Canada - English - Health Canada
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Naproxen Sodium Tablets USP
275 mg and 550 mg
Non-Steroidal Anti-Inflammatory Drug
150 Signet Drive,
Submission Control No: 168557
Date of Revision:
May 8, 2014
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Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION........................................................3
SUMMARY PRODUCT INFORMATION .....................................................................3
INDICATIONS AND CLINICAL USE ...........................................................................3
WARNINGS AND PRECAUTIONS...............................................................................5
DRUG INTERACTIONS ...............................................................................................17
DOSAGE AND ADMINISTRATION ...........................................................................19
ACTION AND CLINICAL PHARMACOLOGY .........................................................20
STORAGE AND STABILITY.......................................................................................21
DOSAGE FORMS, COMPOSITION AND PACKAGING ..........................................21
PART II: SCIENTIFIC INFORMATION ............................................................................22
CLINICAL TRIALS .......................................................................................................23
DETAILED PHARMACOLOGY ..................................................................................23
PART III: CONSUMER INFORMATION...........................................................................32
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PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Dosage Form / Strength
Clinically Relevant Non-medicinal
275 mg and 550 mg Film-Coated
For a complete listing see Dosage
Forms, Composition and Packaging
INDICATIONS AND CLINICAL USE
APO-NAPRO-NA or APO-NAPRO-NA DS (naproxen sodium) is indicated for:
The relief of mild to moderately severe pain, accompanied by inflammation in
conditions such as musculo skeletal trauma and post-dental extraction.
The relief of pain associated with post-partum cramping and dysmenorrhea.
For patients with an increased risk of developing cardiovascular and/or
gastrointestinal adverse events, other management strategies that do NOT include the
use of NSAIDs should be considered first. (See CONTRAINDICATIONS and
WARNINGS AND PRECAUTIONS)
Use of APO-NAPRO-NA or APO-NAPRO-NA DS should be limited to the lowest
effective dose for the shortest possible duration of treatment in order to minimize the
potential risk for cardiovascular or gastrointestinal adverse events. (See
CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS)
APO-NAPRO-NA or APO-NAPRO-NA DS, as a NSAID, does NOT treat clinical
disease or prevent its progression.
APO-NAPRO-NA and APO-NAPRO-NA DS, as a NSAID, only relieves symptoms
and decreases inflammation for as long as the patient continues to take it.
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Geriatrics (> 65 years of age):
Evidence from clinical studies and postmarket experience suggests that use in the geriatric
population is associated with differences in safety (see WARNINGS AND PRECAUTIONS).
Pediatrics (< 18 years of age):
Safety and efficacy have not been established in the pediatric population.
APO-NAPRO-NA and APO-NAPRO-NA DS are contraindicated in:
the peri-operative setting of coronary artery bypass graft surgery (CABG). Although
APO-NAPRO-NA and APO-NAPRO-NA DS have NOT been studied in this patient
population, a selective COX-2 inhibitor NSAID studied in such a setting has led to an
increased incidence of cardiovascular/thromboembolic events, deep surgical infections
and sternal wound complications.
the third trimester of pregnancy, because of risk of premature closure of the ductus
arteriosus and prolonged parturition
women who are breastfeeding, because of the potential for serious adverse reactions in
severe uncontrolled heart failure
known hypersensitivity to naproxen sodium or to any of the components/excipients
history of asthma, urticaria, or allergic-type reactions after taking ASA or other NSAIDs
(i.e. complete or partial syndrome of ASA-intolerance - rhinosinusitis,
urticaria/angioedema, nasal polyps, asthma). Fatal anaphylactoid reactions have occurred
in such individuals. 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 reaction. The
potential for cross-reactivity between different NSAIDs must be kept in mind (see
WARNINGS AND PRECAUTIONS: Hypersensitivity Reactions, Anaphylactoid
active gastric / duodenal / peptic ulcer, active GI bleeding.
cerebrovascular bleeding or other bleeding disorders
inflammatory bowel disease
severe liver impairment or active liver disease
severe renal impairment (creatinine clearance <30 mL/min or 0.5 mL/sec) or
deteriorating renal disease (individuals with lesser degrees of renal impairment are at risk
of deterioration of their renal function when prescribed NSAIDs and must be monitored)
(see WARNINGS AND PRECAUTIONS: Renal)
known hyperkalemia (see WARNINGS AND PRECAUTIONS: Renal, Fluid and
children and adolescents less than 18 years of age
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WARNINGS AND PRECAUTIONS
Risk of Cardiovascular (CV) Adverse Events: Ischemic Heart Disease, Cerebrovascular
Disease, Congestive Heart Failure (NYHA II-IV) (See WARNINGS AND
PRECAUTIONS - Cardiovascular).
APO-NAPRO-NA and APO-NAPRO-NA DS are non-steroidal anti-inflammatory drugs
(NSAIDs). Use of some NSAIDs is associated with an increased incidence of
cardiovascular adverse events (such as myocardial infarction, stroke or thrombotic
events) which can be fatal. The risk may increase with duration of use. Patients with
cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
Caution should be exercised in prescribing APO-NAPRO-NA or APO-NAPRO-NA
DS to any patient with ischemic heart disease (including but NOT limited to acute
myocardial infarction, history of myocardial infarction and/or angina),
cerebrovascular disease (including but NOT limited to stroke, cerebrovascular
accident, transient ischemic attacks and/or amaurosis fugax) and/or congestive
heart failure (NYHA II-IV).
Use of NSAIDs, such as APO-NAPRO-NA or APO-NAPRO-NA DS, can promote
sodium retention in a dose-dependent manner, through a renal mechanism, which can
result in increased blood pressure and/or exacerbation of congestive heart failure. (see
also WARNINGS AND PRECAUTIONS: Renal, Fluid and Electrolyte Balance)
Randomized clinical trials with APO-NAPRO-NA and APO-NAPRO-NA DS have not
been designed to detect differences in cardiovascular events in a chronic setting.
Therefore, caution should be exercised when prescribing APO-NAPRO-NA or APO-
Risk of Gastrointestinal (GI) Adverse Events (see WARNINGS AND PRECAUTIONS:
Use of NSAIDs, such as APO-NAPRO-NA or APO-NAPRO-NA DS, is associated with
an increased incidence of gastrointestinal adverse events (such as ulceration, bleeding,
perforation and obstruction of the upper and lower gastrointestinal tract).
Frail or debilitated patients may tolerate side effects less well and therefore special care
should be taken in treating this population. To minimize the potential risk for an adverse
event, the lowest effective dose should be used for the shortest possible duration. As
with other NSAIDs, caution should be used in the treatment of elderly patients who are
more likely to be suffering from impaired renal, hepatic or cardiac function. For high risk
patients, alternate therapies that do not involve NSAIDs should be considered.
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APO-NAPRO-NA or APO-NAPRO-NA DS is NOT recommended for use with other NSAIDs,
with the exception of low-dose ASA for cardiovascular prophylaxis, because of the absence of
any evidence demonstrating synergistic benefits and the potential for additive adverse reactions.
(See DRUG INTERACTIONS: Drug/Drug Interactions, Acetylsalicylic acid (ASA) or other
APO-NAPRO-NA or APO-NAPRO-NA DS (naproxen sodium) should not be used
concomitantly with the related drug naproxen since they circulate in plasma as the naproxen
Carcinogenesis and Mutagenesis
There is no evidence from animal data that naproxen sodium is carcinogenic or mutagenic
(see Part II, TOXICOLOGY, for animal studies).
Cardiovascular and Cerebrovascular
APO-NAPRO-NA and APO-NAPRO-NA DS are non-steroidal anti-inflammatory drugs
(NSAIDs). Use of some NSAIDs is associated with an increased incidence of cardiovascular
adverse events (such as myocardial infarction, stroke or thrombotic events) which can be fatal.
The risk may increase with duration of use. Patients with cardiovascular disease or risk factors
for cardiovascular disease may be at greater risk.
Caution should be exercised in prescribing APO-NAPRO-NA or APO-NAPRO-NA DS to
patients with risk factors for cardiovascular disease, cerebrovascular disease or renal disease,
such as any of the following (NOT an exhaustive list)
Dyslipidemia / Hyperlipidemia
Congestive Heart Failure (NYHA I)
Coronary Artery Disease (Atherosclerosis)
Peripheral Arterial Disease
Creatinine Clearance < 60 mL/min or 1 mL/sec
Use of NSAIDs, such as APO-NAPRO-NA or APO-NAPRO-NA DS, can lead to new
hypertension or can worsen pre-existing hypertension, either of which may increase the risk of
cardiovascular events as described above. Thus blood pressure should be monitored regularly.
Consideration should be given to discontinuing APO-NAPRO-NA or APO-NAPRO-NA DS
should hypertension either develop or worsen with its use.
Use of NSAIDs, such as APO-NAPRO-NA or APO-NAPRO-NA DS, can induce fluid retention
and edema, and may exacerbate congestive heart failure, through a renally-mediated mechanism
(See WARNINGS AND PRECAUTIONS: Renal, Fluid and Electrolyte Balance).
For patients with a high risk of developing an adverse CV event, other management strategies
that do NOT include the use of NSAIDs should be considered first. To minimize the potential
risk for an adverse CV event, the lowest effective dose should be used for the shortest
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Endocrine and Metabolism
Corticosteroids: APO-NAPRO-NA or APO-NAPRO-NA DS (naproxen sodium) is NOT a
substitute for corticosteroids. It does NOT treat corticosteroid insufficiency. Abrupt
discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness.
Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a
decision is made to discontinue corticosteroids (see DRUG INTERACTIONS: Drug-Drug
Serious GI toxicity (sometimes fatal), such as ulceration, inflammation, gastrointestinal bleeding,
perforation and obstruction of the upper and lower gastrointestinal tract, can occur at any time,
with or without warning symptoms, in patients treated with NSAIDs, such as APO-NAPRO-NA
or APO-NAPRO-NA DS. Minor upper GI problems, such as dyspepsia, commonly occur at any
time. Health care providers should remain alert for ulceration and bleeding in patients treated
with APO-NAPRO-NA OR APO-NAPRO-NA DS, even in the absence of previous GI tract
symptoms. 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, the lowest effective dose should be used for the shortest possible
duration. For high risk patients, alternate therapies that do not involve NSAIDs should be
considered (see WARNINGS AND PRECAUTIONS: Special Populations, Geriatrics).
Patients should be informed about the signs and/or symptoms of serious GI toxicity and
instructed to discontinue using APO-NAPRO-NA or APO-NAPRO-NA DS and seek emergency
medical attention if they experience any such symptoms. The utility of periodic laboratory
monitoring has NOT been demonstrated, nor has it been adequately assessed. Most patients who
develop a serious upper GI adverse event on NSAID therapy have no symptoms. Upper GI ulcers,
gross bleeding or perforation, caused by NSAIDs, appear to 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, thus increasing the likelihood of developing a serious GI event at some time during the
course of therapy. Even short-term therapy has its risks.
Caution should be taken if prescribing APO-NAPRO-NA or APO-NAPRO-NA DS to
patients with a prior history of peptic / duodenal ulcer disease or gastrointestinal bleeding as
these individuals have a greater than 10-fold higher risk for developing a GI bleed when
taking a NSAID than patients with neither of these risk factors. Other risk factors for GI
ulceration and bleeding include the following: Helicobacter pylori infection, increased age,
prolonged use of NSAID therapy, excess alcohol intake, smoking, poor general health status
or concomitant therapy with any of the following:
Anti-coagulants (e.g. warfarin)
Anti-platelet agents (e.g. ASA, clopidogrel)
Oral corticosteroids (e.g. prednisone)
Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. citalopram, fluoxetine, paroxetine,
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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 a NSAID. Should urinary symptoms occur, in the absence of an
alternate explanation, treatment with APO-NAPRO-NA or APO-NAPRO-NA DS should be
stopped to ascertain if symptoms disappear. This should be done before urological
investigations or treatments are carried out.
NSAIDs inhibiting prostaglandin biosynthesis interfere with platelet function to varying degrees;
patients who may be adversely affected by such an action, such as those on anti-coagulants or
suffering from haemophilia or platelet disorders should be carefully observed when APO-
NAPRO-NA or APO-NAPRO-NA DS is administered.
Anti-coagulants: Numerous studies have shown that the concomitant use of NSAIDs and
anticoagulants increases the risk of bleeding. Concurrent therapy of APO-NAPRO-NA or APO-
NAPRO-NA DS with warfarin requires close monitoring of the international normalized ratio
Even with therapeutic INR monitoring, increased bleeding may occur.
Anti-platelet Effects: NSAIDs inhibit platelet aggregation and have been shown to prolong
bleeding time in some patients. Unlike acetylsalicylic acid (ASA), their effect on platelet
function is quantitatively less, or of shorter duration, and is reversible.
APO-NAPRO-NA or APO-NAPRO-NA DS and other NSAIDs have no proven efficacy as
anti-platelet agents and should NOT be used as a substitute for ASA or other anti-platelet
agents for prophylaxis of cardiovascular thromboembolic diseases. Anti-platelet therapies (e.g.
ASA) should NOT be discontinued. There is some evidence that use of NSAIDs with ASA
can markedly attenuate the cardioprotective effects of ASA. (see DRUG INTERACTIONS:
Drug- Drug Interactions, Acetylsalicylic Acid or other NSAIDs)
Concomitant administration of APO-NAPRO-NA or APO-NAPRO-NA DS with low dose ASA
increases the risk of GI ulceration and associated complications.
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Blood dyscrasias: Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic
anemia and agranulocytosis) associated with the use of NSAIDs are rare, but could occur with
Anemia is sometimes seen in patients receiving NSAIDs, including APO-NAPRO-NA or APO-
NAPRO-NA DS. This may be due to fluid retention, GI blood loss, or an incompletely described
effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including APO-
NAPRO-NA or APO-NAPRO-NA DS, should have their hemoglobin or hematocrit checked if
they exhibit any signs or symptoms of anemia or blood loss.
As with other NSAIDs, borderline elevations of one or more liver enzyme tests (AST, ALT,
alkaline phosphatase) 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 function 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, liver necrosis and hepatic failure, some of them with fatal
outcomes, have been reported with NSAIDs.
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.
Anaphylactoid Reactions: As with NSAIDs in general, anaphylactoid reactions have occurred in
patients without known prior exposure to naproxen sodium . In post-marketing experience, rare
cases of anaphylactic/ anaphylactoid reactions and angioedema have been reported in patients
receiving naproxen sodium. APO-NAPRO-NA or APO-NAPRO-NA DS should NOT be given
to patients with the ASA-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 ASA or other NSAIDs (see CONTRAINDICATIONS).
ASA-Intolerance: APO-NAPRO-NA or APO-NAPRO-NA DS should NOT be given to patients
with complete or partial syndrome of ASA-intolerance (rhinosinusitis, urticaria/angioedema,
nasal polyps, asthma) in whom asthma, anaphylaxis, urticaria/angioedema, rhinitis or other
allergic manifestations are precipitated by ASA or other NSAIDs. 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
reaction (see CONTRAINDICATIONS).
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Cross-sensitivity: Patients sensitive to one NSAID may be sensitive to any of the other NSAIDs
Serious skin reactions: (See WARNINGS AND PRECAUTIONS: Skin)
(See WARNINGS AND PRECAUTIONS: Infection, Aseptic Meningitis)
APO-NAPRO-NA or APO-NAPRO-NA DS, in common with other NSAIDs, may mask signs
and symptoms of an underlying infectious disease.
Aseptic Meningitis: Rarely, 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 tissue
diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the health care provider must
be vigilant to the development of this complication.
Some patients may experience drowsiness, dizziness, blurred vision, vertigo, tinnitus, hearing
loss, insomnia or depression with the use of NSAIDs, such as APO-NAPRO-NA or APO-
NAPRO-NA DS. If patients experience such adverse reaction(s), they should exercise caution in
carrying out activities that require alertness.
Blurred and/or diminished vision has been reported with the use of NSAIDs. If such symptoms
develop APO-NAPRO-NA or APO-NAPRO-NA DS should be discontinued and an
ophthalmologic examination performed. Ophthalmologic examination should be carried out at
periodic intervals in any patient receiving APO-NAPRO-NA or APO-NAPRO-NA DS for an
extended period of time.
(See CONTRAINDICATIONS: Coronary Artery Bypass Graft Surgery)
(See WARNINGS AND PRECAUTIONS: Neurologic)
Long term administration of NSAIDs to animals has resulted in renal papillary necrosis and other
abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis,
hematuria, low grade proteinuria and occasionally nephrotic syndrome.
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Renal insufficiency due to NSAID use is seen in patients with pre-renal conditions leading to
reduction in renal blood flow or blood volume. Under these circumstances, renal prostaglandins
help maintain renal perfusion and glomerular filtration rate (GFR). In these patients, administration
of a NSAID may cause a reduction in prostaglandin synthesis leading to impaired renal function.
Patients at greatest risk of this reaction are those with pre-existing renal insufficiency (GFR < 60
mL/min or 1 mL/s), dehydrated patients, patients on salt restricted diets, those with congestive
heart failure, cirrhosis, liver dysfunction, taking angiotensin-converting enzyme inhibitors,
angiotensin receptor blockers, cyclosporin, diuretics, and those who are 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 a
NSAID under stable conditions may decompensate during periods of added stress (e.g.
dehydration due to gastroenteritis). Discontinuation of NSAIDs is usually followed by recovery to
the pre-treatment state.
Caution should be used when initiating treatment with NSAIDs, such as APO-NAPRO-NA or
APO-NAPRO-NA DS, in patients with considerable dehydration. Such patients should be
rehydrated prior to initiation of therapy. Caution is also recommended in patients with pre-
existing kidney disease.
Advanced Renal Disease: (See CONTRAINDICATIONS)
Fluid and Electrolyte Balance: Use of NSAIDs, such as APO-NAPRO-NA or APO-NAPRO-
NA DS, can promote sodium retention in a dose-dependent manner, which can lead to fluid
retention and edema, and consequences of increased blood pressure and exacerbation of
congestive heart failure. Thus, caution should be exercised in prescribing APO-NAPRO-NA or
APO-NAPRO-NA DS in patients with a history of congestive heart failure, compromised
cardiac function, hypertension, increased age or other conditions predisposing to fluid retention
(see WARNINGS AND PRECAUTIONS: Cardiovascular).
Use of NSAIDs, such as APO-NAPRO-NA or APO-NAPRO-NA DS, can increase the risk of
hyperkalemia, especially in patients with diabetes mellitus, renal failure, increased age, or those
receiving concomitant therapy with adrenergic blockers, angiotensin-converting enzyme
inhibitors, angiotensin-II receptor antagonists, cyclosporin, or some diuretics. Electrolytes
should be monitored periodically (see CONTRAINDICATIONS).
Each APO-NAPRO-NA tablet contains approximately 25 mg of sodium and each APO-
NAPRO-NA DS tablet contains approximately 50 mg of sodium. This should be considered
in patients whose overall intake of sodium must be markedly restricted.
It is possible that patients with questionable or compromised cardiac function may be at greater
risk when taking APO-NAPRO-NA or APO-NAPRO-NA DS.
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.
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The use of APO-NAPRO-NA or APO-NAPRO-NA DS, as with any drug known to inhibit
cyclooxygenase/ prostaglandin synthesis, may impair fertility and is not recommended in
women attempting to conceive. Therefore, in women who have difficulties conceiving, or who
are undergoing investigation of infertility, withdrawal of APO-NAPRO-NA or APO-NAPRO-
NA DS should be considered.
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
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 skin rash they should discontinue their NSAID and contact their physician for
assessment and advice, including which additional therapies to discontinue.
Pregnant Women: APO-NAPRO-NA or APO-NAPRO-NA DS is CONTRAINDICATED
for use during the third trimester of pregnancy because of risk of premature closure of the
ductus arteriosus and the potential to prolong parturition (see TOXICOLOGY).
Caution should be exercised in prescribing APO-NAPRO-NA or APO-NAPRO-NA DS
during the first and second trimesters of pregnancy (see TOXICOLOGY).
Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or the embryo-foetal
development. Data from epidemiological studies suggest an increased risk of miscarriage and of
cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy.
In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in
increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased
incidences of various malformations, including cardiovascular, have been reported in animals
given a prostaglandin synthesis inhibitor during the organogenetic period.
APO-NAPRO-NA or APO-NAPRO-NA DS is not recommended in labour and delivery
because, through their prostaglandin synthesis inhibitory effect, they may adversely affect
Nursing Women: (See CONTRAINDICATIONS)
Pediatrics: (See CONTRAINDICATIONS)
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Geriatrics: Patients older than 65 years (referred to in this document as older or elderly) and
frail or debilitated patients are more susceptible to a variety of adverse reactions from NSAIDs.
The incidence of these adverse reactions increases with dose and duration of treatment. In
addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal GI
events are in this population. Older patients are also at risk of lower esophageal injury including
ulceration and bleeding. For such patients, consideration should be given to a starting dose
lower than the one usually recommended, with individual adjustment when necessary and under
Monitoring and Laboratory Tests
Patients on long-term treatment with APO-NAPRO-NA or APO-NAPRO-NA DS should
have their blood pressure monitored regularly and an ophthalmic examination should be
carried out at periodic intervals (See WARNINGS AND PRECAUTIONS: Cardiovascular
Hemoglobin, hematocrit, red blood cells (RBCs), white blood cells (WBCs), and platelets should
be checked in patients on long-term treatment with APO-NAPRO-NA or APO-NAPRO-NA DS.
Additionally, concurrent therapy with warfarin requires close monitoring of the international
normalized ratio (INR) (See WARNINGS AND PRECAUTIONS: Hematology).
Serum transaminase and bilirubin should be monitored regularly during APO-NAPRO-NA or
APO-NAPRO-NA DS therapy (see WARNINGS AND PRECAUTIONS: Hepatic, Biliary,
Serum creatinine, creatine clearance and serum urea should be checked in patient during
APO-NAPRO-NA or APO-NAPRO-NA DS therapy. Electrolytes including serum
potassium should be monitored periodically (see WARNINGS AND PRECAUTIONS:
Monitoring of plasma lithium concentration is recommended when stopping or starting APO-
NAPRO-NA or APO-NAPRO-NA DS therapy.
The administration of APO-NAPRO-NA or APO-NAPRO-NA DS (naproxen sodium) may result
in increased urinary values for 17-ketogenic steroids because of an interaction between the drug
and/or its metabolites with m-dinitrobenzene used in this assay. Although 17-hydroxy
corticosteroid measurements (Porter Silber test) do not appear to be artifactually altered, it is
suggested that therapy with APO-NAPRO-NA or APO-NAPRO-NA DS be temporarily
discontinued 48 hours before adrenal function tests are performed. The drug may interfere with
some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). (See WARNINGS AND
PRECAUTIONS and DRUG INTERACTIONS sections)
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Adverse Drug Reaction Overview
The most common adverse reactions encountered with nonsteroidal anti-inflammatory drugs are
gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities
have occurred particularly in the elderly.
As with all drugs in this class, the frequency and severity of adverse events depends on several
factors: the dose of the drug and duration of treatment; the age, the sex, physical condition of the
patient; any concurrent medical diagnoses or individual risk factors.
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.
Adverse reactions reported in controlled clinical trials are listed below.
Table 1: Most Common Clinical Trial Adverse Drug Reactions (3%-9% and 1%-3%)
Heartburn, constipation, abdominal pain, nausea
Diarrhea, dyspepsia, stomatitis, diverticulitis
Central Nervous System
Headache, dizziness, drowsiness
Light-headedness, vertigo, depression, fatigue.
because of the severity of some of these complaints
(headache and dizziness).
Pruritus, ecchymoses, skin eruptions
Dyspnea, peripheral edema
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Table 2: Less Common Clinical Trial Adverse Drug Reactions (<1%)
Gastrointestinal: gastrointestinal bleeding, hematemesis, melena, peptic ulceration
with or without bleeding and/or perforation, vomiting, ulcerative
Central Nervous System: inability to concentrate, malaise, myalgia, insomnia and cognitive
memory, difficulty with calculations).
alopecia, urticaria, skin rash, erythema multiforme,
Stevens-Johnson syndrome, epidermal necrolysis, photosensitive
dermatitis, exfoliative dermatitis, erythema nodosum.
abnormal liver function tests, jaundice, cholestasis and hepatitis.
congestive heart failure and vasculitis.
Glomerular nephritis, hematuria, interstitial nephritis, nephrotic
syndrome, nephropathy and tubular necrosis.
agranulocytosis, aplastic anemia and hemolytic anemia.
hearing impairment and visual disturbances.
muscle weakness, anaphylactoid reactions, menstrual disorders,
pyrexia (chills and fever), angioneurotic edema, hyperglycemia,
hypoglycemia and eosinophilic pneumonitis.
Post-Market Adverse Drug Reactions
The following adverse events have been reported with NSAIDs including naproxen and
Gastrointestinal: Inflammation, bleeding (sometimes fatal, particularly in the
elderly), ulceration, perforation and obstruction of the upper or
lower gastrointestinal tract. Oesophagitis, gastritis, pancreatitis,
stomatitis. Exacerbation of ulcerative colitis and Crohn’s disease.
dyspepsia, abdominal pain, nausea, vomiting,
diarrhoea, flatulence, constipation, haematemesis, melaena.
Blood and Lymphatic
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anaemia , leucopoenia, thrombocytopenia
Metabolic and Nutrition
depression, dream abnormalities, insomnia
dizziness, drowsiness, headache, lightheadedness, retrobulbar
visual disturbances, corneal opacity, papillitis, papilloedema
Ear and Labyrinth
hearing impairment, hearing disturbances, tinnitus, vertigo
palpitations, cardiac failure has been reported in association with
NSAID treatment, congestive heart failure
Respiratory, Thoracic and
Clinical trial and epidemiological data suggest that use of coxibs
and some NSAIDs (particularly at high doses and in long term
treatment) may be associated with a small increased risk of
arterial thrombotic events (for example myocardial infarction or
dyspnoea, pulmonary oedema, asthma, eosinophilic pneumonitis.
hepatitis (some cases of hepatitis have been fatal), jaundice.
Skin and Subcutaneous
Renal and Urinary
General Disorders and
ecchymoses, itching (pruritus), purpura, skin eruptions, sweating,
epidermolysis bullosa and angioneurotic oedema.
pseudoporphyria occur, treatment should be discontinued and the
myalgia, muscle weakness.
disease, renal failure, renal papillary necrosis
oedema, thirst, pyrexia (chills and fever), malaise
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abnormal liver function tests, raised serum creatinine
Acetylsalicylic acid (ASA) or other NSAIDs: The use of APO-NAPRO-NA or APO-NAPRO-
NA DS in addition to any other NSAID, including over-the-counter ones (such as ASA and
ibuprofen) for analgesic and/or anti-inflammatory effects is NOT recommended because of the
absence of any evidence demonstrating synergistic benefits and the potential for additive
The exception is the use of low dose ASA for cardiovascular protection, when another NSAID is
being used for its analgesic/anti-inflammatory effect, keeping in mind that combination NSAID
therapy is associated with additive adverse reactions.
Some NSAIDs (e.g. ibuprofen) may interfere with the anti-platelet effects of low dose ASA,
possibly by competing with ASA for access to the active site of cyclooxygenase-1.
Albumin Bound Drugs: Naproxen is highly bound to plasma albumin; it thus has a theoretical
potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants,
sulphonylureas, hydantoins, other NSAIDs and aspirin. Similarly, patients receiving APO-
NAPRO-NA or APO-NAPRO-NA DS and a hydantoin, sulfonamide or sulfonylurea should be
observed for adjustment of dose if required.
Antacids: The rate of absorption of naproxen is altered by concomitant administration of
antacids but is not adversely influenced by the presence of food.
Anti-coagulants: (See WARNINGS AND PRECAUTIONS: Hematologic, Anticoagulants)
Anti-hypertensives: NSAIDs may diminish the anti-hypertensive effect of angiotensin
converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).
Concomitant use of NSAIDs with ACE inhibitors or angiotensin receptor blockers may increase
the risk of renal dysfunction, especially in patients with pre-existing poor renal function (see
WARNINGS AND PRECAUTIONS: Renal).
Combinations of ACE inhibitors, angiotensin-II antagonists, or diuretics with NSAIDs might
have an increased risk for acute renal failure and hyperkalemia. Blood pressure and renal
function (including electrolytes) should be monitored more closely in this situation, as
occasionally there can be a substantial increase in blood pressure.
APO-NAPRO-NA, APO-NAPRO-NA DS and other non-steroidal anti-inflammatory drugs can
reduce the antihypertensive effect of propranolol and other beta blockers as well as other
Page 18 of 35
Anti-platelet Agents (including ASA): There is an increased risk of bleeding, via inhibition of
platelet function, when anti-platelet agents are combined with NSAIDs, such as APO-NAPRO-
NA or APO-NAPRO-NA DS (see WARNINGS AND PRECAUTIONS: Hematologic, Anti-
Concomitant administration of cholestyramine can delay the absorption of naproxen, but does
not affect its extent.
Cyclosporin: Inhibition of renal prostaglandin activity by NSAIDs may increase the plasma
concentration of cyclosporine and/or the risk of cyclosporine induced nephrotoxicity. Patients
should be carefully monitored during concurrent use.
Digoxin: Concomitant administration of an NSAID with digoxin can result in an increase in
digoxin concentrations which may result in digitalis toxicity. Increased monitoring and dosage
adjustments of digitalis glycosides may be necessary during and following concurrent NSAID
Diuretics: Clinical studies as well as post-marketing observations have shown that NSAIDs can
reduce the effect of diuretics.
Glucocorticoids: Some studies have shown that the concomitant use of NSAIDs and oral
glucocorticoids increases the risk of GI adverse events 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 a
NSAID, as increased lithium concentrations can occur.
Methotrexate: Caution is advised in the concomitant administration of naproxen and
methotrexate since naproxen and other non-steroidal anti-inflammatory agents have been
reported to reduce the tubular secretion of methotrexate in an animal model, thereby possibly
enhancing its toxicity.
Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma
half-life significantly. Caution is advised when probenecid is administered concurrently.
Selective Serotonin Reuptake Inhibitors (SSRIs): Concomitant administration of NSAIDs and
SSRIs may increase the risk of gastrointestinal ulceration and bleeding (see Warnings and
Precautions - Gastrointestinal).
Page 19 of 35
Concomitant administration of food can delay the absorption of naproxen, but does not affect its
Interactions with herbal products have not been established.
(See WARNINGS AND PRECAUTIONS: Monitoring and Laboratory Tests).
There are no specific studies about effects on the ability to drive vehicles and to use machinery.
Patients who experience visual disturbances or other central nervous system disturbances should
refrain from these activities.
Concurrent use of alcohol with an NSAID may increase the risk of gastrointestinal side effects,
including ulceration and hemorrhage.
DOSAGE AND ADMINISTRATION
Recommended Dose and Dosage Adjustment
The recommended starting dose of APO-NAPRO-NA (naproxen sodium) for adults is two
275 mg tablets, followed by one 275 mg tablet every 6 to 8 hours, as required. The total
daily dose should not exceed 5 tablets (1375 mg). Alternatively, one APO-NAPRO-NA DS
tablet (550 mg naproxen sodium) given twice daily may be used.
The missed dose should be taken as soon as remembered, and then the regular dosing schedule
should be continued. Two doses of APO-NAPRO-NA or APO-NAPRO-NA DS should not be
taken at the same time.
For management of a suspected drug overdose, contact your regional Poison Control Centre.
Symptoms and Signs
Significant overdosage may be characterized by drowsiness, dizziness, disorientation, indigestion,
epigastric pain, abdominal discomfort, nausea, vomiting, transient alterations in liver function,
hypoprothrombinemia, renal dysfunction , metabolic acidosis and apnea. Because APO-NAPRO-
NA or APO-NAPRO-NA DS may be rapidly absorbed, high and early blood levels should be
anticipated. A few patients have experienced convulsions, but it is not clear whether or not these
were naproxen related.
Page 20 of 35
Gastrointestinal bleeding may occur. Hypertension, acute renal failure, respiratory depression
and coma may occur after the ingestion of NSAIDs but are rare. Anaphylactoid reactions have
been repeated with therapeutic ingestion of NSAIDs, and may occur following an overdose.
Patients should be managed by symptomatic and supportive care following NSAIDs overdose.
There are no specific antidotes. Prevention of further absorption (e.g. activated charcoal) may be
indicated in patients seen within 4 hours of ingestion with symptoms or following a large
overdose. Forced diuresis, alkalinization of urine, haemodialysis, or haemoperfusion may not be
useful due to high protein binding.
ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
Naproxen sodium has demonstrated analgesic and anti-inflammatory properties in human clinical
studies and in classical animal test systems. It exhibits an anti-inflammatory effect even in
adrenalectomized animals and therefore its action is not mediated through the pituitary-adrenal
axis. It is not a corticosteroid. It inhibits prostaglandin synthetase, as do certain other non-
steroidal analgesic/anti-inflammatory agents. As with other agents, however, the exact
mechanism of its anti-inflammatory and analgesic actions is not known.
(See DETAILED PHARMACOLOGY)
Naproxen sodium is freely soluble in water and is completely absorbed from the gastrointestinal
tract. Plasma levels are obtained in patients within 20 minutes and peak levels in approximately 1
hour. It is extensively bound to plasma protein and has a plasma half-life of approximately 13
hours. The preferred route of excretion is via the urine with only 1% of the dose excreted in the
Page 21 of 35
STORAGE AND STABILITY
Store at room temperature (15 to 30°C) in a well-closed container. Keep out of reach
DOSAGE FORMS, COMPOSITION AND PACKAGING
In addition to naproxen sodium, each
tablet and each
tablet contains the
ingredients microcrystalline cellulose, dextrates,
stearate, stearic acid, colloidal silicon dioxide, hydroxypropyl cellulose,
polyethylene glycol, titanium dioxide and FD&C Blue #2.
APO-NAPRO-NA (naproxen sodium 275 mg) is available as oval-shaped blue film-coated
on one side and plain on
other contains 275 mg of naproxen
APO-NAPRO-NA 275 mg tablets are available in bottles of 100 and 500.
APO-NAPRO-NA DS (naproxen sodium 550 mg) is available as oval shaped blue, biconvex
film coated tablets
"AP0-550" on one
side and plain
other, contains 550 mg
sodium. APO-NAPRO-NA DS 550 mg tablets are available in bottles of 100 and 500.
Page 22 of 35
PART II: SCIENTIFIC INFORMATION
Chemical name: 2-Napthaleneacetic acid, 6-methoxy-α-methyl-, sodium salt
Molecular formula and molecular mass: C
Physicochemical properties: Naproxen sodium is a white to creamy white, crystalline
solid, freely soluble in water with a melting point of about
255°C with decomposition.
Page 23 of 35
A randomized, single dose, double-blinded, 2-way crossover comparative bioavailability study,
conducted under fasting conditions, was performed on healthy male volunteers. The results obtained
from 16 volunteers who completed the study are summarized in the following table. The rate and
extent of absorption of naproxen was measured and compared following a single oral dose (2 x 275
mg tablets) of Apo-Napro-Na (naproxen) 275 mg tablet (Apotex Inc.) and Anaprox (naproxen) 275
mg tablet (Hoffmann-La Roche Limited).
(2 x 275 mg)
From Measured Data
Arithmetic Mean (CV%)
94.7 – 99.8
94.4 – 100.0
92.3 – 104.0
* Apo–Napro-Na (naproxen) 275 mg tablets (Apotex Inc.)
(naproxen) 275 mg tablets (Hoffmann-La Roche Limited) was purchased in Canada.
For balanced treatment sequence, results are based on Geometric means. For unbalanced
treatment sequence, results are based on Least Squares Means (LSM).
Expressed as arithmetic means (CV%) only.
A variety of pharmacologic tests were employed in assessing the analgesic and anti-
inflammatory activities of naproxen sodium. It has been convincingly shown in man and animals
that regardless of which drug (naproxen or naproxen sodium) is administered, the circulating
moiety in the plasma is the same naproxen anion. The drug was active in all tests used to identify
analgesic and anti-inflammatory activities where an inflammatory component was present. There
Page 24 of 35
were no discrepancies or exceptions evident.
Depending on the assay used, naproxen sodium had less analgesic activity than indomethacin; it
was more active than ASA, phenylbutazone and mefenamic acid. Like ASA, phenylbutazone and
other “anti-inflammatory analgesics”, naproxen sodium raised the pain threshold only in
experimental pain states involving inflammation (unlike morphine, which raises the pain
threshold in both inflamed and uninflamed states). Further support for this contention is the fact
that naproxen sodium did not raise heat-induced pain threshold responses as shown in the “Hot
Depending on the test system used, naproxen and naproxen sodium are slightly less active than
indomethacin, and more active than hydrocortisone, ASA, phenylbutazone and mefenamic acid.
Based on anti-edema effects in the rat, the duration of anti-inflammatory action of naproxen
appears to be relatively short; however, these findings may only be relevant to this species, since
metabolic half-life determinations in man indicate a much longer duration of action.
Naproxen and naproxen sodium appear to act directly at inflamed tissue sites, as do many other
nonsteroidal anti-inflammatory agents. Their activity is not mediated by corticosteroids; the
compounds do not have thymolitic activity and they have reduced inflammation in
As measured by the cotton-pellet-test, naproxen sodium produced significant inhibition of
granuloma tissue over a relatively wide dose range (5-30 mg/kg/day), without affecting body
weight or inducing other toxic manifestations.
Prostaglandin Synthesis Inhibition
Naproxen sodium inhibits the synthesis of prostaglandins E2 and F2 alpha from arachidonic acid
by bovine seminal vesicle microsomes and by pregnant rat uterine microsomes. It also
suppresses PGE2 production in cultures of rheumatoid synovial tissue and inhibits arachidonate-
induced fetal bone resorption in vitro. The delay of parturition seen with naproxen sodium and
other nonsteroidal anti-inflammatory agents might be explained by this ability to inhibit uterine
prostaglandin biosynthesis since prostaglandins are known to stimulate uterine smooth muscle
contractions both in vitro and in vivo. It has been recognized for some time that they play an
important role in initiating labour at term.
Naproxen sodium inhibited the biosynthesis of both PGF2 alpha and PGE2 by pregnant rat
uterine microsomes in a dose dependent manner. It was about 0.3 to 0.5 times as potent as
indomethacin in this system. In contrast, it was 0.04 to 0.06 times as potent as indomethacin in
inhibiting PGF2 alpha and PGE2 synthesis by bull seminal vesicle microsomes.
Naproxen sodium also greatly decreased PGF2 alpha levels in the uteri of pregnant rats receiving
oral doses of the drug for three days during late stages of pregnancy, confirming the in vitro
effects seen with naproxen sodium in inhibiting PG synthetase.
Page 25 of 35
Cardiovascular and Central Nervous System Effects
Acute studies were carried out to determine the effects of naproxen sodium on the cardiovascular
and central nervous systems. Naproxen sodium was almost inert in cardiovascular system studies.
Its CNS effects were minimal.
It was also determined that the effects of excessive amounts of naproxen sodium can be
controlled by CNS depressants such as phenobarbital, pentobarbital, or chlordiazepoxide.
Effects on Reproductive System
Several studies were carried out to determine the drugs’ effects on the reproductive system.
Naproxen did not demonstrate estrogenic, anti-estrogenic or androgenic effects. High, toxic dose
levels decreased pregnancies; this appeared to be an indirect consequence of general toxicity
rather than a true antifertility effect.
Pharmacology of Major Metabolite
The major metabolite of naproxen, 6-desmethyl naproxen was tested in a variety of
pharmacologic preparations measuring diverse activities. From these studies it was concluded
that the metabolite was only very weakly active in all pharmacologic assays in laboratory
Human Metabolic Studies
Since naproxen is a weak acid with a pKa = 5 and because most of the body fluids have a pH
higher than 5 (except the contents of the stomach) the drug molecules exist in these physiological
fluids in the anionic form.
Therefore, any difference between ingested doses of naproxen sodium and naproxen exist only in
the stomach; in the dissolution rate and the absorption rate. Once absorbed into the central
circulatory system the distributive, metabolic and excretory fate of the two agents are identical.
Following I.V. administration, titrated naproxen appears to be distributed mainly in the blood,
and is present there only as the unchanged drug. It is extensively bound to plasma protein and
has a plasma half-life of approximately 13 hours. The preferred route of excretion is via the
urine with only 1% of the dose excreted in the feces. The drug is excreted similarly by both
the male and the female. Following 14 days of continuous exposure to the drug, there was no
indication of induction of metabolizing enzymes. Naproxen sodium is freely soluble in water
and is completely absorbed from the gastrointestinal tract. Significant plasma levels are
obtained in patients within 20 minutes and the peak level in one hour.
Blood levels achieved in the human following oral administration were only slightly lower than
after rapid intravenous injection.
Naproxen has a relatively small volume of distribution, about 10% of the body weight in man.
This index suggests naproxen has a relatively high affinity for the blood since a large fraction of
the dose is held in the central circulatory system. The small volume of distribution is probably
due to extensive plasma protein binding and the pH-partitioning effect which act together to
restrict naproxen largely to the plasma compartment.
Page 26 of 35
Human metabolism of naproxen (determined by analysis of the urinary radioactivity following a
100 mg intravenous dose) was found to be relatively simple. The parent structure was altered
only by removal of a 6-methoxy group, and by conjugation of the acid function. 70% of the
ingested dose was eliminated either as unchanged naproxen (10%) or as conjugated naproxen
(60%). This conjugated fraction was comprised of 40% naproxen glucuronide and 20% other
conjugates including glycine and sulfate conjugates. Approximately 28% of the dose
underwent 6-demethylation. As a consequence, 5% of the dose appeared in the urine as
demethylated naproxen, and 23% as conjugates of demethylated naproxen. The conjugates are
further separable into 12% glucuronide and 11% other conjugates.
The plasma-level response to oral naproxen doses ranging up to 900 mg twice daily was
studied in normal subjects. Areas under plasma concentration vs. time curves increased
linearly with dose increments up to 500 mg twice a day, but larger doses fell short of the linear
projections. Experiments with tritium labelled naproxen showed that there was no difference
in the fraction of ingested drug excreted in the stools whether the dose was 250 mg or 900 mg,
thus eliminating the possibility that this effect was a result of incomplete absorption.
Accelerated renal clearance at high doses because of disproportionate increases in the amount
of unbound drug appeared to be the most likely explanation.
A bioequivalence study comparing 2 x 275 mg naproxen sodium tablets to one 550 mg
naproxen sodium tablet was conducted in 12 healthy volunteers (6 men, 6 women) using an
open crossover design. Each subject received a different formulation on two separate days with
a one-week interval between doses. Based on the parameters listed in the table below, the 550
mg naproxen sodium tablet is bioequivalent to two 275 mg naproxen sodium tablets.
95 % Fiducial
B/A x 100%
Plasma Half-Life (hours)
Formula A= 2x275 mg naproxen sodium tablets
Formula B=one 550 mg naproxen sodium tablet
=p-values resulting from Analysis of Variance
APO-NAPRO-NA or APO-NAPRO-NA DS (naproxen sodium) is the sodium salt of naproxen.
In a variety of animal species and in man, the circulating plasma entity is the same (naproxen
anion) with oral administration of either naproxen sodium or naproxen. Therefore, for the
purpose of evaluating systemic toxicity, studies carried out with either compound are
Page 27 of 35
Acute Animal Toxicity
The oral LD
values for naproxen are as follows:
Subacute and Chronic Oral Toxicity
In subacute and chronic oral studies with naproxen in a variety of species, the principal
pathologic effect was gastrointestinal irritation and ulceration. The lesions seen were
predominantly in the small intestine and ranged from hyperemia to perforation and peritonitis.
Nephropathy was seen occasionally in rats, mice and rabbits at high dose levels of naproxen, but
not in rhesus monkeys or miniature pigs. In the affected species the pathologic changes occurred
in the cortex and papilla. Some rats examined 14 days after single oral doses of 230 mg/kg or
more of naproxen evidenced necrotic areas of cortical and papillary tissue. Tubular dilation
(ectasia) occurred in rabbits dosed orally for 14 days with 200 mg/kg/day or more of naproxen.
An examination of unfixed renal tissue from rabbits so treated was conducted and revealed the
presence of diffraction patterns similar to that of crystalline naproxen. This suggests that the
ectasia observed was physical response to deposition of excreted naproxen within the tubules.
In mice given oral doses of 120 mg/kg/day or more of naproxen for 6 months, the kidneys were
characterized by a low but non dosage related incidence of cortical sclerosis and papillary tip
necrosis. Chronic administration of high doses of naproxen to mice appears to be associated with
exacerbation of spontaneous murine nephropathy.
In rhesus monkeys given oral doses of 100 mg/kg/day or more of naproxen for 12 months, dose
related renal lesions were observed. The changes included multifocal chronic active nephritis,
which involved all components of the kidney in the most severely affected animals, and papillary
A wide range of susceptibility to gastrointestinal lesions from administration of naproxen was
evident in the various species tested. For example, 30 mg/kg/day was tolerated well by rats for
90 days, but the same dose was ulcerogenic when administered for 6 months. Rhesus monkeys
and miniature swine exhibited no significant pathology when dosed with naproxen at 45
mg/kg/day for 30 days. This dose of naproxen was also tolerated by miniature swine without
obvious evidence of adverse effects when administered daily for 1 year. In rhesus monkeys
doses as high as 180 mg/kg/day (90 mg/kg b.i.d.) for 12 months produced only mild irritation
of the gastric mucosa. In rabbits the maximum tolerated repeated oral dose is 80 to 100
mg/kg/day. Mice survived oral daily doses of 240 mg/kg/day for 6 months. In dogs, on the
other hand, 5.0 mg/kg/day approaches the maximum tolerated dose.
This peculiar canine susceptibility to gastrointestinal effects of non-steroidal anti-inflammatory
agents has also been shown with indomethacin and ibuprofen. In dogs naproxen exhibits a
considerably longer plasma half-life than it does in rats, guinea pigs, miniature swine, monkeys,
and man. The same observation has been made with ibuprofen in dogs compared to rats and man.
Page 28 of 35
In addition, in the species listed, only the dog excretes significant amounts of administered
naproxen in the feces (50%). In the rat, guinea pigs, miniature swine, monkey, and man, 86 90%
of the administered drug is excreted in the urine. The suggested enterohepatic circulation of
naproxen in the dog (as judged by fecal excretion) most likely is a major factor in the
susceptibility of the dog to gastrointestinal irritation by this compound.
Pathologic changes in the spleen and mesenteric lymph nodes as well as peritoneal inflammation
and adhesions were considered to be clearly secondary to the effects of high doses of naproxen
on the gastrointestinal tract.
Moderate weight loss of the male secondary sex glands occurred in some studies in naproxen-
treated rats and dogs. Histopathologically the affected glands in some instances exhibited
atrophic and/or hypoplastic changes characterized by decreased secretory material. A possible
estrogenic action of naproxen as a causative factor seems highly unlikely since in standard
bioassay procedures the drug exhibited no estrogenic activity (see Pharmacology).
Weight loss of the male secondary sex glands as a result of inanition is well documented, and
intestinal irritation with the probability of decreased absorption may have contributed in this
direction. Nevertheless, daily doses of naproxen as high as 30 mg/kg administered for 60 days
before mating had no effect on fertility and reproductive performance of male rats. These results
reflect the physiological integrity of the entire male reproductive apparatus after administration
of naproxen throughout the spermatogenic cycle.
In teratology studies no skeletal or visceral anomalies or pathologic changes were induced in the
fetuses of pregnant rats and rabbits treated during organogenesis with daily oral doses of
naproxen up to 20 mg/kg nor in mice similarly treated with 30 or 50 mg/kg. In these studies
there were also no significant differences from controls in the number of live fetuses, resorption,
fetal weights or ano-genital distances. In another mouse study no malformations were observed
with administration of 60 or 120 mg/kg of naproxen although there was a slight reduction in
number of live fetuses in both dose groups and in fetal body weight in the high dose group.
Daily oral administration of 15, 30 or 60 mg/kg of naproxen to female rabbits from 2 weeks
before mating until day 20 of pregnancy did not affect fertility, gestation, or the number of live
In a peri- and post-natal study in rats, oral doses of naproxen up to 20 mg/kg administered daily
during the last part of pregnancy through weaning did not result in adverse effects in viability of
pups, lactation index, sex ratio or weight gain of offspring.
However, there was a slight increase in gestation length at the 10 and 20 mg/kg dose levels; and,
at the 10 mg/kg dose level, there was a significant increase in stillbirths.
Recent evidence, however, suggests that inhibition of prostaglandin synthesis by non-steroidal
anti-inflammatory compounds may be related to decreased uterine contractibility. Thus, the onset
of labour in a rat model system can be delayed with naproxen administration without causing
maternal or fetal deaths in excess of that seen in controls. Since it has been shown that naproxen
Page 29 of 35
inhibits prostaglandin synthesis in vitro, it has been suggested that the effects of naproxen on
uterine contractility are mediated through that mechanism.
Maternal and fetal deaths seen in naproxen-treated rats were, therefore, apparently related to
dystocia rather than to a direct toxic effect of the compound. Naproxen is not unique in this
regard since comparable results were obtained in the rat with other commonly used non steroidal
anti-inflammatory agents (aspirin, indomethacin, mefenamic acid, and phenylbutazone). Similar
results have been suggested in reports of other animal studies with mefenamic acid and
In a fertility and reproduction study in mice, the dams were dosed daily with 12, 36 or 108 mg/kg
from 14 days prior to mating through weaning. At the highest dose level, there was an increase in
maternal deaths which was reflected in decreased 21 day survival and lactation indices. There
were no other changes in the parameters examined. In a similar study in rats, daily doses were 2,
10 or 20 mg/kg from 14 days before mating through weaning. Other than decreased survival to
weaning which appeared due to poor maternal care in pups born to high dose dams, there were no
differences between control and treated groups. One mid and one high dose dam died during
labour due to delayed parturition.
A mutagenicity study was performed with naproxen using 5 strains of bacteria and one of yeast.
The test was carried out with and without mammalian microsomal activation. Naproxen was not
mutagenic in any of these test systems.
Naproxen sodium was administered with food to Sprague-Dawley rats for 24 months at
doses of 8, 16 and 24 mg/kg/day. Naproxen sodium was not carcinogenic in rats.
Page 30 of 35
1. Adams SS, Bough RG, Cliffee EF, Lessel B, and Mills RFN. Absorption, distribution and
toxicity of ibuprofen. Tox & Appl Pharmacol. 1969;15:310 330.
2. Aiken JW. Aspirin and indomethacin prolong parturition in rats: evidence that prostaglandins
contribute to expulsion of fetus. Nature 1972;240:21 25.
3. Berry H., Bloom B., Hamilton E.B.D., Swinson D.R. Naproxen sodium, diflunisal, and
placebo in the treatment of chronic back pain. 1982 Ann. of Rheum. Dis Vol. 41 pp 129 132.
4. Bloomfield SS, et al. Naproxen, aspirin and codeine in postpartum uterine pain. Clin
Pharmacol Therap 1977;21:414 421.
5. Bodiwala GG. Naproxen sodium and ibuprofen in the treatment of acute soft-tissue injuries.
Brit J Clin Practice 1982;36(7-8):270 275.
6. Chester R, et al. Delay of parturition in the rat by anti-inflammatory agents which inhibit the
biosynthesis of prostaglandins. Nature 1972;240:37 38.
7. Csapo AI, et al. The delay of spontaneous Labour by naproxen in the rat model.
Prostaglandins 1973;3:827 837.
8. Csapo AI, et al. The role of estradiol 17 in the activation of the uterus during premature
labour and the effect of naproxen, an inhibitor of prostaglandin synthesis. Prostaglandins
9. Csapo AI, et al (1977). The effect of naproxen-sodium on the intrauterine pressure and
menstrual pain of dysmenorrheic patients. Prostaglandins 1977;13:193 199.
10. Dysmenorrhea and Prostaglandins. Proceedings of an international symposium in Helsinki,
November 16-17, 1978. Acta Obstet Gynecol Scand 1978;Suppl 87.
11. Geczy M, et al. Naproxen tolerability in the elderly: A summary report. J Rheumatol
12. Halvorsen L, et al. Gastroscopic observations following aspirin and naproxen sodium
administration. J Clin Pharmacol 1981;21:169 172
13. Henzl MR, et al. The treatment of dysmenorrhea with naproxen sodium: a report of two
independent double-blind trials. Amer J Obstet Gynecol 1977;127:818 823.
14. Information letter, Health Protection Branch. Nonsteroidal Anti-Inflammatory Drugs. DD
33;August 21, 1985.
15. Julou L, et al. Etude toxicologique de l’acide metiazinique. Artzn Forsch 1969;19:1207 1214.
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16. McVerry JM, et al. Pharmacokinetics of naproxen in elderly patients. Eur J Clin Pharmacol
17. Ogilvie-Harris, D.J., Bauer, M., Corey P. Prostaglandin Inhibition and the rate of recovery
after orthoscopic meniscectomy. 1985 J of Bone and Joint Surgery. Vol. 67-B (4) pp 567
18. Ouellette RD, et al. Naproxen sodium vs acetaminophen plus codeine in postsurgical pain.
Curr Ther Res 1986;39(5):839 845.
19. Physicians Desk Reference. 1987 p 1535.
20. Runkel R, et al. Absorption, distribution, metabolism, and excretion of naproxen in various
laboratory animals and human subjects. J Pharm Sci 1972;61(5):703 708.
21. Runkel R, et al. Nonlinear plasma level response to high doses of naproxen. Clin Pharmacol
& Therap 1974;15(3):261 266.
22. Runkel R, et al. Pharmacokinetics of naproxen overdoses. Clin Pharmacol Therap
23. Tomlinson RV, et al. Relationship between inhibition of prostaglandin synthesis and drug
efficacy: support for the current therapy on mode of action of aspirin-like drugs. Biochem
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24. Williams RA, et al. Naproxen disposition in patients with alcoholic cirrhosis. Eur J Clin
Pharmacol 1984;27:291 296.
25. G Smith et al. Reversible ovulatory failure associated with the development of luteinized
unruptured follicles in women with inflammatory arthritis taking non-steroidal anti-
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28. Product Monograph ANAPROX, ANAPROX
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Canada). Submission Control No 159219. Date of revision January 8, 2013.
IMPORTANT: PLEASE READ
Page 32 of 35
PART III: CONSUMER INFORMATION
Read this information each time you refill your prescription in
case new information has been added.
This leaflet is a summary designed specifically for you to read.
It will NOT tell you everything about APO-NAPRO-NA or
APO-NAPRO-NA DS. See your health care provider and
pharmacist regularly and ask them questions about your health and
any medications you take.
ABOUT THIS MEDICATION
What the medication is used for:
Your health care provider has prescribed APO-NAPRO-NA or
APO-NAPRO-NA DS for you for one or more of the following
For the relief of mild to moderately severe pain, accompanied
by inflammation in conditions such as musculo skeletal
trauma and post-dental extraction.
For the relief of pain associated with post-partum cramping
What it does:
APO-NAPRO-NA or APO-NAPRO-NA DS (naproxen sodium), as
a nonsteroidal anti-inflammatory drug (NSAID), can reduce the
chemicals produced by your body which cause pain and swelling.
APO-NAPRO-NA or APO-NAPRO-NA DS, as a nonsteroidal
anti- inflammatory drug (NSAID), does NOT cure your illness or
prevent it from getting worse. APO-NAPRO-NA or APO-
NAPRO-NA DS can only relieve pain and reduce swelling as
long as you continue to take it.
When it should not be used:
DO NOT TAKE APO-NAPRO-NA or APO-NAPRO-NA DS if
you have any of the following medical conditions:
Heart bypass surgery (planning to have or recently
Severe, uncontrolled heart failure
Bleeding in the brain or other bleeding disorders
Current pregnancy (after 28 weeks of pregnancy)
Currently breastfeeding (or planning to breastfeed)
Allergy to ASA (Acetylsalicylic Acid) or other NSAIDs
(Nonsteroidal Anti-Inflammatory Drugs)
Bleeding from the stomach or gut (active)
Inflammatory bowel disease (Crohn’s Disease or
Liver disease (active or severe)
Kidney disease (severe or worsening)
High potassium in the blood
Patients who took a drug in the same class as APO-NAPRO-
NA or APO-NAPRO-NA DS after a type of heart surgery
(coronary artery bypass grafting (CABG)) were more likely
to have heart attacks, strokes, blood clots in the leg(s) or
lung(s), and infections or other complications than those who
did NOT take that drug.
APO-NAPRO-NA or APO-NAPRO-NA DS should NOT be
used in patients under 18 years of age since the safety and
effectiveness have NOT been established.
What the medicinal ingredient is:
What the important non-medicinal ingredients are: APO-
NAPRO-NA and APO-NAPRO-NA DS Tablets contain the
following non-medicinal ingredients: microcrystalline cellulose,
stearate, stearic acid, colloidal silicon
dioxide, hydroxypropyl cellulose,
polyethylene glycol, titanium dioxide and
FD&C Blue #2.
What dosage forms it comes in:
APO-NAPRO-NA and APO-NAPRO-NA DS are available as: film
coated tablets (275 mg and 550 mg).
WARNINGS AND PRECAUTIONS
If you have, or previously had, any of the following medical
conditions, see your health care provider to discuss
treatment options other than APO-NAPRO-NA or APO-
Heart Attack or Angina
Stroke or Mini-stroke
Loss of Vision
Current Pregnancy (less than 28 weeks)
Congestive Heart Failure
Before taking this medication, tell your health care provider if you
have any of the following:
High blood pressure
Diabetes mellitus or on a low sugar diet
Poor circulation to your extremities
Smoker or ex-smoker
Kidney disease or urine problems
Previous ulcer or bleeding from the stomach or gut
(small or large intestine)
Previous bleeding in the brain
Family history of allergy to NSAIDs, such as
acetylsalicylic acid (ASA), celecoxib, diclofenac,
IMPORTANT: PLEASE READ
Page 33 of 35
Dose (per day)
For the relief of mild
to moderately severe
pain, accompanied by
conditions such as
trauma and post-
For the relief of pain
associated with post-
partum cramping and
Two 275 mg
tablets or one
550 mg tablet
followed by one
275 mg tablet
every six to
eight hours as
diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen,
indomethacin, ketoprofen, ketorolac, mefenamic acid,
meloxicam, nabumetone, naproxen, oxaprozin, piroxicam,
rofecoxib, sulindac, tenoxicam, tiaprofenic acid, tolmetin,
or valdecoxib (NOT a complete list)
Family history of asthma, nasal polyps, long-term
swelling of the sinus (chronic sinusitis) or hives
Also, before taking this medication, tell your health care provider
if you are planning to get pregnant.
While taking this medication:
tell any other doctor, dentist, pharmacist or other health
care professional that you see, that you are taking this
medication, especially if you are planning to have heart
do NOT drink alcoholic beverages while taking this
medication because you would be more likely to develop
fertility may be decreased. The use of APO-NAPRO-NA
or APO-NAPRO-NA DS is not recommended in women
trying to get pregnant. In women who have difficulty
conceiving, stopping APO-NAPRO-NA or APO-
NAPRO-NA DS should be considered.
Oral hypoglycemics (diabetes medications)
Your health care provider may prescribe low dose ASA
(acetylsalicylic acid) as a blood thinner to reduce your risk of
having a heart attack or stroke while you are taking APO-
NAPRO-NA or APO-NAPRO-NA DS. Take only the amount of
ASA prescribed by your health care provider. You are more
likely to upset or damage your stomach if you take both APO-
NAPRO-NA or APO-NAPRO-NA DS and ASA than if you
took APO-NAPRO-NA or APO-NAPRO-NA DS alone.
PROPER USE OF THIS MEDICATION
Usual dose: 18 years of age and older:
INTERACTIONS WITH THIS MEDICATION
Talk to your health care provider and pharmacist if you are taking
any other medication (prescription or non-prescription) such as any
of the following (NOT a complete list):
Acetylsalicylic Acid (ASA) or other NSAIDs
e.g. ASA, celecoxib, diclofenac, ibuprofen,
indomethacin, ketorolac, meloxicam, naproxen
Selective Serotonin Reuptake Inhibitors (SSRIs)
e.g. citalopram, fluoxetine, paroxetine,
Blood pressure medications
ACE (angiotensin converting enzyme) inhibitors
e.g. enalapril, lisinopril, perindopril,
ARBs (angiotensin II receptor blockers)
e.g. candesartan, irbesartan, losartan,
e.g. warfarin, ASA, clopidogrel
Corticosteroids (including glucocorticoids)
e.g. furosemide, hydrochlorothiazide
Take APO-NAPRO-NA or APO-NAPRO-NA DS only as directed
by your health care provider. Do NOT take more of it, do NOT
take it more often and do NOT take it for a longer period of
time than your health care provider recommended. If
possible, you should take the lowest dose of this medication for
the shortest time period. Taking too much APO-NAPRO-NA
OR APO-NAPRO-NA DS may increase your chances of
unwanted and sometimes dangerous side effects, especially if you
are elderly, have other diseases or take other medications.
If you will be using APO-NAPRO-NA OR APO-NAPRO-NA
DS for more than 7 days, see your health care provider regularly
to discuss whether this medicine is working for you and if it is
causing you any unwanted effects.
This medication has been prescribed specifically for you. Do
NOT give it to anyone else. It may harm them, even if their
symptoms seem to be similar to yours.
APO-NAPRO-NA or APO-NAPRO-NA DS is NOT
recommended for use in patients under 18 years of age since
safety and effectiveness have NOT been established.
IMPORTANT: PLEASE READ
Page 34 of 35
SERIOUS SIDE EFFECTS, HOW OFTEN THEY
HAPPEN AND WHAT TO DO ABOUT THEM
NA DS and get
NA or APO-
and talk to your
Blurred vision, or any
Any change in the amount
or colour of your urine (red
Any pain or difficulty
experienced while urinating
Swelling of the feet, lower
legs; weight gain
Vomiting or persistent
stomach pain or diarrhea
Yellow discolouration of
the skin or eyes, with or
without itchy skin
Malaise, fatigue, loss of
Headaches, stiff neck
SERIOUS SIDE EFFECTS, HOW OFTEN THEY
HAPPEN AND WHAT TO DO ABOUT THEM
NA DS and get
NA or APO-
and talk to your
Bloody or black tarry stools
Shortness of breath,
wheezing, any trouble
breathing or chest tightness
Skin rash, hives, swelling or
It may be a good idea to ask your doctor or pharmacist ahead of
time what to do about missed doses. If you forget to take a dose of
APO-NAPRO-NA or APO-NAPRO-NA DS take it as soon as
possible, then just carry on with the regular times you take your
medication. If you remember your missed dose close to the time
of your next dose, do not take the missed dose.
In case of drug overdose, contact a health care practitioner,
hospital emergency department or regional Poison Control
Centre immediately, even if there are no symptoms.
SIDE EFFECTS AND WHAT TO DO ABOUT THEM
APO-NAPRO-NA or APO-NAPRO-NA DS may cause some side
effects, especially when used for a long time or in large doses.
When these side effects occur, you may require medical attention.
Report all symptoms or side effects to your health care provider.
APO-NAPRO-NA or APO-NAPRO-NA DS may cause you to
become drowsy or tired. Be careful about driving or participating
in activities that require you to be alert. If you become drowsy,
dizzy or light- headed after taking APO-NAPRO-NA OR APO-
NAPRO-NA DS, do NOT drive or operate machinery.
APO-NAPRO-NA or APO-NAPRO-NA DS may cause you to
become more sensitive to sunlight. Any exposure to sunlight or
sunlamps may cause sunburn, skin blisters, skin rash, redness,
itching or discolouration, or vision changes. If you have a
reaction from the sun, check with your health care provider.
Check with your health care provider IMMEDIATELY if you
develop chills, fever, muscle aches or pains, or other flu-like
symptoms, especially if they occur before or together with a skin
rash. These symptoms may be the first signs of a SERIOUS
ALLERGIC REACTION to this medication.
This is NOT a complete list of side effects. If you develop any
other symptoms while taking APO-NAPRO-NA or APO-
NAPRO-NA DS, see your health care provider.
HOW TO STORE IT
Store at room temperature (15-30°C) in a well-closed container.
Store in a dry place.
Do NOT keep outdated medicine or medicine no longer
needed. Any outdated or unused medicine should be returned to
Keep out of reach of children.
IMPORTANT: PLEASE READ
Page 35 of 35
REPORTING SUSPECTED SIDE EFFECTS
You can report any suspected adverse reactions associated with
the use of health products to the Canada Vigilance Program by
one of the following 3 ways:
Report online at www.healthcanada.gc.ca/medeffect
Call toll-free at 1-866-234-2345
Complete a Canada Vigilance Reporting Form and:
- Fax toll-free to 1-866-678-6789, or
- Mail to:
Canada Vigilance Program
Postal Locator 0701E
Postage paid labels, Canada Vigilance Reporting Form and the
adverse reaction reporting guidelines are available on the
MedEffect™ Canada Web site at
NOTE: Should you require information related to the management
of side effects, contact your health professional. The Canada
Vigilance Program does not provide medical advice.
For more information, please contact your doctor, pharmacist
or other healthcare professional.
This leaflet plus the full product monograph, prepared for
health professionals, can be obtained by contacting DISpedia,
Apotex’s Drug Information Service at:
This leaflet can also be found at: http://www.apotex.ca/products.
This leaflet was prepared by Apotex Inc., Toronto, Ontario,
Last revised: M a y 8 , 2 0 1 4