Lomodine 2mg capsules

For the symptomatic treatment of acute diarrhoea in adults and children aged 12 years and over.

For the symptomatic treatment of acute episodes of diarrhoea associated with Irritable Bowel Syndrome in adults and children aged 18 years and over following initial diagnosis by a doctor.

The capsules should be taken with liquid.

Acute diarrhoea:

Adults and children over 12 years: two capsules (4mg) initially, followed by 1 capsule (2mg) after every loose stool. The usual dosage is 3 to 4 capsules (6mg-8mg) a day; the maximum daily dose should not exceed 6 capsules (12mg).

Symptomatic treatment of acute episodes of diarrhoea associated with Irritable Bowel Syndrome in adults and children aged 18 years and over:

Two capsules (4mg) to be taken initially, followed by 1 capsule (2mg) after every loose stool, or as previously advised by your doctor.

The maximum daily dose should not exceed 6 capsules (12mg). If symptoms persist for more than 48 hours consult your doctor.

Use in elderly: No dose adjustment is required for the elderly.

Renal impairment

No dose adjustment is required for patients with renal impairment.

Hepatic impairment

Although no pharmacokinetic data are available in patients with hepatic impairment, Loperamide hydrochloride should be used with caution in such patients because of reduced first pass metabolism (see section 4.4 special warnings and special precautions for use).

Method of administration

Oral use

LoModine 2mg capsules are contraindicated:

• in patients with known hypersensitivity to loperamide hydrochloride or to any of the excipients

• in children aged less than 12 years

• in patients with acute dysentery which is characterised by blood in stools and elevated body temperature.

• when ileus or constipation are present or when abdominal distension develops, especially in severely dehydrated children

• 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.

Loperamide 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. Loperamide must be discontinued promptly when constipation, abdominal distension or ileus develop.

Treatment of diarrhoea with Loperamide is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate.

Cardiac events including QT interval and QRS complex prolongation and torsades 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.

In patients with acute diarrhoea, especially in children, and in the frail and elderly fluid and electrolyte depletion may occur. In such cases administration of appropriate fluid and electrolyte replacement therapy is the most important measure. Loperamide should not be given to children under 12 years without medical prescription and supervision. Use of this product does not preclude the administration of appropriate fluid and electrolyte replacement therapy.

Since persistent diarrhoea can be an indicator of potentially more serious conditions, this medicine should not be used for prolonged periods until the underlying cause of the diarrhoea has been investigated.

In acute diarrhoea, if clinical improvement is not observed within 48 hours, the administration of Loperamide should be discontinued and patients should be advised to consult their doctor.

If patients are taking this medicine to control episodes of diarrhoea associated with Irritable Bowel Syndrome previously diagnosed by their doctor, and clinical improvement is not observed within 48 hours, the administration of Loperamide HCl should be discontinued and they should consult their doctor. Patients should also return to their doctor if the pattern of their symptoms changes or if the repeated episodes of diarrhoea continue for more than two weeks.

Patients with AIDS treated with Loperamide for diarrhoea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of obstipation with an increased risk for toxic megacolon in AIDS patients with infectious colitis (viral or bacterial pathogens) treated with loperamide hydrochloride.

Although no pharmacokinetic data are available in patients with hepatic impairment, Loperamide should be used with caution in such patients because of reduced first pass metabolism, as it may result in a relative overdose leading to CNS toxicity.

Excipients

LoModine 2mg Capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicine because it contains lactose.

Special Warnings to be included in the leaflet:

Only take LoModine 2mg Capsules to treat acute episodes of diarrhoea associated with Irritable Bowel Syndrome if your doctor has previously diagnosed IBS.

If any of the following now apply, do not use the product without first consulting your doctor, even if you know you have IBS:

• If you are aged 40 or over and it is some time since your last IBS attack

• If you are aged 40 or over and your IBS symptoms are different this time

• If you have recently passed blood from the bowel

• If you suffer from severe constipation

• If you are feeling sick or vomiting

• If you have lost your appetite or lost weight

• If you have difficulty or pain passing urine

• If you have a fever

• If you have recently travelled abroad

Consult your doctor if you develop new symptoms, if your symptoms worsen, or your symptoms have not improved over two weeks.

Caution is needed in patients with a history of drug abuse. Abuse and misuse of loperamide has been described (see section 4.9). Loperamide is an opioid with low bioavailability and limited potential to penetrate the blood brain barrier at therapeutic doses. However, addiction is observed with opioids as a class.

Effect of other medications on loperamide

In vitro studies have shown that loperamide is metabolised by cytochrome P450 3A4 and 2C8 enzymes and is a substrate for P-glycoprotein.

Opioid–like central nervous system effects have been reported in volunteer studies with concomitant administration of loperamide (16mg or 24mg single dose) with quinidine (600mg or 800mg). Quinidine may increase penetration of loperamide into the brain due to inhibition of central P-glycoprotein. The clinical significance of the pharmacokinetic interaction with P-glycoprotein inhibitors when loperamide is given at recommended dosages (2mg, up to 16mg maximum daily dose) is unknown.

Concomitant administration of loperamide 16mg and ritonavir, an inhibitor of both P-glycoprotein and CYP3A4, resulted in a two to three-fold increase in the AUC of loperamide but without evidence of enhanced central nervous system effect.

The concomitant administration of loperamide (4mg 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 (16mg 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.

Concomitant treatment with oral desmopressin resulted 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 that accelerate gastrointestinal transit may decrease its effect.

Pregnancy

Although there are no indications that loperamide possesses teratogenic or embryotoxic properties, as with other drugs, it is not advisable to administer loperamide in pregnancy, especially during the first trimester.

Breast-feeding

Small amounts of loperamide may appear in human breast milk. Therefore, loperamide is not recommended during breast feeding.

Women who are pregnant or breast-feeding infants should therefore be advised to consult their doctor for appropriate treatment.

Fertility

The effect on human fertility has not been evaluated.

Tiredness, loss of consciousness, depressed level of consciousness, dizziness or drowsiness may occur in the setting of diarrheal syndromes treated with Loperamide. Therefore, it is advisable to use caution when driving a car or operating machinery(See section 4.8, Undesirable effects).

The most commonly reported (i.e. ≥ 1% incidence) adverse drug reactions (ADRs) in clinical trials with loperamide HCl in acute diarrhoea were: constipation (2.7%), flatulence (1.7%), headache (1.2%) and nausea (1.1%).

Table 1 displays ADRs that have been reported with the use of loperamide HCl from either clinical trial (acute diarrhea or both) or post-marketing experience.

The frequency categories use the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/l,000 to <1/100); rare (≥1/10,000 to <1/1.000); and very rare <1/10,000); not known (cannot be estimated from the available data).

Table 1: Adverse Drug Reactions

a: Inclusion of this term is based on post-marketing reports for loperamide HCL. As the process for determining post marketing ADRs did not differentiate between chronic and acute indications or adults and children the frequency is estimated from all clinical trials with loperamide HCl combined, including trials in children : ≤12years (N=3683).

b: See section 4.4 Special Warnings and Special Precautions for use.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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.

In individuals who have ingested overdoses of loperamide HCl, 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. Overdose can unmask existing Brugada syndrome.

Upon cessation, cases of drug withdrawal syndrome have been observed in individuals abusing, misusing, or intentionally overdosing with excessively large doses of loperamide.

Treatment

If symptoms of overdose occur, ECG monitoring for QT interval prolongation should be initiated.

If CNS symptoms of overdose occur, naloxone can be given as an antidote. 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.

Pharmacotherapeutic Group: Antipropulsives, ATC code: A07D A03

Loperamide binds to the opiate receptor in the gut wall, reducing propulsive peristalsis, increasing intestinal transit time and enhancing resorption of water and electrolytes. Loperamide increases the tone of the anal sphincter, which helps reduce faecal incontinence and urgency. Studies remain to be done to show the value of loperamide in acute infective diarrhoea. It should not be used to treat young children.

Loperamide is also used in ileostomy management to control the volume in discharge.

In a double blind randomised clinical trial in 56 patients with acute diarrhoea receiving loperamide, onset of anti-diarrhoeal action was observed within one hour following a single 4mg dose. Clinical comparisons with other antidiarrhoeal drugs confirmed this exceptionally rapid onset of action of loperamide.

Absorption: Most ingested loperamide is absorbed from the gut, but as a result of significant first pass metabolism, systemic bioavailability is only approximately 0.3%.

Distribution: Studies on distribution in rats show a high affinity for the gut wall with a preference for binding to receptors of the longitudinal muscle layer. The plasma protein binding of loperamide is 95%, mainly to albumin. Non-clinical data have shown that loperamide is a P-glycoprotein substrate.

Metabolism: loperamide is almost completely extracted by the liver, where it is predominantly metabolized, conjugated and excreted via the bile. Oxidative N- demethylation is the main metabolic pathway for loperamide, and is mediated mainly through CYP3A4 and CYP2C8. Due to this very high first pass effect, plasma concentrations of unchanged drug remain extremely low.

Elimination: The half-life of loperamide in man is about 11 hours with a range of 9-14 hours. Excretion of the unchanged loperamide and the metabolites mainly occurs through the faeces.

Non-clinical in vitro and in vivo evaluation of loperamide indicates no significant cardiac electrophysiological effects within its therapeutically relevant concentration range and at significant multiples of this range (up to 47-fold).

However, at extremely high concentrations associated with overdoses (see section 4.4), loperamide has cardiac electrophysiological actions consisting of inhibition of potassium (hERG) and sodium currents, and arrhythmias.

Acute and chronic studies on loperamide showed no specific toxicity. Results of in vivo and in vitro studies carried out indicated that loperamide is not genotoxic. In reproduction studies, very high doses (40 mg/kg/day – 20 times the maximum human use level (MHUL)), based on body surface area dose comparison (mg/m²).

loperamide impaired fertility and foetal survival in association with maternal toxicity in rats. Lower doses (≥ 10mg/kg/day – 5 times MHUL) revealed had no effects on maternal or foetal health and did not affect peri- and post-natal development.

Lactose monohydrate

Maize starch

Magnesium stearate

Cap:

Quinoline yellow oxide (E104)

Indigo carmine (E132)

Titanium dioxide (E171)

Gelatin

Body:

Erythrosine (E127)

Indigo carmine (E132)

Black iron oxide (E172)

Titanium dioxide (E171)

Gelatin

None known

48 months

Do not store above 25°C

White, opaque PVC 250µm/hard temper aluminium foil 25µm blister packs

Blister packaging: 4, 6, 8, 10 and 12

Not all pack sizes may be marketed

No specific instructions for use/handling