APO-NAPRO-NA TABLET

Canada - English - Health Canada

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Active ingredient:
NAPROXEN SODIUM
Available from:
APOTEX INC
ATC code:
M01AE02
INN (International Name):
NAPROXEN
Dosage:
275MG
Pharmaceutical form:
TABLET
Composition:
NAPROXEN SODIUM 275MG
Administration route:
ORAL
Units in package:
100/500
Prescription type:
Prescription
Therapeutic area:
OTHER NONSTEROIDAL ANTIIMFLAMMATORY AGENTS
Product summary:
Active ingredient group (AIG) number: 0113934001; AHFS: 28:08.04.92
Authorization status:
MARKETED
Authorization number:
00784354
Authorization date:
1989-12-31

Page 1 of 35

PRODUCT

MONOGRAPH

Pr

APO-NAPRO-NA

Pr

APO-NAPRO-NA

DS

Naproxen Sodium Tablets USP

275 mg and 550 mg

Tablet

Non-Steroidal Anti-Inflammatory Drug

(NSAID)

APOTEX INC.

150 Signet Drive,

Toronto, Ontario

M9L 1T9

Submission Control No: 168557

Date of Revision:

May 8, 2014

Page 2 of 35

Table of Contents

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

SUMMARY PRODUCT INFORMATION .....................................................................3

INDICATIONS AND CLINICAL USE ...........................................................................3

CONTRAINDICATIONS ................................................................................................4

WARNINGS AND PRECAUTIONS...............................................................................5

ADVERSE REACTIONS...............................................................................................14

DRUG INTERACTIONS ...............................................................................................17

DOSAGE AND ADMINISTRATION ...........................................................................19

OVERDOSAGE .............................................................................................................19

ACTION AND CLINICAL PHARMACOLOGY .........................................................20

STORAGE AND STABILITY.......................................................................................21

DOSAGE FORMS, COMPOSITION AND PACKAGING ..........................................21

PART II: SCIENTIFIC INFORMATION ............................................................................22

PHARMACEUTICAL INFORMATION.......................................................................22

CLINICAL TRIALS .......................................................................................................23

DETAILED PHARMACOLOGY ..................................................................................23

TOXICOLOGY ..............................................................................................................26

REFERENCES ...............................................................................................................30

PART III: CONSUMER INFORMATION...........................................................................32

Page 3 of 35

Pr

APO-NAPRO-NA

Pr

APO-NAPRO-NA

DS

Naproxen Sodium

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form / Strength

Clinically Relevant Non-medicinal

Ingredients

Oral

275 mg and 550 mg Film-Coated

Tablet

None

For a complete listing see Dosage

Forms, Composition and Packaging

section.

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.

Page 4 of 35

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.

CONTRAINDICATIONS

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

nursing infants

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

Reactions).

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

Electrolyte Balance)

children and adolescents less than 18 years of age

Page 5 of 35

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-

NAPRO-NA DS.

Risk of Gastrointestinal (GI) Adverse Events (see WARNINGS AND PRECAUTIONS:

Gastrointestinal).

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).

General

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.

Page 6 of 35

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

NSAIDs)

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

anion.

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)

Hypertension

Dyslipidemia / Hyperlipidemia

Diabetes Mellitus

Congestive Heart Failure (NYHA I)

Coronary Artery Disease (Atherosclerosis)

Peripheral Arterial Disease

Smoking

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

possible duration.

Page 7 of 35

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

Interactions, Glucocorticoids).

Gastrointestinal

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,

sertraline)

Page 8 of 35

Genitourinary

Some NSAIDs are associated with persistent urinary symptoms (bladder pain, dysuria, urinary

frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the

initiation of therapy with 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.

Hematologic

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

(INR).

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.

Page 9 of 35

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

severe consequences.

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.

Hepatic/Biliary/Pancreatic

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.

Hypersensitivity Reactions:

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).

Page 10 of 35

Cross-sensitivity: Patients sensitive to one NSAID may be sensitive to any of the other NSAIDs

as well.

Serious skin reactions: (See WARNINGS AND PRECAUTIONS: Skin)

Immune

(See WARNINGS AND PRECAUTIONS: Infection, Aseptic Meningitis)

Infection

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.

Neurologic

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.

Ophthalmologic

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.

Peri-Operative Considerations

(See CONTRAINDICATIONS: Coronary Artery Bypass Graft Surgery)

Psychiatric

(See WARNINGS AND PRECAUTIONS: Neurologic)

Renal

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.

Page 11 of 35

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.

Respiratory

ASA-induced asthma is an uncommon but very important indication of ASA and NSAID

sensitivity. It occurs more frequently in patients with asthma who have nasal polyps.

Page 12 of 35

Sexual Function/Reproduction

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.

Skin

In rare cases, serious skin reactions such as Stevens-Johnson syndrome, toxic epidermal

necrolysis, exfoliative dermatitis and erythema multiforme have been associated with the use of

some NSAIDs. Because the rate of these reactions is low, they have usually been noted during

post-marketing surveillance in patients taking other medications also associated with the

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.

Special Populations

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

fetal

circulation

inhibit

uterine

contractions,

thus

increasing

risk

uterine

hemorrhage.

Nursing Women: (See CONTRAINDICATIONS)

Pediatrics: (See CONTRAINDICATIONS)

Page 13 of 35

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

close supervision.

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

and Ophthalmic).

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,

Pancreatic).

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:

Renal).

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)

Page 14 of 35

ADVERSE REACTIONS

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%)

Body System

Incidence

Adverse Reaction

Gastrointestinal

3%-9%

Heartburn, constipation, abdominal pain, nausea

1%-3%

Diarrhea, dyspepsia, stomatitis, diverticulitis

Central Nervous System

3%-9%

Headache, dizziness, drowsiness

1%-3%

Light-headedness, vertigo, depression, fatigue.

Occasionally

patients

discontinue

treatment

because of the severity of some of these complaints

(headache and dizziness).

Dermatologic

3%-9%

Pruritus, ecchymoses, skin eruptions

1%-3%

Sweating, purpura

Cardiovascular

3%-9%

Dyspnea, peripheral edema

1%-3%

Palpitations

Special Senses

3%-9%

Tinnitus

1%-3%

Hearing disturbances

General

1%-3%

Thirst

Page 15 of 35

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

stomatitis.

Central Nervous System: inability to concentrate, malaise, myalgia, insomnia and cognitive

dysfunction

(i.e.

decreased

attention

span,

loss

short-term

memory, difficulty with calculations).

Dermatologic:

alopecia, urticaria, skin rash, erythema multiforme,

Stevens-Johnson syndrome, epidermal necrolysis, photosensitive

dermatitis, exfoliative dermatitis, erythema nodosum.

Hepatic:

abnormal liver function tests, jaundice, cholestasis and hepatitis.

Cardiovascular:

congestive heart failure and vasculitis.

Renal:

Glomerular nephritis, hematuria, interstitial nephritis, nephrotic

syndrome, nephropathy and tubular necrosis.

Hematologic:

Eosinophilia,

granulocytopenia,

leukopenia,

thrombocytopenia,

agranulocytosis, aplastic anemia and hemolytic anemia.

Special Senses:

hearing impairment and visual disturbances.

Reproductive, female:

infertility

General:

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

naproxen sodium:

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.

Heartburn,

dyspepsia, abdominal pain, nausea, vomiting,

diarrhoea, flatulence, constipation, haematemesis, melaena.

Infections:

aseptic meningitis

Blood and Lymphatic

agranulocytosis,

aplastic

anaemia,

eosinophilia,

haemolytic

Page 16 of 35

System Disorders:

anaemia , leucopoenia, thrombocytopenia

Immune System

Disorders:

Metabolic and Nutrition

Disorders:

anaphylactoid reactions

hyperkalemia

Psychiatric Disorders:

depression, dream abnormalities, insomnia

Nervous System

Disorders:

dizziness, drowsiness, headache, lightheadedness, retrobulbar

optic

neuritis

convulsions,

cognitive

dysfunction,

inability

concentrate

Eye Disorders:

visual disturbances, corneal opacity, papillitis, papilloedema

Ear and Labyrinth

Disorders:

hearing impairment, hearing disturbances, tinnitus, vertigo

Cardiac Disorders:

palpitations, cardiac failure has been reported in association with

NSAID treatment, congestive heart failure

Vascular Disorders:

hypertension, vasculitis

Respiratory, Thoracic and

Mediastinal Disorders:

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

stroke).

dyspnoea, pulmonary oedema, asthma, eosinophilic pneumonitis.

Hepatobiliary Disorders:

hepatitis (some cases of hepatitis have been fatal), jaundice.

Skin and Subcutaneous

Tissue Disorders:

Musculoskeletal and

Connective Tissue

Disorders:

Renal and Urinary

Disorders:

ReproductiveSystem and

Breast Disorders:

General Disorders and

Administration Site

ecchymoses, itching (pruritus), purpura, skin eruptions, sweating,

alopecia,

epidermal

necrolysis,

very

rarely

toxic

epidermal

necrolysis,

erythema

multiforme,

bullous

reactions,

including

Stevens-Johnson

syndrome,

erythema

nodosum,

fixed

drug

eruption,

lichen

planus,

pustular

reaction,

skin

rashes,

SLE,

urticaria,

photosensitivity

reactions,

including

rare

cases

resembling

porphyria

cutanea

tarda

(“pseudoporphyria”)

epidermolysis bullosa and angioneurotic oedema.

skin

fragility,

blistering

other

symptoms

suggestive

pseudoporphyria occur, treatment should be discontinued and the

patient monitored.

myalgia, muscle weakness.

haematuria,

interstitial

nephritis,

nephrotic

syndrome,

renal

disease, renal failure, renal papillary necrosis

female infertility

oedema, thirst, pyrexia (chills and fever), malaise

Page 17 of 35

Conditions:

Investigations:

abnormal liver function tests, raised serum creatinine

DRUG INTERACTIONS

Drug-Drug Interactions

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

adverse reactions.

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

antihypertensive agents.

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-

platelet Effects).

Cholestyramine

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

therapy.

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

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

Drug-Food Interactions

Concomitant administration of food can delay the absorption of naproxen, but does not affect its

extent.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

(See WARNINGS AND PRECAUTIONS: Monitoring and Laboratory Tests).

Drug-Lifestyle Interactions

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.

Missed Dose

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.

OVERDOSAGE

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.

Treatment

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.

Pharmacodynamics

(See DETAILED PHARMACOLOGY)

Pharmacokinetics

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

feces.

Page 21 of 35

STORAGE AND STABILITY

Store at room temperature (15 to 30°C) in a well-closed container. Keep out of reach

of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

In addition to naproxen sodium, each

APO-NAPRO-NA

tablet and each

APO-NAPRO-NA

tablet contains the

non-medicinal

ingredients microcrystalline cellulose, dextrates,

magnesium

stearate, stearic acid, colloidal silicon dioxide, hydroxypropyl cellulose,

hydroxypropyl

methylcellulose,

polyethylene glycol, titanium dioxide and FD&C Blue #2.

APO-NAPRO-NA (naproxen sodium 275 mg) is available as oval-shaped blue film-coated

tablets engraved

"AP0-275"

on one side and plain on

other contains 275 mg of naproxen

sodium.

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

engraved

"AP0-550" on one

side and plain

on the

other, contains 550 mg

naproxen

sodium. APO-NAPRO-NA DS 550 mg tablets are available in bottles of 100 and 500.

Page 22 of 35

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

Naproxen sodium

Chemical name: 2-Napthaleneacetic acid, 6-methoxy-α-methyl-, sodium salt

Molecular formula and molecular mass: C

; 252.24

Structural formula:

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

CLINICAL TRIALS

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).

Naproxen

(2 x 275 mg)

From Measured Data

Geometric Mean

Arithmetic Mean (CV%)

Parameter

Test*

Reference

Ratio of

Geometric

Means (%)

90% Confidence

Interval (%)

0-32

(mcgh/mL)

828.4

834.9 (12)

852.2

857.3 (11)

97.2

94.7 – 99.8

AUCI (mcgh/mL)

1021.9

1033.4 (15)

1051.7

1060.4 (13)

97.2

94.4 – 100.0

Cmax

(mcg/mL)

80.6

81.2 (12)

82.3

83.0 (13)

98.0

92.3 – 104.0

tmax

0.89 (51)

1.33 (66)

14.2 (10)

14.0 (10)

* Apo–Napro-Na (naproxen) 275 mg tablets (Apotex Inc.)

Anaprox

(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.

DETAILED PHARMACOLOGY

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.

Analgesic Activity

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

Plate Test”.

Anti-inflammatory Activity

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

adrenalectomized rats.

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

animals.

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.

Parameter

Formulation

P-values

Comparison

95 % Fiducial

Form’ln

Period

B/A x 100%

Limits

Cmax (µg/mL)

86.5

92.7

107.1

99.5%,

115.5%

Tmax (min)

75.0

50.0

66.7

33.4%,

110.2%

Plasma Half-Life (hours)

16.1

16.4

102.1

98.1%,

106.4 %

AUC,0-24hr (µg/mLxhr)

946.6

946.5

100.0

95.9%,

104.3%

AUC,Total (µg/mLxhr)

1440.2

1452.3

100.8

97.0%,

104.8%

Formula A= 2x275 mg naproxen sodium tablets

Formula B=one 550 mg naproxen sodium tablet

1

=p-values resulting from Analysis of Variance

TOXICOLOGY

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

interchangeable.

Page 27 of 35

Acute Animal Toxicity

The oral LD

values for naproxen are as follows:

Hamster

4110 mg/kg

Rats

543 mg/kg

Dogs

>1000 mg/kg

Mice

1234 mg/kg

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

tip necrosis.

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.

Teratology

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.

Reproductive Studies

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

fetuses.

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

ibuprofen.

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.

Mutagenicity

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.

Carcinogenicity

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

REFERENCES

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

1973;3:839 846.

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

1987;14:348 354.

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.

Page 31 of 35

16. McVerry JM, et al. Pharmacokinetics of naproxen in elderly patients. Eur J Clin Pharmacol

1986;31:463 468.

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

571.

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

1976;20:269 277.

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

Biophys Res Comun 1972;46(2):552 559.

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-

inflammatory drugs. British J of Rheumatology 1996; 35: 458-462.

26. LLF Mendonca et al. Non-steriodal anti-inflammatory drugs as a possible cause for

reversible infertility. Rheumatology 2000;39:880-882.

27. RJ Norman. Reproductive consequences of COX-2 inhibition. The Lancet October 20,

2001;358:1287-1288.

28. Product Monograph ANAPROX, ANAPROX

DS (Hoffmann-La Roche Limited,

Canada). Submission Control No 159219. Date of revision January 8, 2013.

IMPORTANT: PLEASE READ

Page 32 of 35

PART III: CONSUMER INFORMATION

Pr

APO-NAPRO-NA

Pr

APO-NAPRO-NA DS

naproxen sodium

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

medical conditions:

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

and dysmenorrhea.

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

had)

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)

Ulcer (active)

Bleeding from the stomach or gut (active)

Inflammatory bowel disease (Crohn’s Disease or

Ulcerative Colitis)

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:

Naproxen sodium

What the important non-medicinal ingredients are: APO-

NAPRO-NA and APO-NAPRO-NA DS Tablets contain the

following non-medicinal ingredients: microcrystalline cellulose,

dextrates,

magnesium

stearate, stearic acid, colloidal silicon

dioxide, hydroxypropyl cellulose,

hydroxypropyl

methylcellulose,

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-

NAPRO-NA DS:

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

High cholesterol

Diabetes mellitus or on a low sugar diet

Atherosclerosis

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

Bleeding problems

Family history of allergy to NSAIDs, such as

acetylsalicylic acid (ASA), celecoxib, diclofenac,

IMPORTANT: PLEASE READ

Page 33 of 35

Medical Condition

Starting Dose

Maximum

Dose (per day)

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 and

dysmenorrhea.

Two 275 mg

tablets or one

550 mg tablet

followed by one

275 mg tablet

every six to

eight hours as

required.

Should not

exceed 1375

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

surgery;

do NOT drink alcoholic beverages while taking this

medication because you would be more likely to develop

stomach problems;

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)

Tacrolimus

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

Antacids

Antidepressants

Selective Serotonin Reuptake Inhibitors (SSRIs)

e.g. citalopram, fluoxetine, paroxetine,

sertraline

Blood pressure medications

ACE (angiotensin converting enzyme) inhibitors

e.g. enalapril, lisinopril, perindopril,

ramipril

ARBs (angiotensin II receptor blockers)

e.g. candesartan, irbesartan, losartan,

valsartan

Blood thinners

e.g. warfarin, ASA, clopidogrel

Corticosteroids (including glucocorticoids)

e.g. prednisone

Cyclosporin

Digoxin

Diuretics

e.g. furosemide, hydrochlorothiazide

Lithium

Methotrexate

Oral contraceptives

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

Symptom

STOP taking

APO-NAPRO-NA

or APO-NAPRO-

NA DS and get

emergency

medical attention

IMMEDIATELY

Stop taking

APO-NAPRO-

NA or APO-

NAPRO-NA DS

and talk to your

physician or

pharmacist

Blurred vision, or any

visual disturbance

Any change in the amount

or colour of your urine (red

or brown)

Any pain or difficulty

experienced while urinating

Swelling of the feet, lower

legs; weight gain

Vomiting or persistent

indigestion, nausea,

stomach pain or diarrhea

Yellow discolouration of

the skin or eyes, with or

without itchy skin

Malaise, fatigue, loss of

appetite

Headaches, stiff neck

Mental confusion,

depression

Dizziness, lightheadedness

Hearing problems

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom

STOP taking

APO-NAPRO-NA

or APO-NAPRO-

NA DS and get

emergency

medical attention

IMMEDIATELY

Stop taking

APO-NAPRO-

NA or APO-

NAPRO-NA DS

and talk to your

physician or

pharmacist

Bloody or black tarry stools

Shortness of breath,

wheezing, any trouble

breathing or chest tightness

Skin rash, hives, swelling or

itching

Missed Dose:

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.

Overdose:

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

your pharmacist.

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

Health Canada

Postal Locator 0701E

Ottawa, Ontario

K1A 0K9

Postage paid labels, Canada Vigilance Reporting Form and the

adverse reaction reporting guidelines are available on the

MedEffect™ Canada Web site at

www.healthcanada.gc.ca/medeffect.

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.

MORE INFORMATION

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:

1-800-667-4708

This leaflet can also be found at: http://www.apotex.ca/products.

This leaflet was prepared by Apotex Inc., Toronto, Ontario,

M9L 1T9.

Last revised: M a y 8 , 2 0 1 4

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