1 Summary of Product Characteristics
SUMMARY OF PRODUCT CHARACTERISTICS
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1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains 100 mg racecadotril.
Excipient with known effect: Each hard capsule contains 41 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Hard Capsule
Yellow (ivory) coloured hard capsules capsule size no. 2, imprinted with the name ‘Racecadotril’ in black ink on the cap and containing a white to off white powder.
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 with the first dose, regardless of the time of day.
On the first day, the total daily dose should not exceed 4 capsules (400 mg). On the consecutive days the total daily dose should not exceed 3 capsules (300 mg).
Treatment should be continued until 2 normal stools have been passed. The duration of treatment should not exceed 3 days.
If symptoms worsen or do not improve within the first 2 days after starting treatment, medical advice should be sought.
Long-term treatment with racecadotril is not recommended.
Paediatric population
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The safety and efficacy of
Elderly No dose adjustment is necessary in elderly patients.
Renal impairment Caution is required in patients with renal or hepatic impairment (see section 4.4, 5.2).
Method of administration Oral use.
4.3 Contraindications
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 cases where: Diarrhoea is associated with fever and/or bloody or purulent stools as this may indicate the presence of invasive bacteria or other serious diseases. Diarrhoea is associated with the use of antibiotics (pseudomembranous colitis).
Patients with ulcerative colitis should not treat an acute episode of diarrhoea without medical advice.
There are limited data in patients with renal or hepatic impairment. Special care is required and these patients should be treated only under medical supervision (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.
Hypersensitivity/Angioneurotic Oedema have been reported in patients with racecadotril. This may occur at any time during therapy.
Angioedema of the face, extremities, lips, mucous membranes may occur. Where there is angioedema associated with upper airway obstruction, such as tongue, glottis and/or larynx, emergency therapy should be administered promptly.
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Concomitant use of racecadotril and ACE inhibitors may increase the risk of angioedema (see section 4.5). Hence, a careful benefit-risk assessment is needed before initiating treatment with racecadotril in patients on ACE inhibitors.
Warnings 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 (e.g. 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 and medical advice should be sought.
Contains Lactose-Monohydrate 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.
4.5 Interaction with other medicinal products and other forms of interaction Concomitant use of racecadotril and ACE inhibitors (e.g. captopril, enalapril, lisinopril, perindopril, ramipril) may increase the risk of angioedema (see section 4.4).
4.6 Fertility, pregnancy and lactation
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).
Pregnancy As no specific clinical data are available,
Breastfeeding There is insufficient information on the excretion of racecadotril in human 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
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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 specific overdose symptoms are known. 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
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.
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A randomised crossover study showed that, when given at therapeutic doses (1 capsule) or supratherapeutic doses (4 capsules), racecadotril 100 mg capsules did not induce QT/QTc prolongation in 56 healthy subjects (unlike moxifloxacin, which was used as a positive control).
In a large, multinational, multicentre study 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. However, racecadotril was associated with significantly less constipation than loperamide, and produced more rapid resolution of abdominal distension and pain. The evaluation of the signs and symptoms associated with diarrhoea showed that the median duration of abdominal distension was significantly shorter with racecadotril. Moreover, abdominal distension had become worse in a higher proportion of patients on loperamide by the end of the study, while a greater number of loperamide treated patients reported that abdominal pain was still present at the end of the study. Significantly less patients in the racecadotril group experienced adverse events during treatment compared to the loperamide group. Also in other randomised, double-blind active comparator studies carried out in patients with acute diarrhoea, racecadotril and loperamide were found to be equally effective with respect to onset of action, reduction of stool frequency and duration of diarrhoea. According to an overview of clinical studies with racecadotril the overall tolerability and safety profile of racecadotril was considered more favourable than that of loperamide.
According to a multicentric, randomised, investigator-blind, parallel group study, an equivalent safety profile and both, a faster onset of action as well as a shorter duration of diarrhoea, were exhibited by racecadotril in comparison to saccharomyces boulardii in adults.
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-phenyl- propyl)glycine), is bound to plasma proteins, mainly to albumin. Pharmacokinetic properties of racecadotril are not modified in case of repeated administration.
Biotransformation The half-life of racecadotril, measured as plasma enkephalinase inhibition, is about 3 hours.
Racecadotril is rapidly hydrolysed to its active metabolite thiorphan, which is in turn transformed into inactive metabolites, identified as S-methylthiorphan sulphoxide, S-methylthiorphan, 2- methanesulphinylmethyl propionic acid and 2-methylsulphanylmethyl propionic acid. Each of these
6 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.
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).
Paediatrics: In the paediatric population, pharmacokinetic results are similar to those of the adult population, reaching Cmax at 2 hours 30 min after administration. There is no accumulation after multiple doses administered every 8 hours, for 7 days.
Elderly Single oral doses of 100 mg of racecadotril were evaluated in 7 healthy elderly subjects. The tmax (90 min), maximum NEP inhibition (73%), and AUC (155 arbitrary units) were comparable to those in younger adults. The type of comparison (direct or historical) was not reported.
Renal impairment 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).
Hepatic impairment 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.
5.3 Preclinical safety data
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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), application of racecadotril at a dose of 500 mg/kg/day led to generalised infections and reduced antibody responses, whereas application 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.
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
Capsule content Lactose monohydrate (Ph. Eur.) Pregelatinised starch (Ph. Eur.) (maize) Magnesium stearate, (Ph. Eur.) (vegetable derived) Silica colloidal anhydrous (Ph. Eur.)
Capsule shell Yellow iron oxide (E172) Titanium dioxide (E171) Gelatine, (bovine derived)
Printing Ink Black iron oxide (E172) Potassium hydroxide (E525) Propylene glycol (E1520) Shellac
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6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 30° C.
6.5 Nature and contents of container
Transparent PVC-PVDC/aluminium blisters.
Packs containing 10 or 20 hard capsules.
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.
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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