Dissenten 2 mg 15 tablets

In ottemperanza all'articolo 118 “autorizzazione della pubblicità presso il pubblico” del decreto legislativo 24 aprile 2006, numero 219

INDICATIONS

Dissenten is indicated for the symptomatic treatment of acute diarrhea and exacerbations of chronic diarrhea.

ACTIVE INGREDIENTS

Each tablet contains: Active ingredient: Loperamide hydrochloride 2 mg. For the full list of excipients, see section 6.1.

EXCIPIENTS

Magnesium stearate; microgranular cellulose.

CONTRAINDICATIONS AND SIDE EFFECTS

Hypersensitivity to the active substance or to any of the excipients. DISSENTEN is contraindicated in children under 6 years of age. DISSENTEN must not be used as primary therapy: • in patients with acute dysentery, characterized by blood in the stool and high fever; • in patients with acute ulcerative colitis; • in patients with pseudomembranous colitis associated with the use of broad-spectrum antibiotics; • in patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella and Campylobacter. In general, the use of DISSENTEN is contraindicated in all cases where inhibition of peristalsis must be avoided due to the possible risk of significant consequences such as ileus, megacolon and toxic megacolon. If constipation, abdominal distension or ileus occurs, discontinue treatment immediately.

DOSAGE

The tablets should be taken with a little liquid. Adults and children aged between 6 and 17 The starting dose is 2 tablets (4 mg) for adults and 1 tablet (2 mg) for children; then 1 tablet (2 mg) after each subsequent evacuation of unformed (soft) stools. The maximum daily dose for adults is 8 tablets (16 mg). For children the dose must be related to body weight (3 tablets/20 kg) but must not exceed a maximum of 8 tablets per day. Decrease the dose when stool returns to normal and interrupt treatment in case of constipation. Warning: do not use for more than two days. Children under 6 years of age Dissenten should not be used in children under 6 years of age. Elderly No dose adjustment is necessary in the elderly. Kidney damage No dose adjustment is necessary in patients with renal impairment. Hepatic impairment Although no pharmacokinetic data are available in patients with hepatic impairment, DISSENTEN should be used with caution in these patients due to reduced first pass metabolism (see section 4.4 “Special warnings and precautions for use”).

CONSERVATION

This medicinal product does not require any special precautions for storage.

WARNINGS

Treatment of diarrhea with loperamide hydrochloride is symptomatic only. Whenever an underlying etiology can be determined, specific treatment should be administered when appropriate. Fluid and electrolyte depletion may occur in patients with diarrhea, especially in children. In these cases the most important countermeasure is the administration of adequate replacement therapy based on fluids and electrolytes. It is advisable to suspend treatment with DISSENTEN if there is no improvement in clinical symptoms within 48 hours following the start of therapy and the patient should consult his doctor. AIDS patients treated with DISSENTEN for diarrhea should discontinue therapy at the first signs of abdominal distension. In these patients with infectious colitis of bacterial or viral origin, treated with loperamide hydrochloride, isolated cases of constipation with an increased risk of toxic megacolon have been found. Loperamide hydrochloride is subject to extensive first pass metabolism. Although no pharmacokinetic data are available in patients with hepatic impairment, loperamide hydrochloride should be used with caution in these patients due to reduced first pass metabolism. Therefore, patients with hepatic impairment should be carefully monitored for any signs of central nervous system (CNS) toxicity. In association with overdose, cardiac events including QT interval prolongation, QRS complex prolongation and torsade de pointes have been reported. Some cases have been fatal (see section 4.9). Overdose can manifest the presence of Brugada syndrome. Patients should not exceed the recommended dose and/or prolong the recommended duration of therapy.

INTERACTIONS

Non-clinical data have demonstrated that loperamide is a substrate of P-glycoprotein. Concomitant administration of loperamide (16 mg single dose) with quinidine or ritonavir, both inhibitors of P-glycoprotein, showed a 2- to 3-fold increase in plasma levels of loperamide. The clinical relevance of this pharmacokinetic interaction with P-glycoprotein inhibitors, when loperamide is administered at recommended doses, is unknown. Concomitant administration of loperamide (4 mg single dose) and itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, showed a 3- to 4-fold increase in plasma concentrations of loperamide. In the same study, gemfibrozil, a CYP2C8 inhibitor, increased plasma concentrations of loperamide approximately 2-fold. The combination of itraconazole and gemfibrozil showed a 4-fold increase in peak plasma levels of loperamide and a 13-fold increase in total plasma exposure. These increases were not associated with central nervous system (CNS) effects, as measured by psychomotor tests (e.g. subjective sleepiness and the Digit Symbol Substitution Test). Concomitant administration of loperamide (16 mg single dose) and ketoconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 5-fold increase in plasma concentrations of loperamide. This increase was not associated with an increase in pharmacodynamic effects, as detected by pupillometry. Concomitant treatment with oral desmopressin resulted in a 3-fold increase in plasma concentrations of desmopressin, presumably due to a slowing of gastrointestinal motility. Treatment with substances with similar pharmacological properties can enhance the effect of loperamide, and drugs that accelerate intestinal transit can decrease its effect. Concomitant use of cytochrome CYP 450 inhibitors is not recommended.

SIDE EFFECTS

Adults and children aged ≥12 years The safety of loperamide hydrochloride was evaluated in 3076 adults and children aged ≥12 years who participated in 31 controlled and uncontrolled clinical trials with loperamide hydrochloride used for the treatment of diarrhea. Of these, 26 studies were on acute diarrhea (N=2755) and 5 on chronic diarrhea (N=321). The most commonly reported adverse drug reactions (ADRs) (i.e., ≥1% incidence) during clinical trials with loperamide hydrochloride for the treatment of acute diarrhea were: constipation (2.7%), flatulence (1.7%), headache (1.2%), and nausea (1.1%). In clinical trials for the treatment of chronic diarrhea, the most commonly reported ADRs (i.e., ≥1% incidence) were: flatulence (2.8%), constipation (2.2%), nausea (1.2%), and dizziness (1.2%). Table 1 presents the results of 3076 adult subjects and children aged ≥12 years who participated in 31 controlled and uncontrolled clinical trials with loperamide hydrochloride used for the treatment of diarrhea. Of these, 26 studies dealt with acute diarrhea (N=2755) and 5 with chronic diarrhea (N=321). The frequency categories presented in Table 1 use the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000) and very rare (<1/10,000). Table 1 Frequency of adverse reactions reported with the use of loperamide hydrochloride from clinical trials in adults and children aged ≥12 years

System organ class: Indication.

System organ class: Acute diarrhea Chronic diarrhea.

System organ class: (N=2755) (N=321).

Nervous system disorders.

Headache: Common Uncommon.

Dizziness: Uncommon Common.

Gastrointestinal disorders.

Constipation, nausea, flatulence: Common Common.

Abdominal pain, abdominal discomfort, dry mouth: Uncommon Uncommon.

Upper abdominal pain, vomiting: Uncommon.

Dyspepsia: Uncommon.

Abdominal distension: Rare.

Pathologies of the skin and subcutaneous tissue.

Rash: Uncommon.

Loperamide hydrochloride, post-marketing adverse reaction data Since the loperamide hydrochloride post-marketing ADR determination process did not differentiate between chronic and acute diarrhea indications or between adults and children, the adverse reactions listed below represent the combined indications and subject populations. Adverse reactions identified in the post-marketing period for loperamide hydrochloride are listed through the System Organ Class and the Medical Dictionary for Regulatory Activities (MeDRA) under Preferred Terms (PT): Immune system disorders: hypersensitivity reaction, anaphylactic reaction (including anaphylactic shock), anaphylactoid reaction. Nervous system disorders: drowsiness, loss of consciousness, stupor, depressed levels of consciousness, hypertonia, abnormal coordination. Eye disorders: miosis. Gastrointestinal disorders: ileus (including paralytic ileus), megacolon (including toxic megacolon), glossodynia, acute pancreatitis (frequency not known). Skin and subcutaneous tissue disorders: bullous rash syndrome (including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme), angioedema, urticaria, pruritus. Renal and urinary disorders: urinary retention. Systemic disorders and conditions relating to the administration site: fatigue. Pediatric population The safety of loperamide hydrochloride was evaluated in 607 patients aged 10 days to 13 years who participated in 13 controlled and uncontrolled clinical trials with loperamide hydrochloride used for the treatment of acute diarrhea. Overall, the ADR profile in this patient population was similar to that observed in clinical trials with loperamide hydrochloride in adults and children aged 12 years and older. Reporting of suspected adverse reactions. Reporting suspected adverse reactions that occur after authorization of the medicine is important, as it allows continuous monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system at www.aifa.gov.it/content/segnalazioni-reazioni-avverse

OVERDOSE

Symptoms In case of overdose, including that caused by hepatic dysfunction, CNS depression (stupor, coordination abnormalities, drowsiness, miosis, muscle hypertonia, respiratory depression), urinary retention and ileus may occur. In subjects who have ingested excessive doses of loperamide, cardiac events such as prolongation of the QT interval and that of the QRS complex, torsade de pointes, other serious ventricular arrhythmias, cardiac arrest and syncope have been observed (see section 4.4). Fatal cases have also been reported. Overdose can manifest the presence of Brugada syndrome. Children may be more sensitive than adults to the effects of a loperamide overdose. It is therefore recommended to keep the product out of their reach because accidental ingestion, especially in children under 4 years of age, can cause constipation and depression of the central nervous system with drowsiness and slowing of breathing. In this case the child must be kept under careful observation for 48 hours. Treatment Measures in case of overdose: gastric lavage, provocation of vomiting, enema or administration of laxatives. If symptoms of overdose arise, naloxone may be administered as an antidote. Since the duration of action of loperamide is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone may be indicated. Therefore the patient must be carefully monitored for at least 48 hours to detect any worsening of central nervous system depression.

PREGNANCY AND BREASTFEEDING

Although there is no indication that loperamide hydrochloride possesses teratogenic or embryotoxic properties, the anticipated therapeutic benefits should be weighed against the potential risks before administering loperamide hydrochloride during pregnancy, especially during the first trimester. Small amounts of loperamide may appear in human breast milk. Therefore loperamide hydrochloride is not recommended during breastfeeding.

EFFECTS ON DRIVING ABILITY

In the context of diarrheal syndromes treated with loperamide hydrochloride, tiredness, dizziness or drowsiness may occur. Therefore, caution is advised when driving a vehicle or operating machinery.