SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT <Product name> 100 mg capsules, hard 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 <Product name> is indicated for the symptomatic treatment of acute diarrhoea in adults over 18 years when specific treatment is not possible. If specific treatment is possible, racecadotril can be given as adjunctive treatment. 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 2 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. <Product name> is contraindicated in diarrhoea associated with fever and/or bloody or purulent stools as this may indicate the presence of invasive bacteria or other serious diseases. Medical advice should be sought in these cases. <Product name> is contraindicated in antibiotic-associated diarrhoea (pseudomembranous colitis). <Product name> is contraindicated in patients who experienced angioedema while under treatment with ACE inhibitors (e.g. captopril, enalapril, lisinopril, perindopril, ramipril). 4.4 Special warnings and precautions for use Precautions for use The use of <Product name> does not modify the usual rehydration regimens. 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 <Product name> must not be used unless prescribed by a doctor (see section 5.2). 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 <product name> against acute diarrhoea. 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 3 no specific clinical studies are available, however, <Product name> should not be used in pregnant women. 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 <Product name> has no or negligible influence on the 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 (<Product name>) did not induce QT/QTc prolongation in 56 healthy subjects (unlike moxifloxacin, which was used as a positive control). 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