PRODUCT MONOGRAPH

Children’s MOTRIN® Cold

ibuprofen and pseudoephedrine hydrochloride oral suspension

100 mg/5 mL ibuprofen and

15 mg/5 mL pseudoephedrine hydrochloride

Analgesic/Antipyretic and
Decongestant

McNeil Consumer Healthcare, Date of Revision:

Division of Johnson & Johnson Inc. March 4, 2010
88 McNabb St
Markham, Ontario
L3R 5L2

Submission Control No: 136747

 Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION.........................................................3

SUMMARY PRODUCT INFORMATION ........................................................................3
INDICATIONS AND CLINICAL USE..............................................................................3
CONTRAINDICATIONS ...................................................................................................3
WARNINGS AND PRECAUTIONS..................................................................................5
ADVERSE REACTIONS..................................................................................................12
DRUG INTERACTIONS ..................................................................................................17
DOSAGE AND ADMINISTRATION ..............................................................................20
OVERDOSAGE ................................................................................................................20
ACTION AND CLINICAL PHARMACOLOGY ............................................................21
STORAGE AND STABILITY..........................................................................................26
SPECIAL HANDLING INSTRUCTIONS .......................................................................26
DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................26

PART II: SCIENTIFIC INFORMATION ...............................................................................27

PHARMACEUTICAL INFORMATION..........................................................................27
CLINICAL TRIALS..........................................................................................................28
DETAILED PHARMACOLOGY .....................................................................................33
MICROBIOLOGY ............................................................................................................34
TOXICOLOGY .................................................................................................................34
REFERENCES ..................................................................................................................39

PART III: CONSUMER INFORMATION..............................................................................46

 Children’s MOTRIN® Cold
ibuprofen and pseudoephedrine hydrochloride oral suspension

100mg/5 mL ibuprofen and

15 mg/5 mL pseudoephedrine hydrochloride

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of Dosage Form / Clinically Relevant Nonmedicinal

Administration Strength Ingredients
oral 100mg/5 mL None
ibuprofen and 15 mg/5
mL pseudoephedrine For a complete listing see Dosage Forms,
hydrochloride oral Composition and Packaging section.
suspension

INDICATIONS AND CLINICAL USE

Children’s MOTRIN® Cold (ibuprofen and pseudoephedrine hydrochloride) is indicated for:

ƒ effective relief of symptoms associated with the common cold, flu, or sinusitis, including
nasal and sinus congestion, stuffy nose, headache, sore throat, body aches and pains, and
for the temporary reduction of fever in pediatric patients aged 4 to 11 years of age.

CONTRAINDICATIONS

ƒ Children’s MOTRIN® Cold should not be used in patients:

ƒ who are hypersensitive to ibuprofen, pseudoephedrine hydrochloride, other non-steroidal

anti-inflammatory drugs, or to any ingredient in the formulation. For a complete listing
of ingredients, see the Dosage Forms, Composition and Packaging section of the product
monograph. The potential for cross-reactivity between different NSAIDs must be kept
in mind.

ƒ with kidney disease and or who have suffered significant fluid loss.

ƒ with the complete or partial syndrome of acetylsalicylic acid (ASA) intolerance

(rhinosinusitis, urticaria/angioedema, nasal polyps, asthma) in whom asthma,
anaphylaxis, urticaria/angioedema, rhinitis or other allergic manifestations are

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 precipitated by ASA or other nonsteroidal anti-inflammatory agents. Fatal anaphylactoid
reactions have occurred in such individuals. As well, individuals with the above medical
problems are at risk of a severe reaction even if they have taken NSAIDs in the past
without any adverse effects.

ƒ with active gastric or duodenal ulcer, a history of recurrent ulceration, or active

inflammatory disease of the gastrointestinal system.

ƒ with significant hepatic impairment or active liver disease.

ƒ severely impaired or deteriorating renal function (creatinine clearance <30 ml/min).

ƒ Ibuprofen should not be used in the presence of known hyperkalemia (also see Warnings
and Precautions – Renal section).

ƒ Children with kidney disease and/or who have suffered significant fluid loss.

ƒ Children’s MOTRIN® Cold should not be used during pregnancy because its safety
under this condition has not been established. Ibuprofen levels in breast milk are
extremely low and are unlikely to affect a nursing infant, however because its safety
under these conditions has not been established, consult a physician before use in
nursing mothers.

ƒ Children’s MOTRIN® Cold should not be used in patients with hypertension, coronary
artery disease and in patients on monoamine oxidase inhibitor (MAOI) therapy.

ƒ Ibuprofen is contraindicated in patients with Systemic Lupus Erythematosus as an

anaphylaxis-like reaction with fever may occur, particularly when ibuprofen has been
previously administered. Aseptic meningitis has also been reported.

WARNINGS AND PRECAUTIONS

Although this product is intended for a pediatric population, ibuprofen and pseudoephedrine
should be used only under the supervision of a physician in patients with the following
conditions:

• Patients with heart disease, high blood pressure, thyroid disease, narrow angle glaucoma
or difficulty in urination due to enlargement of the prostate gland should not take this
drug unless directed by a physician (see Warnings and Precautions – General).

• Caution in patients with heart failure, hypertension or other conditions predisposing to

fluid retention (see Warnings and Precautions – Cardiovascular and Drug Interactions –
Anti-hypertensives).

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 • Caution in patients prone to gastrointestinal tract irritation, particularly those with a
history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal
tract such as ulcerative colitis and Crohn’s disease (see Warnings and Precautions –
Gastrointestinal and Drug Interactions).

• Patients at greatest risk of renal toxicity are those with impaired renal function, heart
failure, liver dysfunction, those taking diuretics and the elderly (see Warnings and
Precautions – Renal).

• If persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria and
cystitis occur, the drug should be stopped immediately (see Warnings and Precautions –
Genitourinary).

• Ibuprofen use during pregnancy/nursing should be avoided (see Warnings and

Precautions – Special Populations: Pregnant Women and Nursing Women).

General
Several medical conditions which can predispose patients to the adverse effects of non-steroidal
anti-inflammatory drugs in general may be applicable to ibuprofen.

Children’s MOTRIN® Cold should be used with caution in patients with a history of cardiac
failure or kidney disease because of the possibility of aggravating pre-existing states of fluid-
retention or edema. Mild impairment of renal function (decreased renal blood flow and
glomerular filtration rate) can occur at maximal doses of ibuprofen. Renal papillary necrosis has
been reported.

Patients with underlying medical or pharmacologically-induced hemostatic defects could also

experience further prolongation of bleeding time through the inhibition of platelet aggregation
induced to varying degrees by this class of drugs.

Long-term ingestion of combinations of analgesics has been associated with the condition
analgesic nephropathy. It is therefore appropriate that patients be discouraged from long-term
unsupervised consumption of analgesics, particularly in combination. Patients should be
directed to consult a physician if their underlying condition requires administration of Children’s
MOTRIN® Cold for more than 5 days. Children’s MOTRIN® Cold usually should not be
administered along with acetaminophen or acetylsalicylic acid.

Patients with any serious medical condition should consult a physician before using Children’s
MOTRIN® Cold. There is a possibility of insomnia, if this medicine is taken before bedtime.

Carcinogenesis and Mutagenesis

See Toxicology Section.

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Cardiovascular
Some patients with pre-existing hypertension may develop worsening of blood pressure control
when placed on an NSAID and regular monitoring of blood pressure should be performed under
such circumstances. NSAIDs may exacerbate congestive heart failure.

Patients who are taking low-dose ASA as cardio protective therapy should consult with a health
professional prior to taking ibuprofen (see also Drug Interactions - Acetylsalicylic Acid).
Patients with high blood pressure or heart disease should take Children’s MOTRIN® Cold only
under the advice and supervision of a physician. Conditions such as congestive heart failure and
hypertension may be aggravated by sodium retention and edema caused by ibuprofen in such
patients.

Dependence/Tolerance
Not applicable.

Ear/Nose/Throat
Not applicable.

Endocrine and Metabolism

Patients with thyroid disease should take Children’s MOTRIN® Cold only under the advice and
supervision of a physician.

If Children’s MOTRIN® Cold is taken in conjunction with prolonged corticosteroid therapy and
it is decided to discontinue this therapy, the corticosteroid should be tapered slowly to avoid
exacerbation of disease or adrenal insufficiency.

Gastrointestinal
Serious GI toxicity, such as ulceration, perforation, obstruction and gastrointestinal bleeding,
sometimes severe and occasionally fatal, can occur at any time, with or without symptoms in
patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen.

GI symptoms, such as dyspepsia, are common, usually developing early in therapy. Health
providers should remain alert for ulceration and bleeding in patients treated with non-steroidal
anti-inflammatory drugs, even in the absence of previous GI tract symptoms.

In patients observed in clinical trials of such agents, symptomatic upper GI ulcers, gross
bleeding, or perforation occur in approximately 1% of patients treated for 3-6 months and in
about 2-4% of patients treated for one year. The risk continues beyond one year. The incidence
of these complications is related to dose, past history of known ulcer disease, and advanced age
(see Special Populations). Studies have shown that the use of oral corticosteroids increases the
risk of upper gastrointestinal complications associated with NSAIDs.

Ibuprofen should be given under close medical supervision to patients with a history of ulcer of
the upper gastrointestinal tract or inflammatory disease of the gastrointestinal tract such as

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ulcerative colitis and Crohn's disease. In these cases the health provider must weigh the benefits
of treatment against the possible hazards.

Health providers should inform patients about the signs and symptoms of serious GI toxicity and
instruct them to contact a health provider immediately if they experience persistent dyspepsia or
other symptoms or signs suggestive of gastrointestinal ulceration or bleeding.

Because serious GI tract ulceration and bleeding can occur without warning symptoms, health
providers should follow chronically treated patients and watch for the signs and symptoms of
ulceration and bleeding and should inform the patients of the importance of this follow-up.

If ulceration is suspected or confirmed, or if GI bleeding occurs ibuprofen should be

discontinued immediately, appropriate treatment instituted and the patient monitored closely.

No studies, to date, have identified any group of patients not at risk of developing ulceration and
bleeding. The major risk factors are a prior history of serious GI events and increasing age.
Possible risk factors include Helicobacter pylori infection, excess alcohol intake, smoking, and
concomitant oral steroids, anti-coagulants, anti-platelet agents (including ASA), or selective
serotonin reuptake inhibitors (SSRIs).

The administration of ibuprofen with food or milk is recommended since occasional and mild
heartburn, upset stomach or stomach pain may occur with its use. Patients should be advised to
seek the consultation of a physician if gastrointestinal side effects occur consistently, persist, or
appear to worsen.

Patients taking ibuprofen should be cautioned to report to their physician signs or symptoms of
GI intolerance and/or bleeding.

Patients taking oral corticosteroids should consult with a health professional before taking
ibuprofen. Studies have shown that the use of oral corticosteroids increases the risk of upper
gastrointestinal complications associated with NSAIDs.

Genitourinary
Some NSAIDs are associated with persistent urinary symptoms (bladder pain, dysuria, urinary
frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the
initiation of therapy with an NSAID. Should urinary symptoms occur, in the absence of an
alternate explanation, treatment with ibuprofen should be stopped to ascertain if symptoms
disappear. This should be done before urological investigations or treatments are considered.

Hematologic
Children’s MOTRIN® Cold, like other nonsteroidal anti-inflammatory agents, can inhibit platelet
aggregation but the effect is quantitatively less than that seen with acetylsalicylic acid.
Ibuprofen has been shown to prolong bleeding time (but within the normal range) in normal
subjects. Because this prolonged bleeding effect may be exaggerated in patients with underlying

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haemostatic defects, Children’s MOTRIN® Cold should be avoided by persons with intrinsic
coagulation defects and by those on anticoagulant therapy.

Hepatic/Biliary/Pancreatic
Patients with diabetes should take Children’s MOTRIN® Cold only under the advice and
supervision of a physician.

As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver
enzyme tests (AST, ALT, ALP) may occur in up to 15% of patients. These abnormalities may
progress, may remain essentially unchanged, or may be transient with continued therapy.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal
liver test has occurred, should be evaluated for evidence of the development of a more severe
hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and
cases of fatal hepatitis have been reported with nonsteroidal anti-inflammatory drugs.

Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and
symptoms consistent with liver disease develop (e.g. jaundice), or if systemic manifestations
occur (e.g. eosinophilia, associated with rash, etc.), this drug should be discontinued.

If there is a need to prescribe this drug in the presence of impaired liver function, it must be done
under strict observation.

Immune
Anaphylactoid reactions have occurred after administration of ibuprofen to patients with known
acetylsalicylic acid or other NSAID sensitivity manifested as asthma, swelling, shock or hives.
Patients sensitive to any one of the nonsteroidal anti-inflammatory drugs may be sensitive to any
of the other NSAIDs also.

As with NSAIDs in general, some patients may experience urticaria and angioedema upon
exposure to ibuprofen. Ibuprofen should not be given to patients with the complete or partial
syndrome of ASA-intolerance (see Contraindications).

Neurologic
Some patients may experience drowsiness, dizziness, blurred vision, vertigo, tinnitus or hearing
loss with the use of ibuprofen. If patients experience these side effects, they should exercise
caution in carrying out activities that require alertness.

In occasional rare cases, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck,
severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed.
Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissues
diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the health provider must be
vigilant to the development of this complication.

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Ophthalmologic
Blurred and/or diminished vision, scotoma, and/or changes in colour vision have been reported.
If a patient develops such complaints while taking Children’s MOTRIN® Cold, the drug should
be discontinued. Patients with any visual disturbances should have an ophthalmologic
examination.

Peri-Operative Considerations
In general, NSAIDS should be discontinued prior to surgeries to decrease the risk of post-
operative bleeding.

Psychiatric
Not applicable.

Renal
Like other non-steroidal anti-inflammatory agents, ibuprofen inhibits renal prostaglandin
synthesis which may decrease renal function and cause sodium retention.

Long-term ingestion of combinations of analgesics has been associated with the condition
analgesic nephropathy. It is therefore appropriate that patients be discouraged from long-term
unsupervised consumption of analgesics, particularly in combination. Patients should therefore
be directed to consult a physician if their underlying condition requires administration of
Children’s MOTRIN® Cold for more than 5 days. Children’s MOTRIN® Cold usually should
not be administered along with acetaminophen or acetylsalicylic acid.

Advanced age, hypertension, use of diuretics, diabetes, atherosclerotic cardiovascular disease,

chronic renal failure, cirrhosis and conditions which may be associated with dehydration appear
to increase the risk of renal toxicity. Children’s MOTRIN® Cold should therefore be used with
caution when these risk factors are present.

Mild impairment of renal function (decreased renal blood flow and glomerular filtration
rate) can occur at maximal doses of ibuprofen. Renal papillary necrosis has been reported.

Long-term administration of nonsteroidal anti-inflammatory drugs to animals has resulted in

renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports
of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.

A second form of renal toxicity has been seen in patients with pre-renal conditions leading to
reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive
role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal
anti-inflammatory drug may cause a dose dependent reduction in prostaglandin formation and
may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those
with impaired renal function (Glomerular Filtration Rate (GFR) < 60 ml/min or 1 ml/sec),
patients on salt restricted diets, those with congestive heart failure, cirrhosis, liver dysfunction,
those taking diuretics, angiotensin-converting enzyme inhibitors, angiotensin-II receptor

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blockers, cyclosporin, ASA and the elderly. Serious or life-threatening renal failure has been
reported in patients with normal or impaired renal function after short-term therapy with
NSAIDs. Even patients at risk who demonstrate the ability to tolerate an NSAID under stable
conditions may decompensate during periods of added stress, for example during states of fluid
restriction as can occur during gastroenteritis. Discontinuation of nonsteroidal anti-inflammatory
therapy is usually followed by recovery to the pretreatment state.

NSAIDs can increase the risk of hyperkalemia. In patients on dialysis, NSAIDs should be used
with caution.

Fluid retention and edema have been observed in patients treated with ibuprofen.
Therefore, as with many other NSAIDs, the possibility of precipitating congestive heart
failure in elderly patients or those with compromised cardiac function should be borne in
mind. Ibuprofen should be used with caution in patients with heart failure, hypertension
or other conditions predisposing to fluid retention. Ask patients who are on chronic
therapy and at risk for fluid retention to weigh themselves at regular intervals to assist in
monitoring for fluid accumulation.

With nonsteroidal anti-inflammatory treatment there is a potential risk of hyperkalemia,

particularly in patients with conditions such as diabetes mellitus or renal failure; elderly patients;
or in patients receiving concomitant therapy with angiotensin-II receptor antagonists, adrenergic
blockers, angiotensin-converting enzyme inhibitors or some diuretics. Patients at risk should be
monitored periodically during long-term therapy.

Pseudoephedrine and its active metabolite are excreted chiefly via the kidneys. Therefore, dosage
should be adjusted in patients with impaired kidney function. Myoclonic jerking and bizarre
behaviour were reported in a haemodialysis patient with end-stage renal failure after taking
60mg of pseudoephedrine four times daily for 12 days to treat nasal congestion.

Respiratory
ASA-induced asthma is an uncommon but very important indication of ASA and NSAID
sensitivity. It occurs more frequently in patients with asthma who have nasal polyps.

Sensitivity/Resistance
Not applicable.

Sexual Function/Reproduction
Not applicable.

Skin
In rare cases, serious skin reactions such as Stevens-Johnson syndrome, toxic epidermal
necrolysis, exfoliative dermatitis and erythema multiforme have been associated with the use of
some NSAIDs. Because the rate of these reactions is low, they have usually been noted during
post-marketing surveillance in patients taking other medications also associated with the

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potential development of these serious skin reactions. Thus, causality is not clear. These
reactions are potentially life threatening but may be reversible if the causative agent is
discontinued and appropriate treatment instituted. Patients should be advised that if they
experience a signs or symptoms or skin rash or edema they should discontinue their NSAID and
contact their physician for assessment and advice, including which additional therapies to
discontinue.

Pseudoephedrine may induce non-pigmenting, fixed-type skin eruptions, which are typically
indurated, erythematous, pruritic, tender and oedematous. The reaction tends to occur within 24
hours after administration of pseudoephedrine and to resolve 2 to 3 days after discontinuation.

Special Populations

Pregnant Women:
No evidence specifically identifies exposure to analgesic doses of ibuprofen as a cause of harm
to either mother or fetus during pregnancy [Arthritis Advisory Committee, 1983; Barry et. al.,
1984]. Non-steroidal anti-inflammatory drugs in general, however, are known to affect the
action of prostaglandin synthetase which could alter a variety of the physiological functions of
prostaglandins or platelets during delivery such as facilitating uterine contraction in the mother,
closure of the ductus arteriosus in the fetus, and platelet-related haemostasis. Patients should
therefore be advised not to use Children’s MOTRIN® Cold during pregnancy without the advice
of a physician, particularly during the last trimester. Clinical information is limited on the
effects of ibuprofen in pregnancy.

Nursing Women: Pharmacokinetic studies indicated that following oral administration of

ibuprofen 400 mg the level of drug which appeared in breast milk was below detection levels of
1 µg/mL. The amount of ibuprofen to which an infant would be exposed through this source was
considered negligible. However, since the absolute safety of ibuprofen ingested under these
circumstances has not been determined, nursing mothers should be advised to consult a physician
before using Children’s MOTRIN® Cold.

Pediatrics (>6 months of age): Studies conducted to date have not demonstrated pediatric-
specific problems that would limit the usefulness of ibuprofen in children 6 months and older.
However, Children’s MOTRIN® Cold is indicated in pediatric patients 4 years of age and older.

Geriatrics (> 65 years of age): Particular caution should be observed if elderly patients take
Children’s MOTRIN® Cold, as they are more likely to be taking other medications or have pre-
existing disease states which can increase the likelihood of the complications that have been
associated with ibuprofen. Elderly patients appear to be more susceptible to the effects of
sympathomimetic amines and the central nervous system disease reactions; cognitive
dysfunction (forgetfulness, inability to concentrate, a feeling of separation from the
surroundings). These reactions have been reported in such patients.

Monitoring and Laboratory Tests

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Not applicable.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Experience reported with prescription use of ibuprofen has included the following adverse
reactions. Note: Reactions listed below under Causal Relationship Unknown are those where a
causal relationship could not be established; however, in these rarely reported events, the
possibility of a relationship to ibuprofen also cannot be excluded. The adverse reactions most
frequently seen with ibuprofen therapy involve the gastrointestinal system.

Pseudoephedrine may cause mild CNS stimulation, especially in patients who are hypersensitive
to the effects of sympathomimetic drugs. Nervousness, excitability, restlessness, dizziness,
weakness, and insomnia may occur. Headache and drowsiness have also been reported. Large
doses may cause lightheadedness, nausea, and/or vomiting. In addition, the possibility of other
adverse effects associated with sympathomimetic drugs, including fear, anxiety, tenseness,
tremor, hallucinations, seizures, pallor, respiratory difficulty, dysuria, and cardiovascular
collapse should be considered.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates
observed in the clinical trials may not reflect the rates observed in practice and should not be
compared to the rates in the clinical trials of another drug. Adverse drug reaction information
from clinical trials is useful for identifying drug-related adverse events and for approximating
rates.

Table 1 - Incidence of Adverse Events Attributed to Ibuprofen.

Incidence Incidence
Adverse Effect
3-9% 1-3%
Gastrointestinal ƒ nausea ƒ diarrhea
ƒ epigastric pain ƒ abdominal distress
ƒ heartburn ƒ nausea and vomiting
ƒ indigestion
ƒ constipation
ƒ abdominal cramps and
pain
ƒ gastrointestinal tract
fullness (bloating or
flatulence)
Central Nervous System ƒ dizziness ƒ headache
ƒ nervousness

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 Dermatologic ƒ rash (including maculopapular ƒ pruritis
type)
Special Senses ƒ tinnitus
Metabolic ƒ decreased appetite
ƒ edema
ƒ fluid retention (generally
responds promptly to drug
discontinuation)

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Gastrointestinal: gastric or duodenal ulcer with bleeding and/or perforation, gastrointestinal
hemorrhage, melena, hepatitis, jaundice, abnormal liver function (SGOT, serum bilirubin and
alkaline phosphatase).

Central Nervous System: Depression, insomnia.

Dermatologic: vesiculobullous eruptions, urticaria, erythema multiforme.

Special Senses: amblyopia (blurred and/or diminished vision, scotomata and/or changes in
colour vision).

Cardiovascular: congestive heart failure in patients with marginal cardiac function, elevated
blood pressure.

Allergic: Anaphylaxis.

Reports with an Unknown Causal Relationship

Central Nervous System: paresthesias; hallucinations; dream abnormalities; aseptic meningitis

has been reported in patients with systemic lupus erythematosus or other connective tissue
disease; aseptic meningitis and meningioencephalitis, in one case accompanied by eosinophilia
in the cerebrospinal fluids, has been reported in patients who took ibuprofen intermittently and
did not have any connective tissue disease; cognitive dysfunction has been observed in elderly
patients who took ibuprofen.

Special Senses: conjunctivitis, diplopia; optic neuritis.

Hematologic: hemolytic anemia; thrombocytopenia; granulocytopenia; bleeding episodes (e.g.

purpura, epistaxis, hematuria, menorrhagia); auto-immune hematological anemia occurred in one
patient taking 400 mg of ibuprofen three times a day for ten days; fatal aplastic anemia was
reported in one patient who took 600 mg per day for 8 months.

Cardiovascular: arrhythmias (sinus tachychardia, sinus bradycardia, palpitations).

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Allergic: fever, serum sickness, lupus erythematosus syndrome.

Endocrine: gynecomastia; hypoglycemic reaction; menstrual delays of up to two weeks and

dysfunctional uterine bleeding; occurred in nine patients taking ibuprofen 400 mg three times a
day for three days before menses.

Renal: decreased creatinine clearance; polyuria; azotemia.

Abnormal Hematologic and Clinical Chemistry Findings

Gastrointestinal: The generally modest elevations of serum transaminase activity that has been
observed are usually without clinical sequelae but severe, potentially fatal toxic hepatitis can
occur.

Hepatic: abnormal liver function (SGOT, serum bilirubin and alkaline phosphatase)

Hematologic: leukopenia and decreases in hemoglobin and hematocrit

Renal: Renal blood flow glomerular filtration rate decreased in patients with mild impairment of
renal functions who took 1200 mg/day of ibuprofen for one week.

Pseudoephedrine

Although oral administration of usual doses of pseudoephedrine to normotensive patients usually

produced negligible pressor effects, the drug should be used with caution in hypertensive
patients. Pseudoephedrine may increase the irritability of the heart muscle and may alter the
rhythmic function of the ventricles, especially in large doses or when administered to patients
who are hypersensitive to the myocardial effects of sympathomimetic drugs. Tachycardia or
palpitation may occur. One patient who received 120 mg of pseudoephedrine hydrochloride
every 4 hours developed multifocal premature ventricular contractions which disappeared a few
days after the drug was discontinued. In addition, pseudoephedrine may have precipitated an
attack of atrial fibrillation in an infant. It was postulated that the patient may have had
previously unsuspected idiopathic atrial fibrillation, and therefore may have been especially
sensitive to the myocardial effects of the drug.

Fixed dermatologic eruptions (erythematosus nummular patches) developed in 2 patients after a

combination containing 60mg of pseudoephedrine hydrochloride and 2.5 mg of triprolidine
hydrochloride was administered. Sensitivity testing indicated that pseudoephedrine was the
cause of this reaction. In one patient with latent Horner’s syndrome, administration of
pseudoephedrine in combination with triprolidine caused ansocoria .

Post-Market Adverse Drug Reactions

Since the inception of marketing of combination ibuprofen/pseudoephedrine products, data from

the United States shows that more than 3 billion doses have been administered in that country

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alone. During the period between August 1, 2000 and July 31, 2004, 265 adverse drug reactions
worldwide have been reported for Children’s MOTRIN® Cold. A list of the reported adverse
events is provided in the Table 2.

Table 2: U.S. Reported Adverse Events for Children’s MOTRIN® Cold (August 1, 2000 to July 31, 2004)
Body System Number of Reported Events
Adverse Event

Body as a Whole 8
Aggravation Rxn - Autism (Worsening Symptoms) 1
Body Temperature Increased 1
Confusion 1
Fever 1
Headache 2
Malaise 1
Red Blood Cell Count Increased 1

Cardiovascular 5
Chest Pain 1
Heart Rate Increased / Tachycardia 4

Digestive 40
Abdominal Pain - General or Upper 8
Dyspepsia 3
Glossodynia 2
Nausea 2
Oral Discomfort 2
Retching 2
Vomiting 20
Vomiting Projectile 1

Endocrine 3
Aggravation Reaction - Diabetic (Increased Fasting Blood Sugars) 1
Goitre 1
Hyperglycemia 1

General Disorders / 31
Administrative Site Conditions
Drug Ineffective / Lack of Effect / No Drug Effect 26
No Adverse Drug Effect 1
Reaction Unevaluable 3
Therapeutic Response Decreased 1

Hepatobiliary 2
Jaundice NOS 1
Liver Function Tests NOS Abnormal 1

Immune 1
Hypersensitivity NOS 1

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Table 2: U.S. Reported Adverse Events for Children’s MOTRIN® Cold (August 1, 2000 to July 31, 2004)
Body System Number of Reported Events
Adverse Event
Injury, Poisoning and 15
Procedural Complications
Accidental Exposure 6
Accidental Overdose 7
Medication Error 2

Central Nervous System 32

Abnormal Gait 1
Ataxia 1
Convulsions 2
Dizziness 1
Dysgeusia 5
Movement Disorder 1
Nervousness 4
Paresthesia 1
Restlessness / Agitation 3
Somnolence 9
Speech Disorder 2
Tremor 1
Vasodilation 1

Psychiatric 16
Abnormal Dreams 1
Hallucinations 4
Hostility / Irritability 2
Insomnia 6
Screaming / Screaming Syndrome 3

Respiratory, Thoracic 19
and Mediastinal
Apnea 1
Asthma 3
Dyspnea 2
Epistaxis 3
Hyperventilation 2
Rhinitis 2
Throat Irritation / Burning Throat 4
Ulcer – Mouth 1
Wheezing 1

Skin and Appendages 82

Allergic Reaction (face - redness, itchiness; eyes and mouth - puffiness) 1
Erythema 2
Facial Edema / Swelling Face 17
Pruritus (Generalized) 15
Rash - Generalized or Pruritic 26
Sweating 1
Urticaria 19
Vesiculobullous Rash 1

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Table 2: U.S. Reported Adverse Events for Children’s MOTRIN® Cold (August 1, 2000 to July 31, 2004)
Body System Number of Reported Events
Adverse Event

Special Senses – Eye 10

Eye Disorder NOS 1
Eye(lid) Edema / Swelling 4
Increased Blinking 1
Irregular Eye Contact 1
Ocular Icterus 1
Vision Blurred 1
Visual Disturbance NOS 1

Urogenital 1
Abnormal Urine – Discolouration 1

DRUG INTERACTIONS

Overview
Although ibuprofen binds to a significant extent to plasma proteins, interactions with other
protein-bound drugs occur uncommonly. Nevertheless, caution should be observed when other
drugs also having a high affinity for protein binding sites are used concurrently. Some
observations have suggested a potential for ibuprofen to interact with furosemide, pindolol,
digoxin, methotrexate, phenytoin and lithium salts. However, the mechanisms and clinical
significance of these observations are presently not known. No interactions have been reported
when ibuprofen has been used in conjunction with probenecid, thyroxine, steroids, antibiotics or
benzodiazepines.

One manufacturer states that β-adrenergic blocking drugs such as propranolol may also increase
the pressor effects of pseudoephedrine and that pseudoephedrine may reduce the anti-
hypertensive effects of reserpine, methyldopa, mecamylamine hydrochloride, and veratrum
alkaloids.

A general precaution is appropriate for patients to assure the compatibility of Children’s

MOTRIN® Cold with their other prescribed medications through consultation with a physician.

Drug-Drug Interactions

Serious Drug Interactions

• Use with acetylsalicylic acid (ASA) or other NSAIDs, including ibuprofen, may result in
possible additive adverse side effects.

• Although interactions have not been reported, concurrent use with acetaminophen is not
advisable; it may increase the risk of adverse renal effect.

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 • Use with anticoagulants may increase the risk of GI adverse events (e.g. bleeding).

• Use with hypoglycemic agents (oral agents and insulin) may increase the risk of
hypoglycaemia.

• Use with antihypertensives may interfere with circulatory control.

• Use with diuretics may reduce the diuretic effect.

• Use with methotrexate may increase the risk of methotrexate toxicity.

• Use with lithium may increase the risk of lithium toxicity.

Coumarin Type Anticoagulants

Several short-term controlled studies failed to show that ibuprofen significantly affected
prothrombin time or a variety of other clotting factors when administered to individuals on
Coumarin-type anticoagulants. However, bleeding has been reported when ibuprofen and other
NSAID agents have been administered to patients on Coumarin-type anticoagulants. The use of
Children’s MOTRIN® Cold in patients who are taking anticoagulants should therefore be
avoided because of the possibility of enhanced GI bleeding or an additive effect due to
ibuprofen's reversible anti-platelet actions.

Acetylsalicylic Acid
Animal studies show that ASA given with NSAID agents, including ibuprofen, yields a net
decrease in anti-inflammatory activity with lowered blood levels of the non-ASA drug. Single
dose bioavailability studies in normal volunteers have failed to show an effect of ASA on
ibuprofen blood levels. Correlative clinical studies have not been done.

The platelet inhibiting effects of ibuprofen, although less potent and of shorter duration than
those induced by acetylsalicylic acid, warrant cautionary supervision by a physician before co-
administration of Children’s MOTRIN® Cold and anti-coagulants.

Other Anti-Inflammatory Agents (NSAIDs)

The addition of Children’s MOTRIN® Cold to a pre-existent prescribed NSAID regimen in
patients with a condition such as rheumatoid arthritis may result in increased risk of adverse
effects.

Diuretics
Ibuprofen, because of its fluid retention properties, can decrease the diuretic and anti-
hypertensive effects of diuretics, and increased diuretic dosage may be needed. Patients with
impaired renal function taking potassium-sparing diuretics who develop ibuprofen-induced renal
insufficiency might be in serious danger of fatal hyperkalemia.

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Acetaminophen
Although interactions have not been reported, concurrent use with Children’s MOTRIN® Cold is
not advisable. Use with acetaminophen may increase the risk of adverse renal effect (see
Warnings and Precautions – Renal).

Hypoglycemic Agents
Ibuprofen may increase hypoglycemic effects of oral anti-diabetic agents and insulin.

Sympathomimetic Agents
Pseudoephedrine should be administered with extreme caution, if at all, with other
sympathomimetic agents because of the possibility of additive effects and increased toxicity.

Monoamine Oxidase Inhibitors

Monoamine oxidase (MAO) inhibitors, by increasing the quantity of norepinephrine in
adrenergic nervous tissue, potentiate the pressor effects of indirectly acting sympathomimetic
drugs such as pseudoephedrine. Infrequently, a hypertensive crisis may result. Pseudoephedrine
should therefore be avoided in patients receiving drugs with MAO inhibiting activity.

Anti-hypertensives
NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE)
inhibitors.

Combinations of ACE inhibitors, diuretics and NSAIDs might have an increased risk for acute
renal failure and hyperkalemia.

Glucocorticoids
Some studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increases
the risk of GI side effects such as ulceration and bleeding. This is especially the case in older
(>65 years of age) individuals.

Lithium
Monitoring of plasma lithium concentrations is advised when stopping or starting an NSAID, as
increased lithium concentrations can occur.

Drug-Food Interactions
Interaction with food have not been established.

Drug-Herb Interactions
Interaction with herbs have not been established.

Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.

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DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Weight Age Dose

lbs kg Years mL tsp
Under 36 Under 16 Under 4* Calculate based on weight and target
ibuprofen dose of 7.5 mg/kg.
36-47 16-21.9 4-5 5 mL 1 tsp
48-95 22-43.9 6-11 10 mL 2 tsp
Dose may be repeated every 6 hours, but not more than 4 times a day.
*Consumer labelling does not offer dosing information for children under 4 years of age; this information is provided as a guide for professional
recommendation to patients.

Children’s MOTRIN® Cold should not be taken for more than 5 days. If symptoms do not
improve, or are accompanied by fever that persists for more than 3 days, or if new symptoms
occur, patient should consult a physician.

Do not give to children under 4 years of age, except as directed by a physician.

Missed Dose
If you miss a dose, take the missed dose as soon as you remember. If it is almost time for your
next dose, wait until then to take your medicine and skip the missed dose. Do not take two doses
at the same time.

Administration
Take with food or milk if mild upset stomach occurs with use.

OVERDOSAGE

Clinical Features
A clear pattern of clinical features associated with accidental or intentional overdose of
ibuprofen has not been established. Reported cases of overdose have often been complicated by
co-ingestions or additional suicidal gestures. The range of symptoms observed has included
nausea, vomiting, abdominal pain, drowsiness, nystagmus, diplopia, headache, tinnitus, impaired
renal function, coma and hypotension. A review of 4 fatalities associated with ibuprofen
overdose indicates other contributing factors co-existed so it would be difficult to identify the
toxicity of ibuprofen as a specific cause of death.

Post-ingestion blood levels may be useful to confirm a diagnosis and to quantify the degree of
exposure but otherwise have not been helpful in predicting clinical outcome. Generally, full
recovery can be expected with appropriate symptomatic management.

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The following cases of overdose have been reported: A 19 month old child, 1-1/2 hours after the
ingestion of 7 to 10 X 400 mg tablets of ibuprofen presented apnea, cyanosis and responded only
to painful stimuli. After treatment with 02, NaHCO3, infusion of dextrose and normal saline, the
child was responsive and 12 hours after ingestion appeared completely recovered. Blood levels
of ibuprofen reached 102.9 μg/mL, 8-1/2 hours after the accident. Two other children weighing
approximately 10 kg, had taken an estimated 120 mg/kg. There were no signs of acute
intoxication or late sequelae. In 1 child the ibuprofen blood level at 90 minutes after ingestion
was approximately 700 μg/mL. A 19 year old male who ingested 8000 mg of ibuprofen reported
dizziness and nystagmus was noted. He recovered with no reported sequelae after parenteral
hydration and 3 days of bed rest.

For perspective, a single 200 mg oral dose study in 6 fasting healthy men produced a peak
plasma concentration of 15.0 μg/mL at 0.75 hr. Another study using a single oral 400 mg dose
in humans produced a peak serum level of 31.9 ± 8.8 μg/mL 0.5 hour after ingestion, and at 16
hours serum concentrations had dropped to 1 μg/mL. (See Pharmacology)

Management of Overdose
Appropriate interventions to decontaminate the gastrointestinal tract may be beneficial within the
first 4 hours after ingestion. Routine symptomatic and supportive treatment is then
recommended. Physicians should contact the Regional Poison Control Centre for additional
guidance about ibuprofen overdose management.

Due to the rapid absorption of pseudoephedrine and ibuprofen from the gut, emetic and gastric
lavage must be instituted within 4 hours of overdosage to be effective. Charcoal is useful only if
given within 1 hour. Cardiac status should be monitored and the serum electrolytes measured. If
there are signs of cardiac toxicity, propranolol may be administered intravenously. A slow
infusion of a dilute solution of potassium chloride should be initiated in the event of a drop in the
serum potassium level. Despite hypokalemia, the patient is unlikely to be potassium-depleted;
therefore, overload must be avoided. Monitoring of the serum potassium is advisable for several
hours after administration of the salt. For delirium or convulsions, intravenous administration of
diazepan is indicated.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action
Ibuprofen is a member of the class of agents commonly known as non-steroidal anti-
inflammatory drugs (NSAID). Like all NSAIDs, ibuprofen is an analgesic, antipyretic, and anti-
inflammatory medication.

It is generally accepted that the basic mechanism of pharmacological action of ibuprofen, and
other NSAIDs, is the inhibition of prostaglandin synthesis.

Nonselective NSAIDs (such as ibuprofen) and ASA act by inhibiting systemic (peripheral and
central) prostaglandin G/H synthase isoenzymes, also known as cyclooxygenase-1 (COX-1) and

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cyclooxygenase-2 (COX-2). These isoenzymes are responsible for the conversion of arachidonic
acid to various tissue specific prostaglandins and thromboxanes. COX-1 is constitutively
expressed in all tissues and is responsible for generating prostaglandins that maintain organ
function, protect the integrity of the gastric mucosa and generate platelet-derived thromboxane
responsible for platelet aggregation and vasoconstriction. During the inflammatory process
COX-2 is induced, generating prostaglandins that mediate pain and inflammation. COX-2 is
also present constitutively in the kidneys and vascular endothelium. Reported adverse
experiences with ASA and other NSAIDs can be understood on the basis of this mechanism of
action.

Pharmacodynamics

Ibuprofen: Ibuprofen is a member of the class of agents commonly known as non-steroidal

anti-inflammatory drugs (NSAID). Consistent with this classification, ibuprofen exhibits anti-
inflammatory activity at higher dosage ranges. At lower adult single doses relevant to a
nonprescription dosage (200 mg to 400 mg) ibuprofen relieves pain of mild to moderate intensity
and reduces fever. Analogous to acetylsalicylic acid, the prototype of this class, this
analgesic/antipyretic activity of ibuprofen occurs at lower doses than necessary for anti-
inflammatory effects which are thought to require sustained administration of higher individual
doses.

Pseudoephedrine: Pseudoephedrine acts directly on both α- and, to a lesser degree, β-

adrenergic receptors. It is believed that α-adrenergic effects result from the inhibition of the
production of cyclic adenosine-3', 5'-monophosphate (cAMP) by inhibition of the enzyme adenyl
cyclase, whereas β-adrenergic effects result from stimulation of adenyl cyclase activity. Like
ephedrine, pseudoephedrine also has an indirect effect by releasing norepinephrine from its
storage sites.

Pseudoephedrine acts directly on α-adrenergic receptors in the mucosa of the respiratory tract
producing vasoconstriction which results in shrinkage of swollen nasal mucous membranes,
reduction of tissue hyperemia, edema, and nasal congestion, and an increase in nasal airway
patency. Drainage of sinus secretions is increased and obstructed eustachian ostia may be
opened.

Pseudoephedrine may relax bronchial smooth muscle by stimulation of β2-adrenergic receptors;

however, substantial bronchodilation has not been demonstrated consistently following oral
administration of the drug.

Oral administration of usual doses of pseudoephedrine to normotensive patients usually produces

a negligible effect on blood pressure. Pseudoephedrine may increase the irritability of the heart
muscle and may alter the rhythmic function of the ventricles, especially in large doses or after
administration to patients such as those with cardiac disease who are hypersensitive to the
myocardial effects of sympathomimetic drugs. Tachycardia, palpitation, and/or multifocal
premature ventricular contractions may occur.

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Pseudoephedrine may cause mild CNS stimulation, especially in patients who are sensitive to the
effects of sympathomimetic drugs.
Pharmacokinetics

Absorption: Ibuprofen is rapidly absorbed after oral administration, with peak serum or plasma
levels generally appearing within 1½ to 2 hours. Oral absorption is estimated to be 80% of the
dose. Both the rate of absorption and peak plasma concentrations are reduced when the drug is
taken with food but bioavailability as measured by total area under the concentration-time curve
is minimally altered.

A single 200 mg oral dose study in 6 fasting healthy men produced a peak plasma concentration
of 15.0 g/mL at 0.75 hr. Another study using a single oral 400 mg dose in humans produced a
peak serum level of 31.9 + 8.8 g/mL 0.5 hours after ingestion, and at 16 hours serum
concentrations had dropped to 1 g/mL. Comparable serum levels and time to peak within 1-2
hours were confirmed by other investigations with 200 mg and 400 mg solid doses. A multiple
dose study of administration of a 200 mg ibuprofen tablet three times a day for 2 weeks showed
no evidence of accumulation of ibuprofen. As is true with most tablet and suspension
formulations, Children’s MOTRIN® Cold is absorbed somewhat faster than a tablet with a time
to peak generally within one hour.

Pseudoephedrine is readily and almost completely absorbed from the GI tract and there is no
evidence of first-pass metabolism. Following oral administration of a 60- or 120-mg dose of
pseudoephedrine hydrochloride as an oral solution, peak plasma concentrations of about 180-300
or 397-422 ng/mL, respectively, were achieved in approximately 1.39-2 or 1.84-1.97 hours,
respectively. Absorption from extended-release preparations is slower and peak plasma
concentrations of the drug are achieved in about 3.8-6.1 hours. Following oral administration of
single 30- or 60-mg doses of pseudoephedrine hydrochloride as a solution in pediatric patients
(6-12 years of age), mean peak serum concentrations of 244 or 492 ng/mL, respectively, were
achieved after 2.1 or 2.4 hours, respectively. Food delays absorption of the drug as a solution,
but appears not to have an effect on absorption when the drug is administered as extended-
release preparations.

Plasma pseudoephedrine concentrations of 274 ng/mL have been associated with a mean nasal
decongestant response of 57.2%. Following oral administration of 60 mg of pseudoephedrine
hydrochloride as tablets or oral solution, nasal decongestion occurs within 30 minutes and
persists for 4-6 hours. Nasal decongestion may persist for 8 hours following oral administration
of 60 mg and up to 12 hours following 120 mg of the drug in extended-release capsules.

Distribution: Clinical studies indicate a duration of clinical effect for ibuprofen of up to 8 hours
for fever and 6 hours for pain.

Ibuprofen like most drugs of its class, is highly protein bound (>99% bound at 20 g/mL). Based
on oral dosing data there is an age- or fever-related change in volume of distribution for

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ibuprofen. Febrile children <11 years old have a volume of approximately 0.2 L/kg while adults
have a volume of approximately 0.12 L/kg. The clinical significance of these findings is
unknown. Tissue distribution of ibuprofen is also extensive in humans. Studies comparing
synovial fluid levels with serum concentrations indicated that equilibration time post-ingestion
occurred within approximately 3 to 5 hours.

Results of pre-clincal studies showed that pseudoephedrine is distributed to body tissues and
fluids, including fetal tissue, breast milk and the central nervous system. Although specific
clinical information is lacking, pseudoephedrine is presumed to cross the placenta and to enter
CSF. Pseudoephedrine distributes into breast milk; about 0.5% of an oral dose is distributed into
breast milk over 24 hours.

Metabolism: Ibuprofen is rapidly metabolized through oxidation and glucuronic acid

conjugation with urinary excretion of the inactive metabolites usually complete within 24 hours.
In humans, 84% is recoverable in the urine, primarily as conjugated hydroxy- and carboxy-
metabolites, with only approximately l% excreted unchanged. Less than 10% is excreted in the
urine. The 2 major metabolities of ibuprofen in humans have been found to have no activity in
the ultraviolet erythema test in guinea pigs and in the acetylcholine-induced mouse writhing test
at doses of l0 mg/kg and l5 mg/kg respectively.

Pseudoephedrine is incompletely metabolized in the liver (less than 1%) by N-demethylation to

an inactive metabolite.

Excretion: Ibuprofen is rapidly metabolized and eliminated in the urine. The excretion of
ibuprofen is virtually complete 24 hours after the last dose. It has a biphasic plasma elimination
time curve with a half-life of approximately 2.0 hours. There is no difference in the observed
terminal elimination rate or half-life between children and adults, however, there is an age- or
fever-related change in total clearance. This suggests that the observed difference in clearance is
due to differences in the volume of distribution of ibuprofen, as described above. The clinical
relevance of these differences in clearance is unknown, although extensive clinical experience
with ibuprofen in children at the pertinent dosage range (5 - 10 mg/kg) indicates a wide margin
of safety.

Pseudoephedrine and its metabolite are excreted in urine; 55-96% of a dose is excreted
unchanged, with the remainder apparently metabolized in the liver to inactive compounds by N-
demethylation, parahydroxylation and oxidative deamination. Urinary excretion of unchanged
pseudoephedrine has been reported to be 70-90% of the administered dose within 24 hours.
Urinary pH can affect the elimination half-life of pseudoephedrine, prolonging it when alkaline
(pH 8) and reducing it when acidic (pH 5). The elimination half-life of pseudoephedrine ranges
from 3-6 or 9-26 hours when urinary pH is 5 or 8, respectively. When urinary pH is 5.8, the
elimination half-life of the drug ranges from 5-8 hours. In one study in children (6-12 years of
age), the elimination half-life of pseudoephedrine averaged about 3 hours when urinary pH was
6.5. The rate of urinary excretion of pseudoephedrine is accelerated when urine is acidified to a
pH of about 5 by prior administration of ammonium chloride. When the urine is alkalinized to a

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pH of about 8 by prior administration of sodium bicarbonate, some of the drug is re-absorbed in
the kidney tubule and the rate of urinary excretion is slowed.

Renal clearance of pseudoephedrine is about 7.3-7.6 mL/minute per kg in adults. Following oral
administration of a single 30- or 60-mg dose of pseudoephedrine hydrochloride given as an oral
solution in children (6-12 years of age), total body clearance was faster than that reported in
adults, averaging about 10.3 or 9.2 mL/min/kg, respectively.

Special Populations and Conditions

Pediatrics: Although there is little evidence of clinically significant age dependent kinetics in
febrile children ages 3 months to 12 years, some differences in the pharmacokinetic parameters
of volume of distribution and clearance have been observed between adults and children.

Controlled clinical trials comparing doses between 5 and 10mg/kg of ibuprofen and 10-15 mg/kg
of acetaminophen have been conducted in children 6 months to 12 years of age with fever
primarily due to viral illnesses. In these studies, there were few differences between treatments
in fever reduction in the first hour and maximum fever reduction occurred between 2 and 4
hours. There was some evidence that the higher dosage range of ibuprofen (10mg/kg) resulted in
a prolonged duration of effect (from 6 to 8 hours) and that it was more effective for children with
higher baseline temperatures (above 102.5oF/39.1°C) but the numbers of patients were not
adequate to draw definitive conclusions. In children with baseline temperatures at or below
102.5oF (39.1°C) both ibuprofen doses and acetaminophen were equally effective in their
maximum effect.

Following oral administration of a single 30 or 60 mg dose of pseudoephedrine hydrochloride as

a solution in children (6-12 years of age), the mean apparent volume of distribution at steady-
state was 2.6 or 2.4 L/kg, respectively. The steady–state volume of distribution from the multiple
dose study was 2.5 L/kg.

A multiple dose pharmacokinetic study was conducted to describe the steady-state

pharmacokinetics of pseudoephedrine HCl and ibuprofen in assessing the potential for a drug
interaction between pseudoephedrine and ibuprofen. Table 3 summarizes study results. A total
of five doses were administered. Single doses were administered every 6 hours and each dose
provided 7.5mg/kg ibuprofen and 1.125mg/kg psuedophedrine HCl. Neither drug accumulated
considerably and no interaction between ibuprofen and pseudoephedrine observed.

TABLE 3 IN VIVO PHARMACOKINETIC DATAA FOR IBUPROFEN AND PSEUDOEPHEDRINE HCL WHEN
ADMINISTERED IN COMBINATION AS A SUSPENSION
Ingredient AUCτ CMAX,ss CMAX,1 TMAX, TMAX,1 CI/F Vd/F kA kEL t½
(µg·h/mL) (µg/mL) (µg/mL) SS (h) (mL/h/kg) (L/kg) (1/h) (1/h) (h)
(h)
Ibuprofen 99.3 32.0 29.6 0.97 1.02 77.5 0.15 1.887 0.546 1.3
Pseudoephedrine 1276 295 218 1.39 1.68 12.3 2.5 1.417 0.303 2.5

AUCτ : area under the curve of the dosing interval at steady state

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CMAX,1 : maximum plasma concentration after the first dose
TMAX, SS: time to reach maximum plasma concentration at steady state
TMAX,1 : time to reach peack concentration after the first dose
CI/F: oral clearance
Vd/F : apparent Volume of distribution
kA : absorption rate constant
kEL : elimination rate constant
t½ : elimination half-life
Geriatrics: Studies demonstrate no apparent clinically significant alterations in ibuprofen
pharmacokinetics in the elderly.

Hepatic Insufficiency: Ibuprofen pharmacokinetics has been studied in patients with alcoholic
liver disease who have been assessed to have fair to poor hepatic function. Results suggest
despite the liver being the primary organ of metabolism of ibuprofen, its kinetic parameters are
not substantially altered by this condition.

STORAGE AND STABILITY

Stability studies were conducted on the product in HDPE bottles with Polypropylene caps. The
recommended storage condition is: Store at room temperature, 15°C to 30°C (59°F to 86°F).

SPECIAL HANDLING INSTRUCTIONS

None.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Children’s MOTRIN® Cold is available in Berry, Grape and Dye-Free Berry in a 120 mL bottle:

Medicinal Ingredients: 100 mg/5 mL ibuprofen

15 mg/5 mL pseudoephedrine HCl

Non-Medicinal Ingredients:

Berry Flavour Grape Flavour Dye-Free Berry

ƒ Acesulfame K ƒ Artificial Grape Flavour ƒ Acesulfame K

ƒ Citric Acid ƒ Acesulfame K ƒ Citric Acid
ƒ D&C Yellow No. 10 ƒ Citric Acid ƒ Glycerin
ƒ FD&C Red No. 40 ƒ D&C Red No. 33 ƒ N&A Cherry Berry
ƒ Glycerin ƒ FD&C Blue No.1 Flavour
ƒ N&A Cherry Berry ƒ FD&C Red No. 40 ƒ Polysorbate 80
Flavour ƒ Glycerin ƒ Pre-Gelatinized Starch
ƒ Polysorbate 80 ƒ Polysorbate 80 ƒ Purified Water
ƒ Pre-Gelatinized Starch ƒ Pre-Gelatinized Starch ƒ Sodium Benzoate
ƒ Purified Water ƒ Purified Water ƒ Sucrose
ƒ Sodium Benzoate ƒ Sucrose ƒ Xanthan Gum
ƒ Sucrose ƒ Sodium Benzoate
ƒ Xanthan Gum ƒ Xanthan Gum

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PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Ibuprofen

Chemical name: (±)-2-(p-isobutylphenyl) propionic acid

Molecular formula and molecular mass: C13H18O2, 206.3

CH3
OH
CH3
O
H3C
Structural formula:

Physicochemical properties:
ƒ White crystalline powder with a characteristic odour and
slight taste
ƒ Soluble:
o 1 in 1.5 of alcohol
o 1 in 1 of chloroform
o 1 in 2 of ether
o 1 in 1.5 of acetone
o in aqueous solution of alkali hydroxides and carbonates.
ƒ Very slightly soluble in water and very soluble in alcohol
and other common organic solvents
ƒ Apparent pKa 5.2.

Proper name: pseudoephedrine hydrochloride

Chemical name: [S-(R*,R*)]-α-[1(methylamino)ethyl]-Benzenemethanol hydrochloride

Molecular formula and molecular mass: C10H15NO,HCl, 201.7

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 OH
H H
N
. H Cl
CH3
H
H3C
Structural formula:
Physicochemical properties:
ƒ Soluble in:
o water
o alcohol
o chloroform.
ƒ pH (1 in 20 solution): 4.6 - 6.0
ƒ Melting Point: 180-186 °C

CLINICAL TRIALS

Safety

Study demographics and trial design

An open-label, multiple-dose pediatric outpatient clinical safety study using the ibuprofen-
pseudoephedrine suspension product (Children’s MOTRIN® Cold) was conducted.

Table 4 - Summary of patient demographics for clinical trials in specific indication

Study # Trial design Dosage, route of Study subjects Mean age Gender
administration and (n=number) (Range)
duration
99-086 Open-label study of Dosage: Ibuprofen 114 patients 5.8 years (2- Male and
the safety of an 6.3 - 9.2 mg/kg and 11) Female
ibuprofen- Pseudoephedrine 0.9
pseudoephedrine HCl - 1.4 mg/kg.
suspension a in
Route: Oral
children
suspension
Duration: up to 3
days.
a) Administered as Children’s MOTRIN® Cold Suspension

Of the 114 subjects in the study, 53.5% were male, 65.8% were Caucasian, 33.3% were between 2-3 years of age, 68.4% were below 7 years of
age, and 30.7% weighted between 10.9 –15.9 kg.

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Study results

Table 5 - Results of study 99-086 in specific indication

Primary Endpoints Associated value and statistical Associated value and statistical
significance for Drug at specific significance for Placebo or active
dosages control
To describe the safety profile of a Overall 13.2% of subjects reported Not applicable.
pediatric drug related adverse events, and
ibuprofen/pseudoephedrine HCl most were of mild to moderate
combination suspension product in intensity.
children with symptoms of the
common cold, flu or sinusitis.

The number and percent of subjects with drug-related adverse events are shown in Table 6. One
or more drug-related adverse events were reported by 13.2% of subjects. The most common
adverse event was somnolence, reported by 7.0% of subjects.

Table 6: Number (Percent) of Subjects With Drug-Related Adverse Events, McNeil Study 99-086
All Subjects
Body System (N = 114)
Adverse Eventa n (%)
Any adverse event 15 (13.2)

Body as a whole 2 (1.8)

Abdominal pain 2 (1.8)

Digestive 1 (0.9)
Nausea 1 (0.9)

Nervous 11 (9.6)
Hyperkinesia 1 (0.9)
Insomnia 1 (0.9)
Nervousness 1 (0.9)
Somnolence 8 (7.0)

Respiratory 1 (0.9)
Cough increased 1 (0.9)

Skin and appendages 1 (0.9)

Urticaria 1 (0.9)
a
Includes all adverse events noted as definitely, probably, or possibly drug-related and adverse events of unknown
relationship to study drug.

Comparative Bioavailability Studies

A three-way single dose comparative bioavailability study was conducted in adults comparing
the rate and extent of absorption of Children’s MOTRIN® Cold with single ingredient reference

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products. The ibuprofen reference product used in the study was Children’s MOTRIN®
Ibuprofen Suspension. The pseudoephedrine reference product used in the study was Children’s
Sudafed® Nasal Decongestant Liquid (US). There were no statistically significant differences
for any pharmacokinetic variables concluding bioequivalence of the treatments. Summary tables
of comparative bioavailability data for ibuprofen and pseudoephedrine are presented in Tables 7
and 8, respectively.

Table 7: Summary table of comparative bioavailability data for ibuprofen**

Ibuprofen
(1 x 7.5 mg/kg)

Geometric Mean
Arithmetic Mean (CV %)

% Ratio of 90 % Confidence
Parameter Test* Reference†
Geometric Means Intervals
AUCT 199 179
111 105 - 118
(µg·h/mL) 202 (19) 181 ( 17)

AUCI 201 181

111 105 - 118
(µg·h/mL) 205 (19) 183 (18)

CMAX 60.7 59.0

103 94.6 - 112
(µg/mL) 61.9 (20) 60.3 (21)

TMAX 0.70 0.74

(h) (36) (46)

T½ 2.2 2.2
(h) (12) (13)
*
Children’s MOTRIN® Cold Suspension
†
Children’s MOTRIN® Ibuprofen Suspension, McNeil Consumer Healthcare, (USA).
**
In 24 healthy subjects

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Table 8: Summary table of comparative bioavailability data for pseudoephedrine**

Pseudoephedrine
(1x 15 mg/5 mL)
From measured data

Geometric Mean
Arithmetic Mean (CV %)

% Ratio of 90 % Confidence
Parameter Test* Reference†
Geometric Means Intervals
AUCT 2199 2098
2223 (15) 2125 (16) 105 101 - 109
(µg·h/mL)
AUCI 2568 2566
2614 (19) 2633 (23) 100 95.3 - 105
(µg·h/mL)
CMAX 320 272
322 (11) 273 (10) 118 113 - 123
(µg/mL)
TMAX 1.48 2.60
(h) (50) (27)
T½ 4.7 5.1
(h) (20) (25)
*
Children’s MOTRIN® Cold Suspension
†
Children’s Sudafed® Nasal Decongestant Liquid (Pseudoephedrine HCl)
**
In 24 healthy subjects

Clinical Trials:
The efficacy of ibuprofen as an analgesic and antipyretic has been demonstrated by a variety of
clinical studies and pain models.

Dental Pain
In adults, the effects of a drug on post-surgical dental extraction pain serves as a standard model
for relief of pain of mild to moderate intensity. Ibuprofen 200 mg and 400 mg has been clearly
demonstrated to provide pain relief significantly superior to placebo. When compared to the
"standard" non-prescription analgesics, ibuprofen 200 mg is found to be comparable to ASA 650
mg.

Sore Throat or Ear Pain (Pediatric Models)

In children 6-12 years, ibuprofen 10 mg/kg was found to be effective for the relief of pain using
a sore throat model, both post-op sore throat (tonsillectomy) and pharyngitis due to upper
respiratory infection.

Controlled clinical trials comparing doses of 5 and 10mg/kg ibuprofen and 12.5 mg/kg
acetaminophen have been conducted in children 5-12 years of age with sore throat pain believed
due to an infectious agent or ear pain believed due to acute otitis media. All 3 active treatments
provided significant pain relief versus placebo within 1 to 2 hours of administration and had a
duration of action of up to 6 hours. There were no statistically significant differences among the
3 active treatments in the degree of maximum pain relief, although the trends favoured ibuprofen

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10 mg/kg. Ibuprofen 5 mg/kg demonstrated pain relief comparable to acetaminophen 12.5
mg/kg. Ibuprofen 10 mg/kg demonstrated greater pain relief than acetaminophen 12.5 mg/kg
from 3 to 6 hours after administration. A pediatric dosage schedule has been developed for
Children’s MOTRIN® based on an ibuprofen dose of approximately 7.5 mg/kg body weight.

Dysmenorrhea
Nonsteroidal anti-inflammatory drugs which inhibit prostaglandin synthesis such as ibuprofen
are particularly suitable for management of primary dysmenorrhea. Menstrual pain is now
thought to result from abnormal uterine activity which is secondary to increased production and
release of endometrial prostaglandins at the time of menstruation.

Several adequate and well-controlled clinical trials provide substantial evidence of the safety and
efficacy of ibuprofen at doses of 200 to 400 mg in relieving the pain of menstrual cramps.

A summary of trials of ibuprofen in the treatment of dysmenorrhea indicates the usual dose
administered to be 400 mg. The few studies which are available at a 200 mg dosage indicate
superiority of both ibuprofen 200 mg and 400 mg compared with ASA 650 mg.

Pain of Osteoarthritis
Several controlled clinical studies in adults provide substantial evidence of the safety and
efficacy of ibuprofen at doses of 1200 mg or less per day in relieving the pain of osteoarthritis.
Collectively these studies support an indication for the temporary relief of minor pains of
arthritis and, in conjunction with single dose analgesia studies, support the broader indication for
the temporary relief of minor aches and pains.

Headache
Ibuprofen has also been used satisfactorily in the management of headache. The efficacy of 200
mg of ibuprofen has been reported to be significantly superior to placebo and ASA 650 mg in the
treatment of muscle contraction headaches. No differences in the frequency of side effects were
found in the treatment groups. Similar results were reported in a study with patients referred to a
Headache Clinic with frequent muscle contraction headache.

Soft Tissue Injury

Several studies also document the efficacy of analgesic doses of ibuprofen in the treatment of
soft tissue injuries such as muscular aches or athletic.

Fever
Studies of its efficacy in the management of fever in adults and children demonstrate ibuprofen
to be an effective antipyretic, with a duration of action of up to 8 hours when administered at a
dose of 7.5 mg/kg.

One controlled clinical trial comparing a single dose of ibuprofen 7.5 mg/kg with acetaminophen
12.5 mg/kg demonstrated the superiority of ibuprofen over an 8 hour period.

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DETAILED PHARMACOLOGY

Ibuprofen
Studies in rats indicate that while limited absorption of ibuprofen occurs in the stomach, the
principal site of absorption is the intestine. Single dose studies using C14 labelled ibuprofen in
rats, rabbits and dogs show rapid absorption rates.

Tissue distribution studies performed in rats after both single and repeated doses of 20 mg/kg of
C14 labelled ibuprofen demonstrate broad distribution with accumulation of radioactivity in the
thyroid, adrenals, ovaries, fat and skin. Transplacental passage of ibuprofen was also noted with
similar plasma levels measured in both the pregnant rats and fetuses.

Protein binding studies with plasma levels of 20 μg/mL indicate the percent bound in rats 96%,
dogs 99%, baboons 95% and humans 99.

Four metabolites of ibuprofen have been found in the plasma of rabbits, 3 in rats, none in dogs, 2
in baboons and 2 in humans, with the liver suggested as the principal organ of metabolism.
Excretion of metabolites was noted to varying degrees through both urine and feces indicating
species variability in the bile and kidney excretion ratios.

While the mechanism of action of ibuprofen is not definitely known, it is generally believed to
involve the inhibition of prostaglandin synthesis. Inhibition of prostaglandin biosynthesis
prevents sensitization of tissues by prostaglandins to other inflammatory, pain and
thermoregulatory mediators, hence accounting for the activity of ibuprofen and other
nonsteroidal anti-inflammatory drugs against pain, inflammation and fever.

Inhibition of prostaglandin synthesis by ibuprofen has been demonstrated in several different

experimental models: bull seminal vesicle microsomes, stomach, duodenum, kidney and brain
of the rat, microsomal preparations from rabbit brain and kidney medulla.

The analgesic efficacy of ibuprofen has been demonstrated in several animal models:
phenylbenzoquinone-induced writhing in the mouse, acetylcholine-induced writhing in the
mouse, the Randall-Selitto inflammed paw model in the rat, the mouse hot plate and adjuvant-
induced arthritis model in the rat.

The antipyretic activity of ibuprofen has been demonstrated in yeast-induced fever in rats.

Pseudoephedrine
Pseudoephedrine is a vasopressor with a potency in dogs of approximately one fifth that of
ephedrine, with more pronounced tachyphylaxis. The positive inotropic and chronotropic effects
of pseudoephedrine in dogs are less than those of ephedrine.

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Pressor responses, as well as increased heart rate, induced by pseudoephedrine in anesthetized
dogs are reduced by reserpinization.

Pseudoephedrine constricts all systemic blood vessels in dogs with the exception of the vertebral
and renal vessels; the latter blood vessels are dilated by pseudoephedrine.

The bronchodilating potencies of pseudoephedrine and ephedrine in anesthetized dogs are

approximately equal, but pseudoephedrine produces a greater degree of nasal decongestion with
less cardiovascular involvement than ephedrine.

Doses as high as 200 mg/kg (i.p.) do not increase locomotor activity in mice, but do reduce
wheel-revolving activity. Rectal temperature is decreased by 50 mg/kg doses of
pseudoephedrine, whereas 200 mg/kg, temperature is first decreased and subsequently increased.
Pseudoephedrine does not alter pentobarbital sleep-time. The effects of pseudoephedrine on the
central nervous system are clearly weaker than those of ephedrine, and may involve different
mechanisms.

MICROBIOLOGY
Not applicable.

TOXICOLOGY

Ibuprofen
Single-dose acute toxicity studies indicate that ibuprofen in lethal doses depresses the central
nervous system of rodents and that large doses are ulcerogenic in both rodents and nonrodents.
Ulcerogenesis may occur with both parenteral and oral administration indicating that the
mechanism may have both a systemic as well as topical component.

Single graded doses of ibuprofen were administered by oral intubation or by intraperitoneal or

subcutaneous injection to groups of l0 male albino mice and male albino rats. Gross reactions
were observed and mortalities recorded over a period of l4 days. The LD50 values determined by
this method were 800 mg/kg orally and 320 mg/kg intraperitoneally in the mouse and l600
mg/kg orally and l300 mg/kg subcutaneously in the rat. Acute signs of poisoning were
prostration in mice, and sedation, prostration, loss of righting reflex and laboured respiration in
rats. Death occurred within 3 days from perforated gastric ulcers in mice and intestinal
ulceration in rats, irrespective of the route of administration.

Similar LD50 determinations in other strains of rats and mice are summarized in Table 9.

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Table 9 - Acute Toxicity in Rodents (LD50)

Species Route LD50 Range (mg/kg)

Albino Miceab Oral 800-1000
Intraperitoneal 320
Albino Ratsa Oral 1600
Subcutaneous 1300
Sprague Dawley Ratc 1050
Long Evans Ratd 1000
a
Adams, Bough et al., 1969
b
Aparicio, 1977
c
Fukawa et al., 1982
d
Cioli et al., 1980

In a comparison of several non-steroidal anti-inflammatory drugs (NSAID) including ibuprofen,

male rats were sacrificed and the stomachs removed and examined for ulceration either 3 or 24
hours after oral administration of various single doses of ibuprofen. Using a standard scoring
technique a mean score for each dosage group was calculated and the ulcerogenic potential was
expressed as a minimum ulcerogenic dose. The minimum oral ulcerogenic dose for ibuprofen in
rats was calculated to be 6-13 mg/kg.

Another group studied the production of gastrointestinal lesions in the rat comparing ulcerogenic
doses of ibuprofen and other NSAIDs after oral or intravenous administration. Both male and
female Long Evans rats were used in all experiments. Prior to drug administration the animals
were fasted for 8 hours. After treatment they were fed a normal diet and sacrificed after l7 hours.
Gastric and intestinal mucosa was examined for presence of ulcers. The ulcerogenic dose in
50% of treated animals (UD50) was calculated. The UD50 following oral administration of
ibuprofen was determined to be 70 mg/kg while for intravenous ibuprofen it was 210 mg/kg.
The intestinal UD50 was 88 mg/kg following oral and 172 mg/kg with intravenous
administrations. A calculated "severity index" of gastric lesions was higher by the oral than the
IV route at all doses tested.

Studies of the ulcerogenic potential of ibuprofen are summarized in Table 10.

Table 10 - Single Dose Ulcerogenicity Studies in Rodents

Species Route UD50*(mg/kg) MUD**(mg/kg)

Long Evans Rata Oral 70 50
IV 210 -
Sprague Dawley Ratb Oral - 6-13
*ulcerogenic dose in 50% treated animals
**minimum ulcerogenic dose
a
Cioli et al., 1980
b
Atkinson and Leach, 1976

Various single oral doses of ibuprofen were administered to dogs with subsequent hematologic
examination and biochemical analyses of blood and urine, and examination of feces for occult

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blood. Gross examination of the major organs occurred after the animals were sacrificed. No ill
effects were seen following doses of 20 or 50 mg/kg. Oral doses of 125 mg/kg or greater
produced emesis, scouring, albuminuria, fecal blood loss and erosions in the gastric antrum and
pylorus.

Rats were dosed by the oral route for a specific number of consecutive days, then sacrificed for
examination. The ulcerogenic effect of oral ibuprofen was graded and reported by various
scoring systems such as percent of animals in whom ulcers were produced by a specific dose, or
the UD50.

In one typical such study, Long Evans rats were administered comparative NSAIDs orally once a
day for 5 days. The gastric and small intestinal mucosa were then examined for ulceration. The
UD50, MUD and potency ratio of the drugs tested were calculated. The minimal ulcerogenic
doses of ibuprofen were 25 mg/kg for the stomach and 50 mg/kg for the intestine.

Similar studies of multiple dose ulcerogenic potential of ibuprofen are summarized in Table 11.

Table 11 - Multiple Oral Dose Toxicity Studies

Species Daily Dose Duration Ulcerogenic Factor

Albino Rata 400mg/kg 30 hours Ulcers in 100%
Albino Ratb 4 days UD50 = 455 mg/kg/day
UD28 = 240 mg/kg/day
Long Evans Ratc 5 days MUD = 25 - 50 mg/kg/day
Sprague Dawley Ratd 5.8-225 mg/kg 10 days None
Albino Rate 7.5mg/kg 26 weeks None
180mg/kg 26 weeks Ulcers in 20%
Doge 4mg/kg 30 days None
8mg/kg 30 days 100%
16mg/kg 30 days 100%
a
Parmer and Ghosh, 1981
b
Aparicio, 1977
c
Cioli et al., 1980
d
Paroli et al., 1978
e
Adams, Bough et al., 1969

No other organ systems were generally noted to be significantly affected by these chronic
administration studies. In one 30 day study, Wistar rats receiving 157 mg/kg/day ibuprofen had
serum transaminase levels approximately double of those of a control, untreated group. Lower
doses of ibuprofen in the same study had no significant effect on the activity of these enzymes.

Chronic toxicity studies in dogs demonstrated no gross or clinical signs of toxicity at 4, 8 or 16

mg/kg/day for 30 days. However, in all dogs given 8 or 16 mg/kg/day, postmortem examination
revealed gastric ulcers or erosions. No lesions were observed in dogs given 4 mg/kg/day.
A more complete assessment of chronic toxicity of ibuprofen in dogs studied the effects of
administration of oral doses of 0, 2, 4 or 26 mg/kg/day over 26 weeks. Periodic blood, urine and

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fecal sample analyses were performed. Histologic examination of selected organs and tissues
was performed at the completion of the study. During the 26 week period, some reversible signs
of gastrointestinal disturbance characterized by frequent vomiting, diarrhea, occasional passage
of fresh blood and weight loss occurred in the 2 female dogs but not the males receiving 16
mg/kg ibuprofen. Occult blood was irregularly detected in fecal samples but urinalysis, liver
function tests and other hematologic and blood biochemical values were not altered significantly.
Gross examination of organs was normal except for ulcerative lesions in the gastrointestinal tract
of organs of all dogs receiving 16 mg/kg/day. Dogs given 2 and 4 mg/kg/day suffered no
adverse reactions or gastrointestinal damage.

A study to evaluate the potential carcinogenic activity of ibuprofen involved administration of a

minimum of 100 mg/kg/day to mice for 80 weeks and 60 mg/kg/day to rats for 2 years. The
proportion of animals with tumours of all types examined did not differ from those in the control
group. The studies confirm that in the rat and mouse, ibuprofen does not induce tumours of the
liver or other organs. Further, despite prolonged treatment, no other drug-induced hepatic
lesions were seen in either species.

Teratogenicity studies of ibuprofen have been conducted in rabbits and rats [Adams, Bough et
al., 1969]. Results of the experiments indicate that ibuprofen is not teratogenic when given in
toxic doses to rabbits nor is there embryotoxic or teratogenic activity in pregnant rats even when
administered in ulcerogenic doses.

Effects of ibuprofen on circular strips of fetal lamb ductus arterious indicate that exposure may
produce contraction of the ductus. Such an effect might be anticipated because of the known
prostaglandin inhibiting properties of ibuprofen.

Pseudoephedrine Hydrochloride
Mice injected with toxic doses of pseudoephedrine manifest increased motor activity, penile
erection, mydriasis, and eventually die in respiratory exhaustion. The intravenous LD50 in mice
is approximately 90 mg/kg.

The approximate oral LD50 values for several species are 726 mg/kg (mouse), 2,206 mg/kg (rat),
1,117 mg/kg (rabbit), 105 mg/kg (beagle dog) and 307 mg/kg (mongrel dog). Toxic effects in
these species include decreased respiratory activity, salivation and lacrimation, loss of pupillary
reflex reaction to light, tremor, convulsions and cardiac arrhythmias.

Ibuprofen and Pseudoephedrine Hydrochloride

The oral toxicity of combinations of ibuprofen and pseudoephedrine were evaluated in mice and
rats. The LD50 values derived from these studies are listed in Table 12. From these values, it
was concluded that the combinations tested have a relatively low order of toxicity.

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Table 12 - LD50 values for Ibuprofen and Pseudoephedrine Hydrochloride Combinations

Combination Rats Mice

LD50 (Range) LD50 (Range)
Ibuprofen 200 mg Pseudoephedrine
1.4 (1.4-1.5) 2.4 (1.7-3.4)
30 mg
Ibuprofen 400 mg
1.4 (1.3-1.6) 1.2 (0.42-2.9)
Pseudoephedrine 60 mg
Ibuprofen 200 mg 0.85 (0.68-1.06) 1.8 (1.3-2.5)

A study was conducted to evaluate the potential toxic and teratogenic effects of the combination
product and its individual components, ibuprofen and pseudoephedrine hydrochloride when
administered orally to pregnant rats during the period of major organogenesis. Three groups of
25 mated female rats were each administered the fixed combination of dosage levels of 11.5,
34.5 and 115 mg/kg/day. Two additional groups, composed of identical numbers of animals
were dosed with the individual components, (ibuprofen and pseudoephedrine) at levels of 100
and 15 mg/kg/day, respectively. The control group received the vehicle, 1% aqueous
methylcellulose. The animals were treated for 10 consecutive days from gestation day 6 through
15. During the study, the animals were observed daily for occurrence of changes in external
appearance and behaviour. Body weight and food intake were measured on gestation days, 0, 6,
9, 12, 16, and 20. Cesarean section was performed on gestation day 20. The fetuses were
weighed and examined for external visceral, skeletal developmental malformations and
variations.

Neither the combination drug product, nor its components, ibuprofen and pseudoephedrine
hydrochloride, affected maternal survival at dosage levels employed in this study. Mean
maternal body weight gains and food consumption were reduced during the treatment period in
the high dose combination of (115 mg/kg/day) and ibuprofen (100 mg/kg/day) groups when
compared with the control group. Increased incidence of enlarged mesenteric lymph nodes was
observed in the high-dose combination (115 mg/kg/day), ibuprofen (100 mg/kg/day) and
pseudoephedrine (15 mg/kg/day) groups when compared to the control group. The biological
significance of this finding is unknown.

Mean numbers of viable and dead fetuses, early and late resorption, as well as mean fetal weights
were comparable between the control and all treated groups. The occurrence of developmental
malformations and variations were similar among the control and the treated animals

No clinical sign of maternal or fetal toxicity having teratogenic effects were observed at the
dosage levels selected for this study.

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 REFERENCES

1. Adams SS, Cliffe EE, Lessel B, Nicholson JS. Some biological properties of 2-(4-
isobutylphenyl)-propionic acid. J Pharm Sci 1967; 56:1686.

2. Adams SS, Bough RG, Cliffe EE, Lessel B, Mills RF. Absorption distribution and
toxicity of ibuprofen. Toxicol Appl Pharmacol 1969; 15:310-330.

3. Adams SS, McCullough KF, Nicholson JS. The pharmacological properties of

ibuprofen, an anti-inflammatory, analgesic and antipyretic agent. Arch Int Pharmacdyn
Ther 1969; 178:115-129.

4. Adams SS, Bough RG, Cliffe EE. Some aspects of the pharmacology, metabolism and
toxicology of ibuprofen. Rheumatol Phys Med 1970; 10 (Suppl 10):9-26.

5. Arthritis Advisory Committee. Review of ibuprofen for non-prescription sale. Transcript

of proceedings. Food and Drug Administration, Department of Health and Human
Services, Bethesda. August 18, 1983.

6. Arthritis Drugs Advisory Committee and Nonprescription Drugs Advisory Committee.

Proceedings of Joint Meeting. Centre for Drug Evaluation and Research. Department of
Health and Human Services, Rockville, Maryland. March 28, 1995.

7. Albert KS, Gernaat CM. Pharmacokinetics of ibuprofen. Amer J Med 1984; 77(1A):40-
46.

8. Albert KS, Gillespie WR, Wagner JG, Pau A, Lockwood GF. Effects of age on the
clinical pharmacokinetics of ibuprofen. Am J Med 1984; 77(1A):47-50.

9. American Formulary Hospital Service (McEvoy) - Refer to McEvoy, GK.

10. Antonicelli L. & Tagliabracci A. Asthma death induced by ibuprofen. Monaldi Arch
Chest Dis 1995;50:276-278.

11. Aparicio L. Some aspects of the pharmacology of butibufen, a non-steroidal anti-

inflammatory agent. Arch Int Pharmacodyn Ther 1977; 227:130-141.

12. Atkinson DC, Leach EC. Anti-inflammatory and related properties of 2-(2,4-
diochlorphenoxy) phenylacetic acid (fenclofenac). Agent Actions 1976; 6:657-666.

13. Aviado DM, Wnuck AL, De Beer ES. A comparative study of nasal decongestion by
sympathomimetic drugs. Arch Otolaryngol 1959; 69: 598-605.

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 14. Aviado DM, Wnuch AL, De Beer EJ. Cardiovascular effects of sympathomimetic
bronchodilators: Epinephrine, pseudoephedrine, isoproterenol, methoxyphenamine and
isoprophenamine. J Pharm & Exper Ther. 1958;122: 406-417.

15. Ayres J.G., Fleming D.M. & Whittington R.M. Asthma dealth due to ibuprofen (letter).
Lancet 1987;1(8541):1082.

16. Barry WS, Meinzinger MM, Howse CR. Ibuprofen overdose and exposure in utero:
results from a postmarketing voluntary reporting system. Am J Med 1984; 77(1A):47-50.

17. Bertin L, Pons G, dAthis P, et al. Randomized, double-blind, multi-centre, controlled

trial of ibuprofen versus acetaminophen (paracetamol) and placebo for treatment of
symptoms of tonsillitis and pharyngitis in children. J. Pediatr 1991; 119:811-814.

18. Billings CE, et. Al. Aerospace Medicine. 1974; 45: 551.

19. Bombardier C, Laine L, Reicin A, Shapiro D, Burgo-Vargas R, Davis B, et al.

Comparison of upper gastrointestinal toxicity of refecoxib and naproxen in patients with
rheumatoid arthritis. N Engl J Med 2000; 343:1520-1528.

20. Bright TP, et. al. J Clin Pharmac. 1981; 21:488.

21. Brooks CD, Schlagel CA, Sikhar NC, Sobota JT. Tolerance and pharmacology of
ibuprofen. Curr Ther Res 1973; 15:180-190.

22. Bye C, Hill HM, Hughes DTD, et. al. A comparison of plasma levels of 1(+)
pseudoephedrine following different formulations, and their relation to cardiovascular
and subjective effects in man. Eur J Clin Pharmacol. 1975; 8:47-53.

23. Chahade WH, Federico WA, Joseph H, Cohen M. The evaluation of the analgesic
activity and anti-inflammatory activity of ibuprofen in comparison with aspirin in
patients suffering from osteoarthritis of the hips, knee and/or cervical, dorsal and/or
lumbar spinal column in a double blind study. Revista Brasileria de Medicina 1976;
33:347-350.

24. Cioli V, Putzolu S, Rossi V, Corradino C. A toxicological and pharmacological study of

ibuprofen guaiaicol ester (AF 2259) in the rat. Toxicol Appl Pharmacol 1980; 54:332-
339.

25. Coceani F, White E, Bodach E, Olley PM. Age-dependent changes in the response of the
lamb ductus areriosus to oxygen and ibuprofen. Can J Physiol Pharmacol 1979; 57:825-
831.

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 26. Cooper SA, Needle SE, Kruger GO. Comparative analgesic potency of aspirin and
ibuprofen. J Oral Surgery 1977; 35:898-903.

27. Cooper SA. Five studies on ibuprofen for postsurgical dental pain. Am J Med 1984;
77(1A):70-77.

28. Court H, Volans GN. Poisoning after overdose with non-steroidal anti-inflammatory
drugs. Adv Drug React AC Pois Rev 1984; 3:1-21.

29. Cushman DW, Cheung HS. Effect of substrate concentration on inhibition of

prostaglandin synthetase of bull seminal vesicles by anti-inflammatory drugs and fenamic
acid analogs. Biochim Biophys Acta 1976; 424:449-459.

30. Dawood MY. Ibuprofen and dysmenorrhea. Am J Med 1984; 77(1A):87-94.

31. deBlecourt JJ. A comparative study of ibuprofen (Brufen) and indomethacin in

uncomplicated arthroses. Curr Med Res Opin 1975; 3:477-480.

32. Diamond S. Ibuprofen versus aspirin and placebo in the treatment of muscle contraction
headache. Headache 1983; 23:206-210.

33. Drew CDM, et. Al. Br J Clin Pharmac. 1978; 6:221.

34. Dudkeiwicz J. Ibuprofen-induced gastrointestinal changes. Acta Physiol Pol (Poland)

1981: 32:693-701.

35. FitzGerald GA, Patrono C. The Coxibs, selective inhibitors of cyclooxygenase-2. N

Engl J Med 2001; 345:433-442. Review

36. Fitzpatrick FA, Wynaida MA. In Vivo suppression of prostaglandin biosynthesis by non-
steroidal anti-inflammatory agents. Prostaglandins 1976; 12:1037-1051.

37. Flower RJ, Moncada S, Vane JR. Analgesic-antipyretics and anti-inflammatory agents;
drugs employed in the treatment of gout. In: Gilman AG, Goodman LS, Rall TW, Murad
F. Goodman and Gilman's The pharmacological basis of therapeutics. Toronto: Collier
MacMillan, Canada 1985; 674-689, 700-703.

38. Friedlander A.H., Friedlander I.K. & Yagiela J. Dental management of the child with
developmental dyslexia. ASDC J Dent Child (United States) Jan-Feb 1994; 61:39-45.

39. Fukawa K, Kanezuka T, Ohba S, Kawano O, Hibi M, Misaki N, Sawbe T. Studies on an

anti-inflammatory agent. III. Pharmacological investigations of a new non-steroidal
anti-inflammatory agent: 2-OXO-3(4-(1-OXO-2-isoindolynyl)-phenyl)-butanamide (GP

Children’s MOTRIN Cold McNeil Consumer Healthcare,

(100 mg/5 mL ibuprofen, 15 mg/5 mL pseudoephedrine HCl) Division of Johnson & Johnson Inc.
Page 41 of 48
 650). Arzneimittelforsh 1982; 32:225-230.

40. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal

complications related to use of nonsteroidal anti-inflammatory drugs. Ann Internal Med
1991; 115: 787-796.

41. Gaitonde BB, Dattani K, Morwani K. Antipyretic activity of ibuprofen (Brufen). J

Assoc Physicians India 1973; 21:579-584.

42. Gallardo F, Rossi E. Double-blind evaluation of naproxen and ibuprofen in periodontal

surgery. Pharm Ther Dent 1980; 5:69-72.

43. García Rodríguez LA, Hernández-Díaz S. The risk of upper gastrointestinal

complications associated with non-steroidal anti-inflammatory drugs, glucocorticoids,
acetaminophen, and combinations of these agents. Arthritis Res 2001; 3:98-101.

44. Glass RC, Swannell AJ. Concentrations of ibuprofen in serum and synovial fluid from
patients with arthritis. Br J Clin Pharmacol 1978; 6:453-454.

45. Gookin KS, Forman ES, Vecchio TJ, Wiser WL, Morrison JC. Comparative efficacy of
ibuprofen, indomethacin and placebo in the treatment of primary dysmenorrhea. South
Med J 1983; 76:1361-1362, 1367.

46. Health Canada, TPD Draft Guidance for Industry: Basic Product Monograph Information
for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), June 9, 2003

47. Hillis WS. Areas of emerging interest in analgesia: Cardiovascular complications. Am J

Ther 2002; 9:259-269.

48. Ihles JD. Relief of post-operative pain by ibuprofen: a report of two studies. Can J Surg
1980; 23:288-290.

49. Insel PA. Analgesic-antipyretic and anti-inflammatory agents and drugs employed in the
treatment of gout. In Molinoff PB, Ruddon RW, editors. Goodman & Gilman’s The
Pharmacological Basis of Therapeutics. New York: McGraw-Hill, 1996: 617-657.

50. Jain AK, Ryan Jr C, McMahon FD, Kuebel JO, Walters PJ, Novech C. Analgesic
efficacy of low doses of ibuprofen in dental extraction pain. Clin Pharmacol Ther 1984;
35:249.

51. Juhl RP, Van Thiel DH, Dittert LW, Albert KS, Smith RB. Ibuprofen and sulindac
kinetics in alcoholic liver disease. Clin Pharmacol Therap 1983; 34:104-109.

52. Kaiser DG, Martin RS. Electron-capture GLC determination of ibuprofen in serum. J

Children’s MOTRIN Cold McNeil Consumer Healthcare,

(100 mg/5 mL ibuprofen, 15 mg/5 mL pseudoephedrine HCl) Division of Johnson & Johnson Inc.
Page 42 of 48
 Pharm Sci 1978; 67:627-630.

53. Kaiser DG, Vangiessen GJ. GLC determination of ibuprofen (+)-2-(P-isobutylphenyl)

propionic acid in plasma. J Pharm Sci 1974; 63:219-221.

54. Kauffman RE, Fox B, Gupta N. Ibuprofen antipyresis and pharmacokinetics in children.
Clin Pharmacol Ther 1989; 45:139 (abstract).

55. Kober A, Sjoholm I. The binding sites of human serum albumin for some non-steroidal
anti-inflammatory drugs. Mol Pharmacol 1980; 8:421-426.

56. Konstam MA, Weir MR, Reicin A, Shapiro D, Sperling RS, Barr E, et al. Cardiovascular
thrombotic events in controlled, clinical trials of refecoxib. Circulation 2001; 104:2280-
2288.

57. Kuntzman RG, et. al. The influence of urinary pH on the plasma half-life of
pseudoephedrine in man and dog and a sensitive assay for its determination in human
plasma. Clin Pharmacol Ther. 1971; 12:62.

58. McEvoy GK, Editor. Ibuprofen. In: AFHS DI 1999. Bethesda: American Society of
Health - Systems Pharmacists, 1999. p. 1715 - 1720.

59. McEvoy GK, Editor. Pseudoephedrine. In: AHFS DI 1999. Bethesda: American Society
of Health - Systems Pharmacists, 1999. p. 1140-1142.

60. Miller AC, Buckler JW, Sheldrake FE. Clinical studies of ibuprofen. Curr Med Res Opin
1975; 3:589-593.

61. Mills RF, Adams SS, Cliffe EE, Dickinson W, Nicholson JS. The metabolism of
ibuprofen. Xenobiotica 1973: 3:589-598.

62. Molla AL, Donald JF. A comparative study of ibuprofen and paracetamol in primary
dysmenorrhea. J Int Med Res 1974; 2:395-399.

63. Moller Hansen J, Hallas J, Lauritsen JM, Bytzer P. Non-steroidal anti-inflammatory

drugs and ulcer complications: a risk factor analysis for clinical decision-making. Scand
J Gastroenterol 1996; 31:126-130.

64. Muckle DS. Comparative study of ibuprofen and aspirin in soft tissue injuries.
Rheumatol Rehab 1974; 13:141-147.

65. Naustion AR. Study of the analgesic activities of ibuprofen compared with paracetamol.

Children’s MOTRIN Cold McNeil Consumer Healthcare,

(100 mg/5 mL ibuprofen, 15 mg/5 mL pseudoephedrine HCl) Division of Johnson & Johnson Inc.
Page 43 of 48
 Proceeding of the 13th International Congress of Rheumatology, Kyoto, Japan 1973.

66. Parmer NS, Ghosh MN. Gastric anti-ulcer activity of (+)-cyanidanol-3, a histidine
decarboxylase inhibitor. Eur J Pharmacol 1981; 69:25-32.

67. Paroli E, Nenceni P, Anania MC. Correlations of DNA, RNA and protein levels in
duodenal mucosa with anti-inflammatory potency and disposition to gut damage of non-
steroidal agents. Comparative behaviour of glucametacine, indomethacin,
phenylbutazone and ibuprofen. Arzneimittelforsh 1978; 28:819-824.

68. Patil PN, Tye A, LaPidus JB. A pharmacological study of the ephedrine isomers. J
Pharmacol & Exp Ther. 1965; 148:158-168.

69. Physicians Desk Reference (PDR). Medical Economics Company, Oradell, NJ. 1989:
p.760.

70. Piper JM, Ray WA, Daugherty JR, Griffin MR. Corticosteroid use and peptic ulcer
disease: role of nonsteroidal anti-inflammatory drugs. Ann Internal Med 1991; 114:735-
740.

71. Product Monograph, Children’s MOTRIN* Suspension (Ibuprofen Oral Suspension 100
mg/5mL). McNeil Consumer Healthcare, Feb. 25, 2005.

72. Product Monograph, MOTRIN* Cold and Sinus Caplets (Ibuprofen USP 200 mg/
Pseudoephedrine Hydrochloride USP 30 mg). McNeil Consumer Healthcare, April 16,
2002

73. Romer D. Pharmacological evaluation of mild analgesics. Br J Clin Pharmacol 1980;

10:247S-251S.

74. Roth RP, Cantekin EI, Bluestone CD. Nasal decongestant activity of pseudoephedrine.
Ann Otol Rhinol Laryngol Ther, 1977; 86:235-242.

75. Ruoff G, Williams S, Cooper W, Procaccini RL. Aspirin-acetaminophen vs ibuprofen in

a controlled multi-center double blind study with patients experiencing pain associated
with osteoarthritis. Curr Ther Res 1982; 31:821-831.

76. Schachtel BP, Thoden WR. A placebo-controlled model for assaying systemic analgesics
in children. Clin Pharmacol Ther 1993; 53:593-601.

77. Shapiro SS, Diem K. The effect of ibuprofen in the treatment of dysmenorrhea. Curr
Ther Res 198l; 30:324-334.

78. Sheth UK, Gupta K, Paul T, Pispati PK. Measurement of antipyretic activity of

Children’s MOTRIN Cold McNeil Consumer Healthcare,

(100 mg/5 mL ibuprofen, 15 mg/5 mL pseudoephedrine HCl) Division of Johnson & Johnson Inc.
Page 44 of 48
 ibuprofen and paracetamol in children. J Clin Pharmacol 1980; 20:672-675.

79. Simila S, Kouvalainen K, Keinahen S. Oral antipyretic therapy: evaluation of ibuprofen.

Scand J Rheumatol 1976; 581-583.

80. Szczeklik A, Gryglewski RJ, Czerniawska-Mysik G, Ymuda A. Aspirin induced asthma:

hypersensitivity to fenoprofen and ibuprofen in relation to their inhibitory action on
prostaglandin generation by different microsomal enzymic preparations. J Allergy Clin
Immunol 1976; 58:10-18.

81. Tylson VC, Glynne A. A comparative study of benoxaprofen and ibuprofen in

osteoarthritis in general practice. J Rheumatol 1980; 7 (Suppl 6):132-138.

82. Vecchio TJ, Heilman CJ, O'Connel MJ. Efficacy of ibuprofen in muscle extraction
headache. Clin Pharmacol Ther 1983; 33:199.

83. Walson PD, Galletta G, Braden NJ, et al. Ibuprofen, acetaminophen and placebo
treatment of febrile children. Clin Pharmacol Ther 1989; 46:9-17.

84. Wilson JT, Brown RD, Kearns GL, et al. Single-dose, placebo controlled comparative
study of ibuprofen and acetaminophen antipyresis in children. J Pediatr 1991; 119:803-
811.

85. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal anti-
inflammatory drugs. N Engl J Med 1999; 340:1888-1899.

Children’s MOTRIN Cold McNeil Consumer Healthcare,

(100 mg/5 mL ibuprofen, 15 mg/5 mL pseudoephedrine HCl) Division of Johnson & Johnson Inc.
Page 45 of 48
 IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION salicylates or any ingredient in the

Children’s MOTRIN® Cold formulation (see What the nonmedicinal
ibuprofen and pseudoephedrine hydrochloride ingredients are).
oral suspension • have ASA-sensitive asthma, active or
recurrent stomach or intestinal ulcer,
100 mg/5 mL ibuprofen and gastrointestinal (GI) bleeding or active
15 mg/5 mL pseudoephedrine hydrochloride inflammatory bowel disease (e.g. Crohn’s,
colitis), liver or kidney disease and/or
This leaflet is part III of a three-part suffered significant fluid loss (i.e. diarrhea,
"Product Monograph" published when dehydration), high blood pressure or heart
Children’s MOTRIN® Cold was approved for disease, hyperkalemia (high potassium
sale in Canada and is designed specifically for levels) or Systemic Lupus Erythematosus.
Consumers. This leaflet is a summary and • are pregnant, nursing or taking a
will not tell you everything about Children’s prescription monoamine oxidase inhibitor
MOTRIN® Cold. Contact your doctor or (MAOI - drugs for depression, psychiatric
pharmacist if you have any questions about or emotional conditions or Parkinson’s
the drug. disease) or for two weeks after stopping an
MAOI drug.
ABOUT THIS MEDICATION
What the medicinal ingredients are:
Ibuprofen and Pseudoephedrine
What the medication is used for:
Hydrochloride
Relief of symptoms associated with sinusitis,
the common cold or flu including:
What the nonmedicinal ingredients are:
ƒ Stuffy Nose
(To be supplied as appropriate for the
ƒ Sinus Pressure
formulation)
ƒ Sinus Pain
ƒ Fever
Berry: acesulfame potassium, citric acid, corn starch,
ƒ Body Aches & Pains
D&C yellow #10, FD&C red #40, flavours, glycerin,
ƒ Sore Throat Pain
polysorbate 80, purified water, sodium benzoate, sucrose,
ƒ Headache
xanthan gum.
What it does:
Dye Free Berry: acesulfame potassium, citric acid, corn
Ibuprofen is a pain reliever and fever reducer
starch, flavours, glycerin, polysorbate 80, purified water,
and pseudoephedrine hydrochloride is a nasal
sodium benzoate, sucrose, xanthan gum.
decongestant.
Grape: acesulfame potassium, citric acid,
Ibuprofen is a non-steroidal anti-
corn starch, D&C red #33, FD&C blue #1,
inflammatory drug (NSAID). NSAIDs block
FD&C red #40, flavours, glycerin, polysorbate
the production of prostaglandins that are
80, purified water, sodium benzoate, sucrose,
involved in pain and fever development.
xanthan gum
Pseudoephedrine hydrochloride acts on
What dosage forms it comes in:
receptors in the respiratory mucosa. This
Children’s MOTRIN® Cold is available in
helps to shrink swollen nasal membranes and
Berry, Grape and Dye-Free Berry in a 120 mL
to relieve congestion.
bottle.
When it should not be used:
Do not use Children’s MOTRIN® Cold in WARNINGS AND PRECAUTIONS
patients who:
• are taking acetylsalicylic acid (ASA), BEFORE giving Children’s MOTRIN® Cold to
other NSAIDs, other ibuprofen- or your child, talk to your doctor or pharmacist if:
pseudoephedrine-containing products or ƒ your child is dehydrated (significant fluid
any other pain or fever medicine. loss) due to continued vomiting, diarrhea or
• are allergic to ibuprofen, lack of fluid intake.
pseudoephedrine hydrochloride, products ƒ your child has peptic ulcers or a history of
containing ASA, other NSAIDs or peptic ulcers, stomach bleeding or other

Children’s MOTRIN Cold McNeil Consumer Healthcare,

(100 mg/5 mL ibuprofen, 15 mg/5 mL pseudoephedrine HCl) Division of Johnson & Johnson Inc.
Page 46 of 48
 IMPORTANT: PLEASE READ

bleeding problems, GI tract irritation or is Weight Age Single Oral Dose

prone to GI tract irritation, diabetes, lbs. kg Years mL tsp
glaucoma, high blood pressure, thyroid or Under 36 Under Under 4 As directed by your
heart disease, serious kidney or liver disease, 16 doctor.
asthma, blood problems (low white or red 36-47 16-21.9 4-5 5 mL 1 tsp
blood cell count), bladder problems (pain, 48-95 22-43.9 6-11 10 mL 2 tsp
frequent urination, infection) or is pregnant,
nursing, under a doctor's care for any other Doses may be repeated every 6 hours, up to 4 times a day.
serious condition or taking any other drug.
Do not use Children’s MOTRIN® Cold for children under
Also, see to your doctor if: 4 years of age, unless instructed by your doctor.
ƒ your child does not get any relief within 24
hours. If stomach upset occurs, take with food or milk. If the
ƒ a sore throat is severe, lasts for more than 2 stomach upset does not go away, talk to your doctor.
days or occurs with fever, headache, rash,
nausea or vomiting. Children’s MOTRIN® Cold should not be taken for more
ƒ if any new symptoms appear than 5 days. If symptoms do not improve, or are
accompanied by fever that persists for more than 3 days,
Always tell any other doctor or pharmacist you if new symptoms occur, or if your child feels nervous,
consult, that your child is taking this medicine. dizzy or cannot sleep, stop use and consult your doctor.

INTERACTIONS WITH THIS MEDICATION Overdose:

Call a Poison Control Centre or doctor at once, even if
Do not use this product if your child is taking a there are no symptoms.
prescription monoamine oxidase inhibitor
(MAOI) (certain drugs for depression, Missed Dose:
psychiatric/emotional conditions, Parkinson’s If you miss a dose, take the missed dose as soon as you
disease), or for 2 weeks after stopping a MAOI remember. Do not take two doses at the same time.
drug. If you are uncertain that your
prescription drug contains a MAOI, talk to your SIDE EFFECTS AND WHAT TO DO ABOUT THEM
doctor before taking this product.
If unusual symptoms or any of the following reactions
Talk to a doctor before using Children’s develop during treatment stop using the product and see
MOTRIN® Cold if your child is taking ASA or a doctor immediately:
other NSAIDs, blood thinning medications
(anticoagulants), blood pressure medication ƒ nausea, vomiting, abdominal pain or diarrhea;
(anti-hypertensives), diuretics (water pills), heartburn; bloating; constipation; fluid retention;
lithium, diabetes medications (hypoglycemics), skin rash, itching or high fever; dizziness; any change
decongestant or stimulant products in vision; ringing or buzzing in the ears.
(sympathomimetic agents), methotrexate,
phenytoin, digoxin, oral glucocorticoids or any Ibuprofen may cause a severe allergic reaction that could
other pain or fever medicine (such as include: facial swelling, hives, wheezing, shortness of
acetaminophen). breath, shock or a fast, irregular heartbeat. Any of these
reactions could be serious. If they occur, stop using this
PROPER USE OF THIS MEDICATION product and get emergency medical help immediately.

This is not a complete list of side effects. For any

Shake well before using. Use only enclosed unexpected effects while taking Children’s MOTRIN®
measuring cup. Replace original bottle cap to Cold, contact your doctor or pharmacist.
maintain child resistance.

Use the chart below to find the correct dose. If HOW TO STORE IT
possible, use weight to dose, otherwise use age.
Store at room temperature, 15°C - 30°C (59°F to 86°F). .
Do not keep medicine that is outdated (after the expiry
date).

Children’s MOTRIN Cold McNeil Consumer Healthcare,

(100 mg/5 mL ibuprofen, 15 mg/5 mL pseudoephedrine HCl) Division of Johnson & Johnson Inc.
Page 47 of 48
 IMPORTANT: PLEASE READ

Keep this medication out of the reach of children.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects

information on serious and unexpected effects of drugs . If
you suspect you have had a serious or unexpected reaction
to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789
By email: cadrmp@hc-sc.gc.ca

By regular mail:
National AR Centre
Marketed Health Products Safety and Effectiveness
Information Division
Marketed Health Products Directorate
Tunney’s Pasture, AL 0701C
Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should

contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for

health professionals can be found at:
http://www.website.document
or by contacting the sponsor, McNeil Consumer Healthcare,
Division of Johnson & Johnson Inc. at:
1-888-6MOTRIN (1-888-666-8746)

This leaflet was prepared by McNeil Consumer Healthcare,

Division of Johnson & Johnson Inc.

Last revised: March 4, 2010

Children’s MOTRIN Cold McNeil Consumer Healthcare,

(100 mg/5 mL ibuprofen, 15 mg/5 mL pseudoephedrine HCl) Division of Johnson & Johnson Inc.
Page 48 of 48