Loperastat Syrup 1 mg per 5 ml Syrup

LOPERASTAT u00ae SYRUP is indicated for symptomatic relief of acute and chronic non specific diarrhoea and to inhibit peristalsis and slow intestinal transit time in patients with iloestomies, colostomies and other intestinal resections. For children under the age of 6 years: LOPERASTAT u00ae SYRUP is indicated for inhibition of peristalsis and slowing of intestinal transit time.

ACUTE NON SPECIFIC DIARRHOEA:

One medicine measure (5 ml) per 12,5 kg body mass followed by half medicine measure (2,5 ml) per 12,5 kg after each subsequent loose stool. Daily dosage should not exceed three medicine measures (15 ml) per 12,5 kg body mass.

Weight in kilograms (kg) Initial dose (ml) On subsequent loose stools Maximum daily dose

• 10 - 14,9 5 ml 2,5 ml 15 ml
• 15 - 19,9 7,5 ml *3,7 ml 20 ml
• 20 10 ml 5 ml 30 ml
• 40 15 ml 7,5 ml 60 ml
• 70 20 ml 10 ml 80 ml

* 3, 7 ml is equal to 3/4 of a medicine measure.

IMPORTANT Stop LOPERASTAT u00ae SYRUP as soon as diarrhoea is under control. In acute diarrhoea, if clinical improvement is not observed within 48 hours, the administration of LOPERASTAT u00ae SYRUP should be discontinued and patients should be advised to consult their doctor.

CHRONIC NON-SPECIFIC DIARRHOEA: (Consult your doctor) With individual adjusted dosage it is usually possible to obtain a virtually normal bowel movement. Starting dose is 1 medicine measure (5 ml) per 12, 5 kg body mass a day for children. The daily dose should be adjusted until 1-2 solid stools per day are obtained. This is usually achieved on a maintenance dose of u00bd - 2 medicine measures (2,5 ml u2013 10 ml) daily. If constipation occurs, the dosage should be decreased.

Elderly No dose adjustment is required for the elderly.

Hepatic impairment Although no pharmacokinetic data are available in patients with hepatic impairment, LOPERASTAT u00ae SYRUP should be used with caution in such patients because of reduced first pass metabolism. (see Section 4.4).

Method of Administration For oral use.

• LOPERASTAT u00ae SYRUP is contraindicated in patients with a known hypersensitivity to the active substance, loperamide hydrochloride or to any of the excipients listed in section 6.1
• LOPERASTATu00ae SYRUP is contraindicated in infants below 24 months of age
• LOPERASTAT u00ae SYRUP should not be used as the primary therapy in patients with acute dysentery, which is characterised by blood in stools and high fever
• LOPERASTAT u00ae SYRUP must not be used:
• in patients with acute ulcerative colitis,
• in patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella, and Campylobacter,
• in patients with pseudomembranous colitis associated with the use of broad spectrum antibiotics.

In general, LOPERASTAT u00ae SYRUP should not be used when inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon and toxic megacolon. LOPERASTAT u00ae SYRUP must be discontinued promptly when constipation, abdominal distension or ileus develop.

Treatment of diarrhoea with LOPERASTAT u00ae SYRUP is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate (or when indicated).

In patients with diarrhoea, especially in infants, fluids and electrolyte depletion may occur. In such cases administration of appropriate fluid and electrolyte replacement (oral rehydration therapy) [ORT] is the most important measure.

LOPERSTAT u00ae SYRUP should not be given to children less than 6 years of age without a medical prescription and supervision. LOPERSTAT u00ae SYRUP is not recommended for routine use in acute or chronic diarrhoea in children under the age of 6 years.

Patients with AIDS treated with LOPERASTAT u00ae SYRUP for diarrhoea should have therapy stopped at the earliest signs of abdominal distension. There have been reports of toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with LOPERASTAT u00ae SYRUP.

Although no pharmacokinetic data are available in patients with hepatic impairment, LOPERASTAT u00ae SYRUP should be used with caution in such patients because of reduced first pass metabolism. Patients with hepatic dysfunction should be monitored closely for signs of central nervous system toxicity. In acute diarrhoea, if clinical improvement is not observed within 48 hours, the administration of LOPERASTAT u00ae SYRUP should be discontinued and patients should be advised to consult their doctor. Patients with hepatic dysfunction should be monitored closely for signs of Central Nervous System toxicity because of the high first-pass metabolism.

Cardiac events including QT and QRS complex prolongation, torsade de pointes have been reported in association with overdose. Some cases had a fatal outcome (see section 4.9). Overdose can unmask existing Brugada syndrome. Patients should not exceed the recommended dose and/or the recommended duration of treatment.

LOPERASTAT u00ae SYRUP contains:

• Glycerol which may cause headache, stomach upset and diarrhoea.
• Methylparahydroxybenzoate and propylparahydroxybenzoate may cause allergic reactions (possibly delayed).
• Small amounts of ethanol (alcohol), less than 100 mg per dose.

Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with quinidine, or navir, which are both P-glycoprotein inhibitors, resulted in a 2 to 3-fold increase in loperamide plasma levels. The clinical relevance of this pharmacokinetic interaction with P-glycoprotein inhibitors, when loperamide is given at recommended dosages (2 mg, up to 16 mg maximum daily dose), is unknown. The concomitant administration of loperamide (4 mg single dose) and itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 3 to 4-fold increase in loperamide plasma concentrations. In the same study a CYP2C8 inhibitor, gemfibrozil, increased loperamide by approximately 2-fold. The combination of itraconazole and gemfibrozil resulted in 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 (i.e., subjective drowsiness and the Digit Symbol Substitution Test). The concomitant administration of loperamide (16 mg single dose) and ketoconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 5-fold increase in loperamide plasma concentrations.

This increase was not associated with increased pharmacodynamic effects as measured by pupillometry. The concomitant administration of loperamide with oral desmopressin may result in a 3-fold increase of desmopressin plasma concentrations, presumably due to slower gastrointestinal motility. It is expected that drugs with similar pharmacological properties may potentiate loperamide's effect and that drugs which accelerate gastrointestinal transit may decrease its effect.

The safety of use during pregnancy and lactation has not been established. Small amounts of loperamide may appear in human breast milk. Therefore, LOPERSTAT u00ae SYRUP is not recommended during breastfeeding. Women who are breast feeding infants should therefore be advised to consult their doctor for appropriate treatment.

Tiredness, dizziness, or drowsiness may occur in the setting of diarrhoeal syndromes treated with LOPERSTAT u00ae SYRUP. Therefore, it is advisable to use caution when driving a car or operating machinery. See section 4.8.

System Organ Class (SOC) Adverse Drug Reaction Frequency

• Immune System Disorders Hypersensitivity reaction, Anaphylactic reaction (including Less frequent
• Nervous System Disorders Headache, Dizziness Frequent
• Somnolence Less frequent
• Loss of consciousness, Stupor, Depressed level of consciousness, Hypertonia, Coordination abnormality Less frequent
• Eye Disorders Miosis Less frequent
• Gastrointestinal Disorders Constipation, Nausea, Flatulence Frequent
• Abdominal pain, Abdominal discomfort, Dry mouth, Abdominal pain upper, Vomiting, Dyspepsia, acute pancreatitis Less frequent
• Ileus (including paralytic ileus), Megacolon (including toxic megacolon u2013 see section 4.4), Abdominal distension Less frequent
• Skin and Subcutaneous Tissue Disorders Rash, Bullous eruption (including Stevens-Johnson syndrome, Toxic epidermal necrolysis and Erythema multiforme), Angioedema, Urticaria, Pruritus Less frequent
• Renal and Urinary Disorders Urinary retention Less frequent
• General Disorders and Administration Site Conditions Fatigue Less frequent

A number of the adverse reactions reported during the clinical investigations and post-marketing experience with loperamide hydrochloride are frequent symptoms of the underlying diarrhoeal syndrome (for example abdominal pain/discomfort, nausea, vomiting, dry mouth, tiredness, drowsiness, dizziness, constipation, and flatulence). These symptoms are often difficult to distinguish from undesirable drug effects.

Paediatric 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 of loperamide hydrochloride used for the treatment of acute diarrhoea. In general, the adverse reactions profile in this patient population was similar to that seen in clinical trials of loperamide hydrochloride in adults and children aged 12 years and over.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Convulsions have been reported in children under the age of two years.

Symptoms In case of overdose (including relative overdose due to hepatic dysfunction), CNS depression (stupor, coordination abnormality, somnolence, miosis, muscular hypertonia, and respiratory depression), constipation, urinary retention and ileus may occur. Children and patients with hepatic dysfunction may be more sensitive to CNS effects than adults.

In individuals who have ingested overdoses of loperamide, cardiac events such as QT interval and QRS complex prolongation, torsades de pointes, other serious ventricular arrhythmias, cardiac arrest and syncope have been observed (see section 4.4). Fatal cases have also been reported.

Treatment In cases of overdose, ECG monitoring for QT interval prolongation should be initiated. If the patient develops respiratory depression, airway obstruction, vomiting with impaired consciousness or other CNS symptoms of overdose, give naloxone urgently. Since the duration of action of loperamide is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone might be indicated. Therefore, the patient should be monitored closely for at least 48 hours in order to detect possible CNS depression. Other measures should be as indicated by the patient's clinical condition.