CLINICAL PHARMACOLOGY

Pharmacodynamics properties

• Pharmacotherapeutic group: Other Anti-Diarrheal.
• Mechanism of Action: Racecadotril is a pro-drug that needs to be hydrolyzed to its active metabolite Thiorphan, which is an inhibitor of Enkephalinase, a cell membrane peptidase enzyme located in various tissues, notably the epithelium of the small intestine. This enzyme contributes both to the digestion of Exogenous Peptides and to the breakdown of Endogenous Peptides such as Enkephalins.
  Racecadotril protects Enkephalins from enzymatic degradation thereby prolonging their action at Enkephalinergic synapses in the small intestine and reducing hyper secretion. Racecadotril is a pure intestinal anti-secretory active substance. It decreases the intestinal hyper secretion of water and electrolytes induced by the cholera toxin or inflammation, and does not have effects on basal secretory activity. Racecadotril exerts rapid anti-diarrheal action, without modifying the duration of intestinal transit. Racecadotril does not produce abdominal distension. During its clinical development, Racecadotril produced secondary constipation at a rate comparable to placebo. When administered via the oral route, its activity is exclusively peripheral, with no effects on the central nervous system.

Pharmacokinetic properties

• Absorption: Following oral administration, Racecadotril is rapidly absorbed. The exposure at steady state is comparable with the exposure following a single dose.
• Distribution: After oral administration of 14C-labeled Racecadotril in healthy volunteers, Racecadotril concentration was more than 200 fold higher in plasma than in blood cells and 3-fold higher in plasma than in total blood. Thus, the drug did not bind to blood cells to any significant extent. Radiocarbon distribution in other body tissues was moderate, as indicated by the mean apparent volume of distribution in plasma of 66.4 kg. Ninety percent 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. The duration and extent of the effect of Racecadotril are dose dependent. Time to peak plasma Enkephalinase inhibition is approximately 2 hours and corresponds to an inhibition of 90% with the dose of 1.5 mg/kg. The duration of plasma Enkephalinase inhibition is approximately 8 hours.
• Metabolism: The half-life of Racecadotril, measured as plasma Enkephalinase inhibition, is approximately 3 hours. Racecadotril is rapidly hydrolyzed to Thiorphan (RS)-N-(1-oxo-2-(Mercaptomethyl)-3-phenylpropyl) Glycin, the active metabolite, which is in turn transformed into inactive metabolites identified as Sulfoxyde of Smethylthiorphan, S-methyl Thiorphan, 2-methanesulfinylmethyl propionic acid and 2-methylsulfanylmethyl propionic acid, which all were formed at greater than 10% of parent drug systemic exposure. Additional minor metabolites were also detected and quantified in urine and faeces.
  In vitro data indicate that Racecadotril/Thiorphan and the four major inactive metabolites do not inhibit the major CYP enzymes isoforms 3A4, 2D6, 2C9, 1A2 and 2C19 to an extent that would be clinically relevant. In vitro data indicate that Racecadotril/Thiorphan and the four major inactive metabolites do not induce the CYP enzymes isoforms (3A family, 2A6, 2B6, 2C9/2C19, 1A family, 2E1) and UGTs conjugating enzymes to an extent that would be clinically relevant. In the Pediatrics 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 dose administrated every 8 hours, for 7 days.
• Excretion: Racecadotril is eliminated as active and inactive metabolites. Elimination is mainly via the renal route (81.4%), and to a much lesser extent via the faecal route (around 8%). The pulmonary route is not significant (less than 1% of the dose).

DRUG-DRUG INTERACTIONS

• To date, no interactions with other medicinal products have been described in humans. In humans, joint treatment with Racecadotril and Loperamide or Nifuroxazide does not modify the kinetics of Racecadotril.

INDICATIONS

• Indicated for the treatment of symptoms of Acute Diarrhea in adults, when Diarrhea cannot be treated causally.
• Racecadotril can be administered as a complementary treatment when causal treatment is possible.

DOSAGE AND ADMINISTRATION

• The usual dose is one capsule three times daily to be swallowed with a glass of water.
• Racecadotril should be taken preferably before the main meals, but to begin with your treatment, you may take one capsule of Racecadotril at any time during the day.
• It should be continued until two normal stools are produced, not exceeding 7 days.
• To compensate for the loss of liquid due to your Diarrhoea, this medicinal product should be used together with an adequate replacement of fluid and salts (Electrolytes). The best replacement of fluid and salts is achieved with a so-called Oral Rehydration Solution.
• No dosage adjustment is required in the elderly.
• Children: Other forms of Racecadotril are available for use in children and infants.

SIDE- EFFECTS

• The most common side effects are Headache (affects 1 to 10 users in 100).
• Uncommon side effects have been reported (affects 1 to 10 users in 1,000): Rash and Erythema (skin redness).
• Other side effects (frequency cannot be estimated from the available data) are: Erythema Multiform(Pink lesions in the extremities and inside the mouth), Inflammation of the tongue, Inflammation of the face, Inflammation of the lip, Inflammation of the eyelid, Angioedema (inflammation below the skin in different parts of the body), Urticaria, Erythema nodosum (inflammation in the form of a nodule under the skin), Rash Papular (Eruption in the skin with small lesions, hard and nodulated), Prurigo (Itching Skin Lesions), Pruritus (generalized itching), Toxic Skin Eruption.

You should stop taking Racecadotril and see your doctor immediately if you experience symptoms of Angioedema, such as:

• Swollen face, tongue or pharynx
• Difficulty to swallow
• Hives and difficulties to breath

WARNNING AND PRECAUTIONS

Precautions for use:

• The administration of Racecadotril does not modify the usual rehydration regimens.
• Rehydration is highly important in the management of acute diarrhoea in infants.
• The requirement for rehydration and route should be adapted to the age and weight of the patient and the stage and severity of the condition, specifically in case of serious or prolonged Diarrhoea with significant Vomiting or a lack of appetite.
• In the event of serious or prolonged Diarrhoea with important vomiting or a lack of appetite, intravenous Rehydration should be considered.
• The presence of bloody or purulent stools and fever may indicate the presence of invasive bacteria as a reason for Diarrhoea, or the presence of other severe disease. Also, Racecadotril has not been tested in antibiotic-associated Diarrhoea.
• You are suffering from chronic diarrhoea or diarrhoea caused by antibiotics.
• You are suffering from kidney disease or impaired liver function.
• You are suffering from prolonged or uncontrolled vomiting.

Therefore, Racecadotril should not be administered under these conditions. Chronic diarrhoea has not been sufficiently studied with this product.

Warnings:

• The product must not be administered to infants less than 3 months old, as there are no clinical trials in this population.
• The product must not be administered to children with renal or liver impairment, whatever the degree of severity, due to a lack of information on these patient populations.
• Because of possible reduced bioavailability, the product must not be administered in cases of prolonged or uncontrolled vomiting.
• 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. Association with Racecadotril cannot be fully excluded. When experiencing severe Skin Reactions, the treatment has to be stopped immediately.
• Fertility: Fertility studies conducted with Racecadotril on Rats demonstrate no impact on fertility.
• 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, embryo-foetal development, childbirth/delivery or postnatal development. However, since no specific clinical studies are available, Racecadotril should not be administered to pregnant women.
• Lactation: Due to the lack of information regarding Racecadotril excretion in human milk, this medicinal product should not be administered to breastfeeding women.

CONTRAINDICATIONS

• Hypersensitivity to the active substance or to any of the excipients.