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 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 aged 18 years and over following initial diagnosis by a doctor.
4.2 Posology and method of administration
Posology
The tablets should be taken with liquid.
Acute diarrhoea
Adults and children over 12 years
Take two tablets (4mg) initially, followed by one tablet (2mg) after every loose stool. The maximum daily dose should not exceed 8 tablets (16mg).
Symptomatic treatment of acute episodes of diarrhoea associated with Irritable Bowel Syndrome already diagnosed by a doctor
Adults aged 18 years and over
Two tablets (4mg) to be taken initially, followed by 1 tablet (2mg) after every loose stool, or previously advised by your doctor.
The maximum daily dose should not exceed 8 tablets (16mg).
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 under 12 years of age.
• patients with acute dysentery, which is characterised by blood in stools and high fever.
• patients with acute ulcerative colitis.
• patients with bacterial enterocolitis caused by invasive organisms including
Salmonella, Shigella and Campylobacter.
• 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. This medicine must be used with caution in patients with hepatic impairment as it may result in relative overdose leading to CNS toxicity.
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.
If patients are taking loperamide 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 should be discontinued and they should consult with 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.
Special warnings to be included on the leaflet
Only take loperamide to treat acute episodes of diarrhoea associated with Irritable Bowel Syndrome (IBS) if your doctor has previously diagnosed IBS.
If any of the following apply, do not use the product without first consulting your doctors, 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, or if your symptoms worsen, or your symptoms have not improved over two weeks.
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 (16mg 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 (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.
4.6 Fertility, pregnancy and lactation
It is not advisable to administer this medicine in pregnancy. Women who are pregnant or breast feeding 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 2755 adults and children aged >12 years who participated in 26 controlled and uncontrolled clinical trials of loperamide used for the treatment of acute diarrhoea.
The most commonly reported (i.e. >1% incidence) adverse drug reactions (ADRs) in clinical trials with loperamide 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 from either clinical trial (acute diarrhoea) 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) |
Post-marketing Experience | |
|
Immune System Disorders | ||
|
Hypersensitivity reaction Anaphylactic reaction (including Anaphylactic shock) Anaphylactoid reaction |
Rare a | |
|
Nervous System Disorders | ||
|
Headache |
Common | |
|
Dizziness |
Uncommon | |
|
Somnolence |
Uncommon a | |
|
Loss of consciousness, Stupor, Depressed level of consciousness, Hypertonia, Coordination abnormality. |
Rare a | |
|
Eye Disorders | ||
|
Miosis |
Rare a | |
|
Gastrointestinal Disorders | ||
|
Constipation, Nausea, Flatulence |
Common | |
|
Abdominal pain, Abdominal discomfort, Dry mouth, Abdominal pain upper, Vomiting. |
Uncommon | |
|
Dyspepsia. |
Uncommon a | |
|
Abdominal distension, Ileus (including paralytic ileus), Megacolon (including toxic megacolon b), Glossodynia |
Rare a | |
|
Skin and Subcutaneous Tissue Disorders | ||
|
Rash |
Uncommon | |
|
Bullous eruption (including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme) Angioedema Urticaria Pruritus |
Rare a | |
|
Renal and Urinary Disorders | ||
|
Urinary retention |
Rare a | |
|
General Disorders and Administration Site Conditions | ||
|
Fatigue |
Rare a | |
|
a. Inclusion of this term is based on post-mar |
ceting reports for loperamide. 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 (acute and chronic), including trials in children < 12 years (N=3683).
b' See section 4.4.
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 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 retention and 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 4mg 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 result 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 effect, 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
No relevant information additional to that contained elsewhere in the Summary of Product Characteristics.
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 6 tablets.
7
MARKETING AUTHORISATION HOLDER
Cipla (EU) Limited,
Hillbrow House,
Hillbrow Road,
Esher,
Surrey,
KT10 9NW
8
9
10