NDA 17-463/S-104

Page 3

Motrin®
Ibuprofen Tablets, USP

Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events,
myocardial infarction, and stroke, which can be fatal. This risk may increase with
duration of use. Patients with cardiovascular disease or risk factors for
cardiovascular disease may be at greater risk (See WARNINGS).

• MOTRIN tablets are contraindicated for treatment of peri-operative pain in the

setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of the stomach or intestines, which
can be fatal. These events can occur at any time during use and without warning
symptoms. Elderly patients are at greater risk for serious gastrointestinal events.
(See WARNINGS).

DESCRIPTION
MOTRIN tablets contain the active ingredient ibuprofen, which is (±) - 2 - (p - isobutylphenyl)
propionic acid. Ibuprofen is a white powder with a melting point of 74-77° C and is very slightly
soluble in water (<1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone.
The structural formula is represented below:

MOTRIN tablets, a nonsteroidal anti-inflammatory drug (NSAID), is available in 400 mg, 600 mg,
and 800 mg tablets for oral administration. Inactive ingredients: carnauba wax, colloidal silicon
dioxide, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose,
propylene glycol, titanium dioxide.
CLINICAL PHARMACOLOGY
MOTRIN tablets contain ibuprofen which possesses analgesic and antipyretic activities. Its mode of
action, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin
synthetase inhibition.
In clinical studies in patients with rheumatoid arthritis and osteoarthritis, MOTRIN tablets have been
shown to be comparable to aspirin in controlling pain and inflammation and to be associated with a
statistically significant reduction in the milder gastrointestinal side effects (see ADVERSE
REACTIONS). MOTRIN tablets may be well tolerated in some patients who have had gastrointestinal
side effects with aspirin, but these patients when treated with MOTRIN tablets should be carefully
followed for signs and symptoms of gastrointestinal ulceration and bleeding. Although it is not
definitely known whether MOTRIN tablets causes less peptic ulceration than aspirin, in one study
involving 885 patients with rheumatoid arthritis treated for up to one year, there were no reports of
NDA 17-463/S-104
Page 4

gastric ulceration with MOTRIN tablets whereas frank ulceration was reported in 13 patients in the
aspirin group (statistically significant p<.001).
Gastroscopic studies at varying doses show an increased tendency toward gastric irritation at higher
doses. However, at comparable doses, gastric irritation is approximately half that seen with aspirin.
Studies using 51Cr-tagged red cells indicate that fecal blood loss associated with MOTRIN tablets in
doses up to 2400 mg daily did not exceed the normal range, and was significantly less than that seen in
aspirin-treated patients.
In clinical studies in patients with rheumatoid arthritis, MOTRIN tablets have been shown to be
comparable to indomethacin in controlling the signs and symptoms of disease activity and to be associated
with a statistically significant reduction of the milder gastrointestinal (see ADVERSE REACTIONS) and
CNS side effects.
MOTRIN tablets may be used in combination with gold salts and/or corticosteroids.
Controlled studies have demonstrated that MOTRIN tablets are a more effective analgesic than
propoxyphene for the relief of episiotomy pain, pain following dental extraction procedures, and for the
relief of the symptoms of primary dysmenorrhea.
In patients with primary dysmenorrhea, MOTRIN tablets have been shown to reduce elevated levels of
prostaglandin activity in the menstrual fluid and to reduce resting and active intrauterine pressure, as well
as the frequency of uterine contractions. The probable mechanism of action is to inhibit prostaglandin
synthesis rather than simply to provide analgesia.
The ibuprofen in MOTRIN tablets is rapidly absorbed. Peak serum ibuprofen levels are generally attained
one to two hours after administration. With single doses up to 800 mg, a linear relationship exists between
amount of drug administered and the integrated area under the serum drug concentration vs time curve.
Above 800 mg, however, the area under the curve increases less than proportional to increases in dose.
There is no evidence of drug accumulation or enzyme induction.
The administration of MOTRIN tablets either under fasting conditions or immediately before meals
yields quite similar serum ibuprofen concentration-time profiles. When MOTRIN tablets are administered
immediately after a meal, there is a reduction in the rate of absorption but no appreciable decrease in the
extent of absorption. The bioavailability of the drug is minimally altered by the presence of food.
A bioavailability study has shown that there was no interference with the absorption of ibuprofen when
MOTRIN tablets were given in conjunction with an antacid containing both aluminum hydroxide and
magnesium hydroxide.
Ibuprofen is rapidly metabolized and eliminated in the urine. The excretion of ibuprofen is virtually
complete 24 hours after the last dose. The serum half-life is 1.8 to 2.0 hours.
Studies have shown that following ingestion of the drug, 45% to 79% of the dose was recovered in the
urine within 24 hours as metabolite A (25%), (+)-2-[p-(2hydroxymethyl-propyl) phenyl] propionic acid
and metabolite B (37%), (+)-2-[p-(2carboxypropyl)phenyl] propionic acid; the percentages of free and
conjugated ibuprofen were approximately 1% and 14%, respectively.

INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of MOTRIN tablets and other treatment options
before deciding to use MOTRIN. Use the lowest effective dose for the shortest duration consistent
with individual patient treatment goals (see WARNINGS).

MOTRIN tablets are indicated for relief of the signs and symptoms of rheumatoid arthritis and
osteoarthritis.
MOTRIN tablets are indicated for relief of mild to moderate pain.
MOTRIN tablets are also indicated for the treatment of primary dysmenorrhea.
NDA 17-463/S-104
Page 5

Controlled clinical trials to establish the safety and effectiveness of MOTRIN tablets in children have not
been conducted.

CONTRAINDICATIONS
MOTRIN tablets are contraindicated in patients with known hypersensitivity to Ibuprofen.

MOTRIN tablets should not be given to patients who have experienced asthma, urticaria, or allergic-
type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to
NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions, and
PRECAUTIONS, Preexisting Asthma).

MOTRIN tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary
artery bypass graft (CABG) surgery (see WARNINGS).

WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar
risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To
minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest duration possible. Physicians and patients should remain
alert for the development of such events, even in the absence of previous CV symptoms. Patients
should be informed about the signs and/or symptoms of serious CV events and the steps to take if they
occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious
CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does
increase the risk of serious GI events (see GI WARNINGS).
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first
10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke
(see CONTRAINDICATIONS).

Hypertension
NSAIDs including MOTRIN tablets, can lead to onset of new hypertension or worsening of pre-
existing hypertension, either of which may contribute to the increased incidence of CV events. Patients
taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including MOTRIN tablets, should be used with caution in patients with hypertension. Blood
pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout
the course of therapy.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. MOTRIN tablets
should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including MOTRIN tablets, can cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine,
NDA 17-463/S-104
Page 6

which can be fatal. These serious adverse events can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI
adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation
caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of
patients treated for one year. These trends continue with longer duration of use, increasing the
likelihood of developing a serious GI event at some time during the course of therapy. However, even
short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those
with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic
ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased
risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other
factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use
of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol,
older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or
debilitated patients and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest possible duration. Patients and physicians should remain
alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly
initiate additional evaluation and treatment if a serious GI event is suspected. This should include
discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients,
alternate therapies that do not involve NSAIDs should be considered.

Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-
dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may
precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired
renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the
elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

No information is available from controlled clinical studies regarding the use of MOTRIN tablets in
patients with advanced renal disease. Therefore, treatment with MOTRIN tablets is not recommended
in these patients with advanced renal disease. If MOTRIN tablet therapy must be initiated, close
monitoring of the patients renal function is advisable.

Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure
to MOTRIN tablets. MOTRIN tablets should not be given to patients with the aspirin triad. This
symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal
polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). Emergency help should be
sought in cases where an anaphylactoid reaction occurs.

Skin Reactions
NSAIDs, including MOTRIN tablets, can cause serious skin adverse events such as exfoliative
dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be
fatal. These serious events may occur without warning. Patients should be informed about the signs
NDA 17-463/S-104
Page 7

and symptoms of serious skin manifestations and use of the drug should be discontinued at the first
appearance of skin rash or any other sign of hypersensitivity.

Pregnancy
In late pregnancy, as with other NSAIDs, MOTRIN tablets should be avoided because it may cause
premature closure of the ductus arteriosus.

PRECAUTIONS
General

MOTRIN tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid

insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on
prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to
discontinue corticosteroids.

The pharmacological activity of MOTRIN tablets in reducing fever and inflammation may diminish
the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful
conditions.

Hepatic effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs,
including MOTRIN tablets. These laboratory abnormalities may progress, may remain unchanged, or
may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or
more times the upper limit of normal) have been reported in approximately 1% of patients in clinical
trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice, fulminant
hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or with abnormal liver test values,
should be evaluated for evidence of the development of a more severe hepatic reaction while on
therapy with MOTRIN tablets. If clinical signs and symptoms consistent with liver disease develop, or
if systemic manifestations occur (e.g., eosinophilia, rash, etc.), MOTRIN tablets should be dis-
continued.

Hematological effects
Anemia is sometimes seen in patients receiving NSAIDs, including MOTRIN tablets. This may be
due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon
erythropoiesis. Patients on long-term treatment with NSAIDs, including MOTRIN tablets, should have
their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

In two postmarketing clinical studies the incidence of a decreased hemoglobin level was greater than
previously reported. Decrease in hemoglobin of 1 gram or more was observed in17.1% of 193 patients
on 1600 mg ibuprofen daily (osteoarthritis), and in 22.8% of 189 patients taking 2400 mg of ibuprofen
daily (rheumatoid arthritis). Positive stool occult blood tests and elevated serum creatinine levels were
also observed in these studies.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.
NDA 17-463/S-104
Page 8

Patients receiving MOTRIN tablets who may be adversely affected by alterations in platelet function,
such as those with coagulation disorders or patients receiving anticoagulants should be carefully
monitored.

Preexisting asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-
sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross
reactivity, including bronchospasm, between aspirin and NSAIDs has been reported in such aspirin-
sensitive patients, MOTRIN tablets should not be administered to patients with this form of aspirin
sensitivity and should be used with caution in patients with preexisting asthma.

Ophthalmological effects
Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported. If a
patient develops such complaints while receiving MOTRIN tablets, the drug should be discontinued, and
the patient should have an ophthalmologic examination which includes central visual fields and color
vision testing.

Aseptic Meningitis
Aseptic meningitis with fever and coma has been observed on rare occasions in patients on ibuprofen
therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus
and related connective tissue diseases, it has been reported in patients who do not have an underlying
chronic disease. If signs or symptoms of meningitis develop in a patient on MOTRIN tablets, the
possibility of its being related to MOTRIN tablets should be considered.

Information for Patients

Patients should be informed of the following information before initiating therapy with an NSAID and
periodically during the course of ongoing therapy. Patients should also be encouraged to read the
NSAID Medication Guide that accompanies each prescription dispensed.
• MOTRIN tablets like other NSAIDs, may cause serious CV side effects, such as MI or stroke,
which may result in hospitalization and even death. Although serious CV events can occur
without warning symptoms, patients should be alert for the signs and symptoms of chest pain,
shortness of breath, weakness, slurring of speech, and should ask for medical advice when
observing any indicative sign or symptoms. Patients should be apprised of the importance of
this follow-up (see WARNINGS, Cardiovascular Effects).

• MOTRIN tablets, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side
effects, such as ulcers and bleeding, which may result in hospitalization and even death.
Although serious GI tract ulcerations and bleeding can occur without warning symptoms,
patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask
for medical advice when observing any indicative signs or symptoms including epigastric pain,
dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this
follow-up (see WARNINGS, Gastrointestinal Effects-Risk of Ulceration, Bleeding and
Perforation).

• MOTRIN tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative
dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious
skin reactions may occur without warning, patients should be alert for the signs and symptoms
NDA 17-463/S-104
Page 9

of skin rash and blisters, fever, or other signs hypersensitivity such as itching, and should ask
for medical advice when observing any indicative sign or symptoms. Patients should be advised
to stop the drug immediately if they develop any type of rash and contact their physicians as
soon as possible.

• Patients should promptly report signs or symptoms of unexplained weight gain or edema to
their physicians.

• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and “flu-like” symptoms).
If these occur, patients should be instructed to stop therapy and seek immediate medical
therapy.

• Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing,
swelling of the face or throat). If these occur, patients should be instructed to seek immediate
emergency help (see WARNINGS).

• In late pregnancy, as with other NSAIDs, MOTRIN tablets should be avoided because it may
cause premature closure of the ductus arteriosus.

Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs
should have their CBC and chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash
etc.), or abnormal liver tests persist or worsen, MOTRIN tablets should be discontinued.

Drug Interactions
ACE-inhibitors:
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This
interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-
inhibitors.

Aspirin
When MOTRIN tablets are administered with aspirin, its protein binding is reduced, although the
clearance of free MOTRIN tablets is not altered. The clinical significance of this interaction is not
known; however, as with other NSAIDs, concomitant administration of ibuprofen and aspirin is not
generally recommended because of the potential for increased adverse effects.

Diuretics
Clinical studies, as well as post marketing observations, have shown that MORTIN tablets can reduce
the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to
inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient
should be observed closely for signs of renal failure (see PRECAUTIONS, Renal Effects), as well as
to assure diuretic efficacy.
NDA 17-463/S-104
Page 10

Lithium
Ibuprofen produced an elevation of plasma lithium levels and a reduction in renal lithium clearance in
a study of eleven normal volunteers. The mean minimum lithium concentration increased 15% and the
renal clearance of lithium was decreased by 19% during this period of concomitant drug
administration.

This effect has been attributed to inhibition of renal prostaglandin synthesis by ibuprofen. Thus, when
ibuprofen and lithium are administered concurrently, subjects should be observed carefully for signs of
lithium toxicity. (Read circulars for lithium preparation before use of such concurrent therapy.)

Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney
slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used
when NSAIDs are administered concomitantly with methotrexate.

Warfarin-type anticoagulants
Several short-term controlled studies failed to show that MOTRIN tablets significantly affected
prothrombin times or a variety of other clotting factors when administered to individuals on coumarin-
type anticoagulants. However, because bleeding has been reported when MOTRIN tablets and other
NSAIDs have been administered to patients on coumarin-type anticoagulants, the physician should be
cautious when administering MOTRIN tablets to patients on anticoagulants. The effects of warfarin
and NSAIDs on GI bleeding are synergistic, such that the users of both drugs together have a risk of
serious GI bleeding higher than users of either drug alone.

H-2 Antagonists
In studies with human volunteers, co-administration of cimetidine or ranitidine with ibuprofen had
no substantive effect on ibuprofen serum concentrations.

Pregnancy
Teratogenic effects: Pregnancy Category C
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental
abnormalities. However, animal reproduction studies are not always predictive of human response.
There are no adequate and well-controlled studies in pregnant women. Motrin should be used in
pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic effects
Because of the known effects of NSAIDs on the fetal cardiovascular system (closure of ductus
arteriosus), use during late pregnancy should be avoided.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an
increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects
of MOTRIN tablets on labor and delivery in pregnant women are unknown.

Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human-milk and because of the potential for serious adverse reactions in nursing infants from
NDA 17-463/S-104
Page 11

MOTRIN tablets, a decision should be made whether to discontinue nursing or discontinue the drug,
taking into account the importance of the drug to the mother.

Pediatric Use
Safety and effectiveness of MOTRIN tablets in pediatric patients have not been established.

Geriatric Use
As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

ADVERSE REACTIONS
The most frequent type of adverse reaction occurring with MOTRIN tablets is gastrointestinal. In
controlled clinical trials the percentage of patients reporting one or more gastrointestinal complaints
ranged from 4% to 16%.
In controlled studies when MOTRIN tablets were compared to aspirin and indomethacin in equally
effective doses, the overall incidence of gastrointestinal complaints was about half that seen in either
the aspirin- or indomethacin-treated patients.
Adverse reactions observed during controlled clinical trials at an incidence greater than 1% are listed
in the table. Those reactions listed in Column one encompass observations in approximately 3,000
patients. More than 500 of these patients were treated for periods of at least 54 weeks.
Still other reactions occurring less frequently than 1 in 100 were reported in controlled clinical trials
and from marketing experience. These reactions have been divided into two categories: Column two of
the table lists reactions with therapy with MOTRIN tablets where the probability of a causal
relationship exists: for the reactions in Column three, a causal relationship with MOTRIN tablets has
not been established.
Reported side effects were higher at doses of 3200 mg/day than at doses of 2400 mg or less per day
in clinical trials of patients with rheumatoid arthritis. The increases in incidence were slight and still
within the ranges reported in the table.
 NDA 17-463/S-104
Page 12
Incidence Greater than 1% Precise Incidence Unknown Precise Incidence Unknown
(but less than 3%) (but less than 1%) (but less than 1%)
Probable Causal Relationship** Causal Relationship
Probable Causal Relationship Unknown**
GASTROINTESTINAL
Nausea*, epigastric pain*, heartburn*, diarrhea, Gastric or duodenal ulcer with bleeding and/or perfo-
abdominal distress, nausea and vomiting, ration, gastrointestinal hemorrhage, melena, gastritis,
indigestion, constipation, abdominal cramps or hepatitis, jaundice, abnormal liver function tests; pan-
Pain, fullness of GI tract (bloating and Creatitis
flatulence)

CENTRAL NERVOUS SYSTEM

Dizziness*, headache, nervousness Depression, insomnia, confusion, emotional liability, Paresthesias, hallucinations,
somnolence, aseptic meningitis with fever and coma dream abnormalities, pseudo-
(see PRECAUTIONS) tumor cerebri

DERMATOLOGIC
Rash* (including maculopapular type), pruritus Vesiculobullous eruptions, urticaria, erythema multi- Toxic epidermal necrolysis, pho-
forme, Stevens-Johnson syndrome, alopecia toallergic skin reactions

SPECIAL SENSES
Tinnitus Hearing loss, amblyopia (blurred and/or diminished Conjunctivitis, diplopia, optic
vision, scotomata and/or changes in color vision) (see neuritis, cataracts
PRECAUTIONS)

HEMATOLOGIC
Neutropenia, agranulocytosis, aplastic anemia, Bleeding episodes (eg epistaxis,
hemolytic anemia (sometimes Coombs positive), menorrhagia)
thrombocytopenia with or without purpura,
eosinophilia, decreases in hemoglobin and hematocrit
(see PRECAUTIONS)

METABOLIC/ENDOCRINE
Decreased appetite Gynecomastia, hypoglycemic
reaction, acidosis

CARDIOVASCULAR
Edema, fluid retention (generally responds Congestive heart failure in patients with marginal car- Arrhythmias (sinus tachycardia,
promptly to drug discontinuation) (see PRE- diac function, elevated blood pressure, palpitations sinus bradycardia)
CAUTIONS)

ALLERGIC
Syndrome of abdominal pain, fever, chills, nausea Serum sickness, lupus erythe-
and vomiting; anaphylaxis; bronchospasm (see CON- matosus syndrome. Henoch-
TRAINDICATIONS) Schonlein vasculitis, angioedema

RENAL
Acute renal failure (see PRECAUTIONS), decreased Renal papillary necrosis
creatinine clearance, polyuria, azotemia, cystitis,
Hematuria

MISCELLANEOUS
Dry eyes and mouth, gingival ulcer, rhinitis

* Reactions occurring in 3% to 9% of patients treated with MOTRIN. (Those reactions occurring in less than 3% of the patients are
unmarked.)
** Reactions are classified under "Probable Causal Relationship (PCR)" if there has been one positive rechallenge or if three or more
cases occur which might be causally related. Reactions are classified under "Causal Relationship Unknown" if seven or more events
have been reported but the criteria for PCR have not been met.
NDA 17-463/S-104
Page 13

OVERDOSAGE
Approximately 1½ hours after the reported ingestion of from 7 to 10 MOTRIN tablets (400 mg), a
19-month old child weighing 12 kg was seen in the hospital emergency room, apneic and cyanotic,
responding only to painful stimuli. This type of stimulus, however, was sufficient to induce respiration.
Oxygen and parenteral fluids were given; a greenish-yellow fluid was aspirated from the stomach with
no evidence to indicate the presence of ibuprofen. Two hours after ingestion the child’s condition
seemed stable; she still responded only to painful stimuli and continued to have periods of apnea
lasting from 5 to 10 seconds. She was admitted to intensive care and sodium bicarbonate was
administered as well as infusions of dextrose and normal saline. By four hours post-ingestion she could
be aroused easily, sit by herself and respond to spoken commands. Blood level of ibuprofen was 102.9
µg/mL approximately 8½ hours after accidental ingestion. At 12 hours she appeared to be completely
recovered.
In two other reported cases where children (each weighing approximately 10 kg) accidentally, acutely
ingested approximately 120 mg/kg, there were no signs of acute intoxication or late sequelae. Blood
level in one child 90 minutes after ingestion was 700 µg/mL — about 10 times the peak levels seen in
absorption-excretion studies.
A 19-year old male who had taken 8,000 mg of ibuprofen over a period of a few hours complained of
dizziness, and nystagmus was noted. After hospitalization, parenteral hydration and three days bed
rest, he recovered with no reported sequelae.
In cases of acute overdosage, the stomach should be emptied by vomiting or lavage, though little drug
will likely be recovered if more than an hour has elapsed since ingestion. Because the drug is
acidic and is excreted in the urine, it is theoretically beneficial to administer alkali and
induce diuresis. In addition to supportive measures, the use of oral activated charcoal may
help to reduce the absorption and reabsorption of MOTRIN tablets.

DOSAGE AND ADMINISTRATION

Carefully consider the potential benefits and risks of MOTRIN tablets and other treatment options
before deciding to use MOTRIN tablets. Use the lowest effective dose for the shortest duration
consistent with individual patient treatment goals (see WARNINGS).

After observing the response to initial therapy with MOTRIN tablets, the dose and frequency should
be adjusted to suit an individual patient’s needs.

Do not exceed 3200 mg total daily dose. If gastrointestinal complaints occur, administer MOTRIN
tablets with meals or milk.

Rheumatoid arthritis and osteoarthritis, including flare-ups of chronic disease:

Suggested Dosage: 1200 mg-3200 mg daily (300 mg qid; 400 mg, 600 mg or 800 mg tid or qid).
Individual patients may show a better response to 3200 mg daily, as compared with 2400 mg, although
in well-controlled clinical trials patients on 3200 mg did not show a better mean response in terms of
efficacy. Therefore, when treating patients with 3200 mg/day, the physician should observe sufficient
increased clinical benefits to offset potential increased risk.
The dose should be tailored to each patient, and may be lowered or raised depending on the severity
of symptoms either at time of initiating drug therapy or as the patient responds or fails to respond.
In general, patients with rheumatoid arthritis seem to require higher doses of MOTRIN tablets than do
patients with osteoarthritis.
NDA 17-463/S-104
Page 14

The smallest dose of MOTRIN tablets that yields acceptable control should be employed. A linear
blood level dose-response relationship exists with single doses up to 800 mg (See CLINICAL
PHARMACOLOGY for effects of food on rate of absorption).
The availability of four tablet strengths facilitates dosage adjustment.
In chronic conditions, a therapeutic response to therapy with MOTRIN tablets is sometimes seen in a
few days to a week but most often is observed by two weeks. After a satisfactory response has been
achieved, the patient’s dose should be reviewed and adjusted as required.
Mild to moderate pain: 400 mg every 4 to 6 hours as necessary for relief of pain.
In controlled analgesic clinical trials, doses of MOTRIN tablets greater than 400 mg were no more
effective than the 400 mg dose.
Dysmenorrhea: For the treatment of dysmenorrhea, beginning with the earliest onset of
such pain, MOTRIN tablets should be given in a dose of 400 mg every 4 hours as necessary for the
relief of pain.
HOW SUPPLIED
MOTRIN tablets are available in the following strengths, colors and sizes:

400 mg (white, round, imprinted with MOTRIN 400)

Bottles of 100 NDC 0009-7385-01
Bottles of 500 NDC 0009-7385-02
Unit dose blister of 100 NDC 0009-7385-04
600 mg (white, elliptical, imprinted with MOTRIN 600)
Bottles of 90 NDC 0009-7386-05
Bottles of 100 NDC 0009-7386-01
Bottles of 270 NDC 0009-7386-09
Bottles of 500 NDC 0009-7386-02
Unit dose blister of 100 NDC 0009-7386-04

800 mg (white, elliptical, imprinted with MOTRIN 800)

Bottles of 100 NDC 0009-7387-01
Bottles of 270 NDC 0009-7387-08
Bottles of 500 NDC 0009-7387-02
Unit dose blister of 100 NDC 0009-7387-04

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

Distributed by:
Pharmacia & Upjohn Company
Division of Pfizer Inc, NY, NY 10017
NDA 17-463/S-104
Page 15

Revised January 2006 LAB-0128-2.1

Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)

What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can lead to
death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a
“coronary artery bypass graft (CABG).”

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time
during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death

The chance of a person getting an ulcer or bleeding increases with:

• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health

NSAID medicines should only be used:

• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical
conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
NDA 17-463/S-104
Page 16

Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?

Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID
medicine
• for pain right before or after heart bypass surgery

Tell your healthcare provider:

• about all your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each
other and cause serious side effects. Keep a list of your medicines to show to your
healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their
pregnancy.
• if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

Serious side effects include: Other side effects include:

• heart attack • stomach pain
• stroke • constipation
• high blood pressure • diarrhea
• heart failure from body swelling (fluid retention) • gas
• kidney problems including kidney failure • heartburn
• bleeding and ulcers in the stomach and intestine • nausea
• low red blood cells (anemia) • vomiting
• life-threatening skin reactions • dizziness
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma

Get emergency help right away if you have any of the following symptoms:
• shortness of breath or trouble breathing • slurred speech
• chest pain • swelling of the face or throat
• weakness in one part or side of your body

Stop your NSAID medicine and call your healthcare provider right away if you have any
of the following symptoms:
• nausea • there is blood in your bowel
• more tired or weaker than usual movement or it is black and sticky
• itching like tar
• your skin or eyes look yellow • unusual weight gain
• stomach pain • skin rash or blisters with fever
• flu-like symptoms • swelling of the arms and legs, hands
• vomit blood and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or
pharmacist for more information about NSAID medicines.
NDA 17-463/S-104
Page 17

Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can
cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach
and intestines.

• Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter).
Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription

Generic Name Tradename

Celecoxib Celebrex
Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal Dolobid
Etodolac Lodine, Lodine XL
Fenoprofen Nalfon, Nalfon 200
Flurbirofen Ansaid
Ibuprofen Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone),
Combunox (combined with oxycodone)
Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen Oruvail
Ketorolac Toradol
Mefenamic Acid Ponstel
Meloxicam Mobic
Nabumetone Relafen
Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac
(copackaged with lansoprazole)
Oxaprozin Daypro
Piroxicam Feldene
Sulindac Clinoril
Tolmetin Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.