after administration. No accumulation occurs following multiple dosing every 8 hours for 7 days
Elimination Racecadotril is eliminated as both active and inactive metabolites. Elimination is mainly via the renal route (81.4%) and, to a much lesser extent, via the faecal route (about 8%). There is no significant elimination via the pulmonary route (< 1% of the dose).
5.3 Preclinical safety data
Chronic toxicity studies carried out in monkeys and dogs over 4 weeks (a period which is relevant for the duration of treatment in man) did not reveal any effects at doses up to 1250 mg/kg/day and 200 mg/kg/day respectively, which correspond to safety margins of 625 and 62 relative to the human dose. No immunotoxicity was observed in mice given racecadotril for a short period (up to 1 month). In monkeys subjected to a longer period of exposure (1 year), vaccination with racecadotril at a dose of 500 mg/kg/day led to generalised infections and reduced antibody responses, whereas vaccination at a dose of 120 mg/kg/day did not lead to infection or immunosuppression. In dogs given 200 mg/kg/ day for 26 weeks, some infection/immune parameters were affected. The clinical relevance of this is unknown (see section 4.8).
Racecadotril has not been found to have any mutagenic or clastogenic effects in the standard in- vitro and in-vivo tests.
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Carcinogenicity testing has not been performed with racecadotril as the drug is used for short- term treatment only.
Racecadotril was not shown to have any unusual or abnormal effects in reproductive and developmental toxicity studies (comprising studies on fertility and early embryonal development, pre- and postnatal development (including maternal function) and embryofoetal development).
Other preclinical effects (such as severe - most probably aplastic - anaemia, increased diuresis, ketonuria and diarrhoea) were observed only at exposures that were sufficiently in excess of the maximum human exposure. Their clinical relevance is unknown. There was no evidence from other safety pharmacology studies that racecadotril has any harmful effects on the central nervous system or on cardiovascular or respiratory function. In animals, racecadotril increased both the effect of butylhyoscine on intestinal transit and the anticonvulsant effect of phenytoin.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate Pregelatinised maize starch Magnesium stearate, vegetable-derived (Ph. Eur.) Colloidal anhydrous silica
Capsule shell Yellow iron oxide (E 172) Titanium dioxide (E 171) Gelatine, bovine-derived
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Transparent PVC-PVDC/aluminium blisters
Packs containing 6 or 10 capsules, hard
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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7. MARKETING AUTHORISATION HOLDER
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
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