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LOPERAMIDE 2 MG CAPSULES HARD

Active substance(s): LOPERAMIDE HYDROCHLORIDE / LOPERAMIDE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Loperamide 2 mg Capsules, hard

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 2mg loperamide hydrochloride.
Excipient(s) with known effect:
Each capsule contains 109.00 mg lactose monohydrate.
For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Capsule, hard
Size '4' (about 14 mm in length) Hard gelatin capsule with Green cap imprinted with 'L' in
black ink & grey body imprinted with '2mg' in black ink, containing white to off-white
powder.

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
ACUTE DIARRHOEA
Adults and children over 12:
Two capsules (4 mg) initially, followed by one capsule (2 mg) after each loose stool..
The total daily dose should not exceed 6 capsules (12 mg).
SYMPTOMATIC TREATMENT OF ACUTE EPISODES OF DIARRHOEA
ASSOCIATED WITH IRRITABLE BOWEL SYNDROME IN ADULTS AGED 18
YEARS AND OVER
Two capsules (4 mg) to be taken initially, followed by 1 capsule (2 mg) after every
loose stool, or as previously advised by your doctor. The maximum daily dose should
not exceed 6 capsules (12 mg).
PAEDIATRIC POPULATION
Loperamide 2 mg Capsules are contraindicated in children less than 12 years of age.
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 2 mg Capsules should be used with caution in such patients because of
reduced first pass metabolism (see 4.4 Special warnings and precautions for use).
Method of administration
Oral use.
The capsules should be taken with liquid.
4.3

Contraindications
Loperamide 2 mg Capsules are contraindicated:
• in patients with a known hypersensitivity to loperamide hydrochloride or to any
of the excipients listed in section 6.1.
• in children less than 12 years of age.
• in patients with acute dysentery, which is characterised by blood in stools and
high fever.
• 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 broadspectrum antibiotics.
Loperamide 2 mg Capsules must 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 2 mg Capsules must be discontinued promptly
when ileus, constipation or abdominal distension develops.

4.4

Special warnings and precautions for use
Treatment of diarrhoea with Loperamide 2 mg Capsules 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 this medicine 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 2 mg Capsules should be discontinued and patients
should be advised to consult their doctor.
Patients with AIDS treated with this medicine 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
hydrochloride.
Although no pharmacokinetic data are available in patients with hepatic impairment,
this medicine 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.
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 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 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.
Cardiac events including QT prolongation and Torsades de Pointes have been reported
in association with overdose. Some cases had a fatal outcome (see section 4.9).
Patients should not exceed the recommended dose and/or the recommended duration
of treatment.
Special Warnings to be included on the leaflet:
Only take Loperamide 2 mg 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.

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 4fold increase in loperamide plasma concentrations. In the same study a
CYP2C8 inhibitor, gemfibrozil, increased loperamide by approximately 2fold. 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-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
Pregnancy
Safety in human pregnancy has not been established, although from animal studies
there are no indications that loperamide HCl posseses any teratogenic or embryotoxic
properties. As with other drugs, it is not advisable to administer loperamide 2 mg
Capsules in pregnancy, especially in the first trimester.

Breast-feeding
Small amounts of loperamide may appear in human breast milk. Therefore,
Loperamide 2 mg Capsules 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.

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 this medicine. Therefore, it is
advisable to use caution when driving a car or operating machinery. See Section 4.8,
Undesirable Effects.

4.8

Undesirable effects
Adults and children aged ≥ 12 years
The safety of loperamide HCl was evaluated in 2755 adults and children aged ≥ 12
years who participated in 26 controlled and uncontrolled clinical trials of loperamide
HCl used for the treatment of acute diarrhoea.
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 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
Immune System
Disorders

Indication
Common

Uncommon

Rare
Hypersensitivity reaction a
Anaphylactic reaction

Nervous System
Disorders

Eye Disorders
Gastrointestinal
Disorders

Skin and
Subcutaneous
Tissue Disorders

Headache

Dizziness
Somnolence a

Constipation
Nausea
Flatulence

Abdominal pain
Abdominal
discomfort
Dry mouth
Abdominal pain
upper
Vomiting
Dyspepsia a
Rash

Renal and Urinary
Disorders
General Disorders
and
Administration Site
Conditions

(including Anaphylactic
shock)a
Anaphylactoid reaction a
Loss of consciousness a
Stupor a
Depressed level of
Consciousness a
Hypertonia a
Coordination
abnormality a
Miosis a
Ileus a (including paralytic
ileus)
Megacolon a (including
toxic megacolon b)
Abdominal distension

Bullous eruption a
(including
Stevens-Johnson
syndrome, Toxic
epidermal necrolysis and
Erythema multiforme)
Angioedema a
Urticaria a
Pruritus a
Urinary retention a
Fatigue a

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 (acute and chronic), including trials in children
≤ 12 years (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

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.
In individuals who have ingested overdoses of loperamide HCl, cardiac events such
as QT interval 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 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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Antipropulsives, ATC code: A07DA03
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.
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 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 Ndemethylation 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 914 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 – 20 times the maximum human
use level (MHUL)), based on body surface area dose comparisons (mg/m2),
loperamide impaired fertility and fetal survival in association with maternal toxicity in
rats. Lower doses (≥ 10mg/kg/day – 5 times MHUL) revealedno effects on maternal or
fetal health and did not affect peri- and post-natal development.
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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose monohydrate,
Microcrystalline cellulose,
Maize starch,
Colloidal Anhydrous Silica,
Purified Talc,
Magnesium stearate.

Capsule cap:
Gelatin
Water
Sodium lauryl sulfate
Patent Blue V (E131)
Quinoline Yellow (E104)
Titanium Dioxide (E171)
Capsule body:
Gelatin
Water
Sodium lauryl sulfate
Brilliant Blue FCF (E133)
Iron Oxide Red (E172)
Titanium Dioxide (E171)
Printing ink:
Shellac (E904)
Propylene Glycol (E1520)
Black Iron Oxide (E172)
Potassium Hydroxide (E525)

6.2

Incompatibilities
Not applicable

6.3

Shelf life
24 months

6.4

Special precautions for storage
Store below 25°C. Store in the original package.

6.5

Nature and contents of container
Blister formed from PVC/PVdC and aluminium containing packs of 2, 4 and 6
capsules
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Not applicable.

7

MARKETING AUTHORISATION HOLDER
Flamingo Pharma (UK) Ltd
1st Floor, Kirkland House,
11-15 Peterborough Road,
Harrow, Middlesex,
HA1 2AX, United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 43461/0036

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
17/03/2017

10

DATE OF REVISION OF THE TEXT
13/09/2017

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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