IMODIUM PLUS CHEWABLE TABLETS

Active substance: SIMETICONE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Imodium Plus Chewable Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each chewable tablet contains loperamide hydrochloride 2 mg and simeticone
equivalent to 125 mg dimeticone.
Excipients: include 300 mg sorbitol (E420) and approximately 50 mg sucrose.

For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Chewable tablet.
White, round, flat-faced tablets with a vanilla-mint odour debossed with “IMO” on
one side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Imodium Plus is indicated for the symptomatic treatment of acute diarrhoea in
adults and adolescents over 12 years when acute diarrhoea is associated with
gas-related abdominal discomfort including bloating, cramping or flatulence.

4.2

Posology and method of administration
Adults over 18 years
Chew two tablets initially, followed by one tablet after every loose stool. Not
more than 4 tablets should be taken in a day, limited to no more than 2 days.
Adolescents between 12 and 18 years

Chew one tablet initially, followed by one tablet after every loose stool. Not
more than 4 tablets should be taken in a day, limited to no more than 2 days.
Use in children
Imodium Plus must not be used in children under 12 years.
Use in the elderly
No dosage adjustments are required for the elderly.
Renal impairment
No dosage adjustment is necessary in renal impairment.
Hepatic impairment
Although no pharmacokinetic data are available in patients with hepatic
insufficiency, Imodium Plus should be used with caution in such patients
because of reduced first pass metabolism (see 4.4 Special warnings and special
precautions for use).

4.3

Contraindications
Imodium Plus must not be used in:
• Children less than 12 years of age
• Patients with a known hypersensitivity (allergy) to loperamide
hydrochloride, simeticone or any of the excipients
• Patients with acute dysentery, which is characterised by blood in stool
and high fever
• Patients with acute ulcerative colitis
• Patients with pseudomembranous colitis associated with broad
spectrum antibiotics
• Patients with bacterial enterocolitis caused by invasive organisms
including Salmonella, Shigella and Campylobacter
Imodium Plus 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. It must be discontinued promptly if
constipation, ileus or abdominal distension develop.

4.4

Special warnings and precautions for use
Treatment of diarrhoea with loperamide-simeticone is only symptomatic.
Whenever an underlying etiology can be determined, specific treatment should
be given when appropriate.

In patients with (severe) diarrhoea, fluid and electrolyte depletion may occur.
It is important that attention is paid to appropriate fluid and electrolyte
replacement.
If clinical improvement is not observed within 48 hours, the administration of
Imodium Plus must be discontinued. Patients should be advised to consult
their physician.
Patients with AIDS treated with Imodium Plus 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, Imodium Plus 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 a relative
overdose leading to central nervous system (CNS) toxicity. Imodium Plus
should be used under medical supervision in patients with severe hepatic
dysfunction.
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 concentrations. 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 measured 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.

Since simeticone is not absorbed from the gastrointestinal tract, no relevant
interactions between simeticone and other drugs are expected.

4.6

Pregnancy and lactation
Use in pregnancy
Safety in human pregnancy has not been established, although from animal studies
there are no indications that loperamide or simeticone possesses teratogenic or
embryotoxic properties. Imodium Plus should not be given during pregnancy,
especially during the first trimester, unless clinically justified.
Use in lactation
Small amounts of loperamide may appear in human breast milk. Therefore Imodium
Plus is not recommended during breast-feeding.

4.7.

Effects on ability to drive and use machines
Tiredness, dizziness and drowsiness have been reported in patients taking
loperamide. If affected, patients should not drive or operate machinery. See
Section 4.8 Undesirable effects.

Undesirable effects
The safety of loperamide-simeticone was evaluated in 2040 patients who participated
in five clinical trials. All trials were in patients with acute diarrhoea with gas related
discomfort and with a chewable tablet loperamide-simeticone formulation. Four trials
compared loperamide-simeticone with loperamide, simeticone and placebo and one
trial compared two formulations of loperamide-simeticone with placebo.

The most commonly reported (i.e., 1% incidence) ADRs in clinical trials were (with



% incidence): dysgeusia (2.6%) and nausea (1.6%).

The safety of loperamide HCl was evaluated in 2755 patients aged



4.8

12 years who

participated in 26 controlled and uncontrolled clinical trials of loperamide HCl used
for the treatment of acute diarrhoea. The most common ADRs (>1%) reported in
these clinical trials were constipation (2.7%), flatulence (1.7%), headache (1.2%), and
nausea (1.1%).

The safety of loperamide HCl was also evaluated in 321 patients who participated in 5
controlled and uncontrolled clinical trials of loperamide HCl used for the treatment of
chronic diarrhoea. The most common ADRs (>1%) reported in these clinical trials
were flatulence (2.8%), constipation (2.2%), dizziness (1.2%), and nausea (1.2%).

The safety of loperamide HCl was evaluated in 607 patients aged 10 days to 13 years
who participated in 13 controlled and uncontrolled clinical trials of loperamide HCl

loperamide HCl-treated patients was vomiting.



used for the treatment of acute diarrhoea. The only ADR reported for

1% of

Table 1 displays ADRs that have been reported with the use of loperamide-simeticone
from either clinical trial or post-marketing experience. Additional ADRs reported
with the use of loperamide HCl (one of the components of loperamide-simeticone)
are also shown.

The frequency categories are based on clinical trial data with loperamide – simeticone
and loperamide HCl and 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
Common

Adverse events
Frequency
Uncommon

Immune System
Disorders

Nervous System
Disorders

Headacheb, Dysgeusia

Somnolencea,
Dizzinessc

Skin and
Subcutaneous Tissue
Disorders

Renal and Urinary
Disorders
General Disorders
and Administration
Site Conditions

Loss of consciousnessa,
Depressed level of
consciousnessa, Stupora,
Hypertoniaa, Coordination
abnormalitya
Miosisa

Eye Disorders
Gastrointestinal
Disorders

Rare
Hypersensitivity reactiona,
Anaphylactic reaction
(including Anaphylactic
shock)a, Anaphylactoid
reactiona

Nausea

Ileusa (including paralytic
Abdominal pain,
b
Abdominal discomfort , ileus), Megacolona
Abdominal pain upperb, (including toxic
Vomiting, Constipation, megacolond)
Abdominal distensionc,
Dyspepsiac, Flatulence,
Dry mouth
Rash

Bullous eruption
(including StevensJohnson syndromea, Toxic
epidermal necrolysisa and
Erythema multiformea),
Angioedemaa, Urticariaa,
Pruritusa
Urinary retentiona

Asthenia

Fatiguea

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 ≤ 12 years (N=3683).
b: Inclusion of this term is based on ADRs reported in clinical trials with loperamide HCl.
Frequency category assigned based on clinical trials with loperamide HCl in acute diarrhoea
(N=2755).
c: Inclusion of this term is based on post-marketing experience with loperamide-simeticone.
Frequency category assigned based on clinical trials with loperamide – simeticone in acute
diarrhoea (N = 618). Dizziness and abdominal distension were also identified as clinical trial
ADRs with loperamide HCl.
d: See section 4.4 Special Warnings and Special Precautions for use.

4.9

Overdose
Symptoms
In case of overdosage (including relative overdosage due to hepatic
dysfunction), central nervous system depression (stupor, co-ordination
abnormality, somnolence, miosis, muscular hypertonia, respiratory
depression), dry mouth, abdominal discomfort, nausea and vomiting,
constipation, urinary retention and paralytic ileus may occur. Children may be
more sensitive to CNS effects than adults.
Treatment
If symptoms of overdosage 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 may 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: Antipropulsive antidiarrheals, ATC code: A07D A53
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 does not change the physiological flora. Loperamide
increases the tone of the anal sphincter. Imodium Plus does not act centrally.

Simeticone is an inert surface-active agent with anti-foaming properties thereby
potentially relieving gas-related symptoms associated with diarrhoea.

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%. The simeticone component of loperamide-simeticone is
not absorbed.
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.

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 reproductive toxicity studies in rats, very high doses of
loperamide, associated with maternal toxicity, impaired fertility and foetal
survival. Lower doses had no effects on maternal or foetal health and did not
affect peri- and post-natal development.
Simeticone is a member of the class of linear polydimethylsilicones, which
have been in wide general and medicinal use for many years and are regarded
as biologically inert and not exhibiting toxic properties and has not been the
subject of specific animal toxicity studies.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Sucrose and corn starch
Microcrystalline cellulose
Basic butylated methacrylate copolymer
Cellulose acetate
Sorbitol (E420)
Dextrates
Natural and artificial vanilla mint flavour (including sucrose, maltodextrin,
modified corn starch, corn syrup solids, polyglycerol ester of fatty acids,
calcium phosphate, enzyme modified milk powder)
Saccharin sodium
Stearic acid
Calcium phosphate.

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 storage conditions.

6.5

Nature and contents of container
Chewable tablets are packaged in non child resistant push through blisters.
The blister consists of: ACLAR/PVC film, aluminium foil and heat seal
coating. The heat seal coating contains vinyl and acrylic.
Blister strips of 2,4,5 or 6 tablets in packs of 2, 4, 5, 6, 8, 10, 12, 15, 16, 18
and 20 tablets packed in printed cardboard cartons.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
McNeil Products Limited
Foundation Park,
Roxborough Way
Maidenhead
Berkshire
SL6 3UG
United Kindgom

8

MARKETING AUTHORISATION NUMBER(S)
PL 15513/0344

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
01/09/2007

10

DATE OF REVISION OF THE TEXT
09/05/2013

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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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