Loperamide 2 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Loperamide 2 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 2 mg loperamide hydrochloride. Excipients with known effects:
Each tablet contains 100 mg lactose monohydrate. For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
Light green coloured capsule shaped, biconvex uncoated tablets with ‘2’ debossed on one side and score line on other side.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For the symptomatic treatment of acute diarrhoea of any aetiology including acute exacerbations of chronic diarrhoea for periods of up to 5 days in adults and children over 9 years. For the symptomatic treatment of chronic diarrhoea in adults.
4.2 Posology and method of administration
Posology
The tablets should be taken with liquid.
Acute diarrhoea
Adults and children over 12 years
Two tablets (4mg) initially, followed by one tablet (2mg) after every loose stool. The usual dosage is 3-4 tablets per day. The maximum daily dose should not exceed 8 tablets (16mg).
Children 9 to 12 years
One tablet (2mg) four times daily until diarrhoea is controlled (up to 5 days). This dose should not be exceeded.
Further investigation into the cause of the diarrhoea should be considered if there is no improvement within two days of starting treatment with loperamide.
Chronic diarrhoea Adults
Patients may need widely differing amounts of loperamide. The starting dose should be between two and four tablets per day in divided doses, depending on severity. If required, this dose can be adjusted according to result up to a maximum of eight tablets daily.
Having established the patient's daily maintenance dose, loperamide may be administered on a twice daily regimen. Tolerance has not been observed and therefore subsequent dosage adjustment should be unnecessary.
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 should be used with caution in such patients because of reduced first pass metabolism (see section 4.4).
Method of administration Oral use.
4.3 Contraindications
Loperamide is contraindicated in:
• patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients listed in section 6.1.
• children less than 9 years of age.
• Loperamide should not be used as the primary therapy:
o patients with acute dysentery, which is characterised by blood in stools and high fever.
o patients with acute ulcerative colitis.
o patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella and Campylobacter.
o 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..
4.4 Special warnings and precautions for use
Treatment of diarrhoea with loperamide is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate. The priority in acute diarrhoea is the prevention or reversal of fluid and electrolyte depletion. This is particularly important in young children and in frail and elderly patients with acute diarrhoea. Use of loperamide does not preclude the administration of appropriate fluid and electrolyte replacement therapy.
Since persistent diarrhoea can be an indicator of potentially more serious conditions, loperamide 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.
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 from both viral and bacterial pathogens treated with loperamide. 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. Patients with hepatic dysfunction should be monitored closely for sign of central nervous system (CNS) toxicity.
Loperamide must be discontinued promptly when constipation, abdominal distension or ileus develop.
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.
4.5 Interaction with other medicinal products and other forms of interaction
Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with quinidine, or ritonavir, 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, 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.
Concomitant treatment with oral desmopressin resulted in a 3 Dfold 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.
4.6 Fertility, pregnancy and lactation
Fertility
There is no relevant data to demonstrate the effect of loperamide on human fertility. Only high doses of loperamide hydrochloride affected female fertility in non-clinical studies (see section 5.3).
Pregnancy
Safety in human pregnancy has not been established although from animal studies there are no indications that loperamide possesses any 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.
4.7 Effects on ability to drive and use machines
Loss of consciousness, depressed level of consciousness, tiredness, dizziness, or drowsiness may occur when diarrhoea is treated with loperamide. Therefore, it is advisable to use caution when driving a car or operating machinery (see section 4.8).
4.8 Undesirable effects
Adults and children aged > 12 years
The safety of loperamide was evaluated in 3076 adults and children aged > 12 years who participated in 31 controlled and uncontrolled clinical trials of loperamide used for
the treatment of diarrhoea. Of these, 26 trials were in acute diarrhoea (N=2755) and 5 trials were in chronic diarrhoea (N=321).
The most commonly reported (i.e. >1% incidence) adverse reactions in clinical trials with loperamide hydrochloride in acute diarrhoea were: constipation (2.7%), flatulence (1.7%), headache (1.2%) and nausea (1.1%). In clinical trials in chronic diarrhoea, the most commonly reported (i.e. >1% incidence) adverse reactions were: flatulence (2.8%), constipation (2.2%), nausea (1.2%) and dizziness (1.2%).
Table 1 displays adverse reactions that have been reported with the use of loperamide from either clinical trials (in acute or chronic diarrhoea or both) or post-marketing experience.
The frequency categories use the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); and very rare (<1/10,000).
Table 1: Adverse Drug Reactions
|
System Organ Class |
Indication | ||
|
Acute Diarrhoea (N=2755) |
Chronic Diarrhoea (N=321) |
Post marketing Experienc e | |
|
Immune System Disorders | |||
|
Hypersensitivity reaction Anaphylactic reaction (including Anaphylactic shock) Anaphylactoid reaction |
Rare | ||
|
Nervous System Disorders | |||
|
Headache |
Common |
Uncommo n | |
|
Dizziness |
Uncommo n |
Common | |
|
Somnolence |
Uncommo n | ||
|
Loss of consciousness, Stupor, Depressed level of consciousness, Hypertonia, Coordination abnormality. |
Rare | ||
|
Eye Disorders | |||
|
Miosis |
Rare | ||
|
Gastrointestinal Disorders | |||
|
Constipation, Nausea, |
Common |
Common | |
|
Flatulence | |||
|
Abdominal pain, Abdominal discomfort, Dry mouth, |
Uncommo n |
Uncommo n | |
|
Abdominal pain upper, Vomiting. |
Uncommo n | ||
|
Dyspepsia. |
Uncommo n | ||
|
Abdominal distension, |
Rare | ||
|
Ileus (including paralytic ileus), Megacolon (includin g toxic megacolon), Glossodynia |
Rare | ||
|
Skin and Subcutaneous Tissue Disorders | |||
|
Rash |
Uncommo n | ||
|
Bullous eruption (including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme) Angioedema Urticaria Pruritus |
Rare | ||
|
Renal and Urinary Disorders | |||
|
Urinary retention |
Rare | ||
|
General Disorders and Administration Site Conditions | |||
|
Fatigue |
Rare |
Paediatric population
The safety of loperamide was evaluated in 607 patients aged 10 days to 13 years who participated in 13 controlled and uncontrolled clinical trials of loperamide used for the treatment of acute diarrhoea. In general, the adverse reaction profile (ADR) profile in this patient population was similar to that seen in clinical trials of loperamide in adults and children aged 12 years and over.
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.
4.9 Overdose
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 retentionand ileus may occur. Children and patients with hepatic dysfunction may be more sensitive to CNS effects.
Management
If 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 any possible CNS depression.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antipropulsives ATC code: A07DA03
Mechanism of action
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.
Clinical efficacy and safety
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 4 mg dose. Clinical comparisons with other antidiarrhoeal drugs confirmed this exceptionally rapid onset of action of loperamide.
5.2 Pharmacokinetic properties
Absorption
Most ingested loperamide is absorbed from the gut, but as a results of significant first pass metabolism, systemic bioavailability in only approximately 0.3%.
Distribution
Studies on distribution in rats show high affinity for the gut wall with preference for binding to the receptors in 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.
Biotransformation
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 effects,plasma concentrations of unchanged drug remain extremely low.
Elimination
The half-life of loperamide in man is 11 hours with a range of 9-14 hours. Excretion of the unchanged loperamide and the metabolites mainly occurs through the faeces.
5.3 Preclinical safety data
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 - 240 times the maximum human use level) loperamide impaired fertility and foetal survival in association with maternal toxicity in rats. Lower doses had no effects on maternal or foetal health and did not affect peri- and post-natal development.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Maize starch
Lactose monohydrate Povidone (K-30)
Brilliant Blue FCF (E133)
Quinoline Yellow (E104)
Magnesium stearate Talc
Colloidal anhydrous silica Sodium starch glycolate (Type A)
Purified water
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
6.5 Nature and contents of container
Clear PVC/PVdC film/Aluminium blister strips. The blister strips are packed in cartons to contain 12 or 30 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements for disposal
7 MARKETING AUTHORISATION HOLDER
Cipla (EU) Limited,
Hillbrow House,
Hillbrow Road,
Esher,
Surrey,
KT10 9NW
8 MARKETING AUTHORISATION NUMBER(S)
PL 36390/0111
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
04/05/2011
23/09/2015