Apo-Napro-Na Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES............................................................................................. 2

TABLE OF CONTENTS ............................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................... 4

1 INDICATIONS ................................................................................................................... 4

1.1 Pediatrics .................................................................................................................. 4

1.2 Geriatrics................................................................................................................... 4

2 CONTRAINDICATIONS ...................................................................................................... 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ................................................................. 5

4 DOSAGE AND ADMINISTRATION ...................................................................................... 6

4.1 Dosing considerations ................................................................................................ 6

4.2 Recommended Dose and Dosage Adjustment............................................................. 7

4.4 Administration........................................................................................................... 7

4.5 Missed Dose .............................................................................................................. 7

5 OVERDOSAGE .................................................................................................................. 7

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ...................................... 8

7 WARNINGS AND PRECAUTIONS ....................................................................................... 8

7.1 Special Populations ...................................................................................................16

7.1.1 Pregnant Women.....................................................................................................16

7.1.2 Breast-feeding ..........................................................................................................17

7.1.3 Pediatrics.................................................................................................................18

7.1.4 Geriatrics .................................................................................................................18

8 ADVERSE REACTIONS .....................................................................................................18

8.1 Adverse Reaction Overview.......................................................................................18

8.2 Clinical Trial Adverse Reactions .................................................................................18

8.3 Less Common Clinical Trial Adverse Reactions ...........................................................19

8.5 Post-Market Adverse Reactions.................................................................................20

9 DRUG INTERACTIONS ......................................................................................................21

9.3 Drug-Behavioural Interactions...................................................................................21

9.4 Drug-Drug Interactions .............................................................................................21

9.5 Drug-Food Interactions .............................................................................................26

9.6 Drug-Herb Interactions .............................................................................................26

9.7 Drug-Laboratory Test Interactions .............................................................................26

10 CLINICAL PHARMACOLOGY .............................................................................................26

10.1 Mechanism of Action ................................................................................................26

10.2 Pharmacodynamics...................................................................................................27

10.3 Pharmacokinetics .....................................................................................................29

11 STORAGE, STABILITY AND DISPOSAL ...............................................................................30

12 SPECIAL HANDLING INSTRUCTIONS .................................................................................31

PART II: SCIENTIFIC INFORMATION ........................................................................................32

13 PHARMACEUTICAL INFORMATION ..................................................................................32

14 CLINICAL TRIALS ..............................................................................................................32

14.3 Comparative Bioavailability Studies ...........................................................................32

15 MICROBIOLOGY .............................................................................................................33

16 NON-CLINICAL TOXICOLOGY ...........................................................................................33

17 SUPPORTING PRODUCT MONOGRAPHS ..........................................................................36

PATIENT MEDICATION INFORMATION ...................................................................................37

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

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 musculoskeletal 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 2 CONTRAINDICATIONS and 7 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 2 CONTRAINDICATIONS and 7 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.

1.1 Pediatrics

Pediatrics (< 18 years of age): APO-NAPRO-NA and APO-NAPRO-NA DS is contraindicated in children and adolescents less than 18 years of age since APO-NAPRO-NA and APO-NAPRO-NA DS have not been studied in subjects under the age of 18. See 2 CONTRAINDICATIONS.

1.2 Geriatrics

Geriatrics (> 65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness. (see 4 DOSAGE AND ADMINISTRATION and 7.1.4 Geriatrics).

2 CONTRAINDICATIONS

• APO-NAPRO-NA and APO-NAPRO-NA DS are contraindicated in the peri-operative setting of coronary artery bypass graft surgery (CABG). Although naproxen sodium has 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
• patients with severe uncontrolled heart failure
• patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• patients with a 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 7 WARNINGS AND PRECAUTIONS).
• patients with active gastric / duodenal / peptic ulcer, active GI bleeding.
• patients with cerebrovascular bleeding or other bleeding disorders
• patients with inflammatory bowel disease
• patients with severe liver impairment or active liver disease
• patients with 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 7 WARNINGS AND PRECAUTIONS)
• patients with known hyperkalemia (see 7 WARNINGS AND PRECAUTIONS)
• children and adolescents less than 18 years of age since APO-NAPRO-NA and APO-NAPRO-NA DS have not been studied in subjects under the age of 18.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing considerations

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 (see 1 INDICATIONS). For all indications, treatment must be initiated with the lowest dose.

4.2 Recommended Dose and Dosage Adjustment

Adult:

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.

4.4 Administration

APO-NAPRO-NA or APO-NAPRO-NA DS should be swallowed with food or milk.

4.5 Missed Dose

If a dose is missed, the patient should take it as soon as it is recognized. If it is almost time for the next dose, skip the missed dose and continue with the next scheduled dose. The patient should be instructed not take 2 doses at the same time.

5 OVERDOSAGE

Frequently observed signs and symptoms of overdose are 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.

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.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 - Dosage Forms, Strengths, Composition and Packaging

APO-NAPRO-NA (naproxen sodium 275 mg) is available as blue, oval, biconvex, film-coated tablets engraved "AP0-275" on one side, other side plain 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 blue, oval biconvex film coated tablets engraved "AP0-550" on one side, other side plain contains 550 mg of naproxen sodium. APO-NAPRO-NA DS 550 mg tablets are available in bottles of 100 and 500.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX

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.

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 9 DRUG INTERACTIONS

APO-NAPRO-NA or APO-NAPRO-NA DS (naproxen sodium) should not be used concomitantly with other drugs that contain naproxen since they circulate in plasma as the naproxen anion.

Carcinogenesis and Mutagenesis

see 16 NON-CLINICAL TOXICOLOGY

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 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 7 WARNINGS AND PRECAUTIONS.

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.

Driving and Operating Machinery

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.

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 9 DRUG INTERACTIONS

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 7 WARNINGS AND PRECAUTIONS

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)

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 9 DRUG INTERACTIONS

Concomitant administration of APO-NAPRO-NA or APO-NAPRO-NA DS with low dose ASA increases the risk of GI ulceration and associated complications.

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.

Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for naproxen dosing is unknown, but caution is advised when high doses are required. It is prudent to use the lowest effective dose

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.

Immune

See 7 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.

Monitoring and Laboratory Tests

Cardiovascular: 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 7 WARNINGS AND PRECAUTIONS

Hematology: 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 7 WARNINGS AND PRECAUTIONS

Monitoring of plasma lithium concentration is recommended when stopping or starting APO-NAPRO-NA or APO-NAPRO-NA DS therapy. See 9 DRUG INTERACTIONS

Hepatic: Serum transaminase and bilirubin should be monitored regularly during APO-NAPRO-NA or APO-NAPRO-NA DS therapy. See 7 WARNINGS AND PRECAUTIONS

Renal: 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 7 WARNINGS AND PRECAUTIONS

Pregnancy: If APO-NAPRO-NA or APO-NAPRO-NA DS are administered in the middle (approximately 20 weeks) to the end of the second trimester, it is recommended that pregnant women on APO-NAPRO-NA or APO-NAPRO-NA DS be closely monitored for amniotic fluid volume since APO-NAPRO-NA or APO-NAPRO-NA DS may result in reduction of amniotic fluid volume and even oligohydramnios. See 7.1 Special Populations

APO-NAPRO-NA or APO-NAPRO-NA DS are contraindicated for use in the third trimester of pregnancy.

Urinary: 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 7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS

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 2 CONTRAINDICATIONS

Psychiatric

Some patients may experience insomnia or depression with the use of NSAIDs, such as APO-NAPRO-NA or APO-NAPRO-NA DS.

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.

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 2 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 7 WARNINGS AND PRECAUTIONS

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 2 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.

Reproductive Health: Female and Male Potential

• Fertility

  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.

Respiratory

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

Sensitivity/Resistance

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 2 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 2 CONTRAINDICATIONS

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

Skin

Serious skin reactions: Use of some NSAIDs, such as APO-NAPRO-NA or APO-NAPRO-NA DS, have been associated with rare post-market cases of serious, fatal or otherwise life-threatening skin reactions, including:

• Drug reaction with eosinophilia and systemic symptoms (DRESS)
• Stevens-Johnson syndrome (SJS)
• toxic epidermal necrolysis (TEN)
• exfoliative dermatitis
• erythema multiforme.

Patients appear to be at higher risk for these events early in the course of therapy, with the onset of cases usually occurring within the first month of treatment. These reactions may be reversible if the causative agent is discontinued and appropriate treatment instituted. Patients should be advised that they should discontinue their NSAID at the first appearance of a skin rash, mucosal lesions or any other sign of hypersensitivity, and contact their physician immediately for assessment and advice, including which therapies to discontinue.

DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection, and eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.

7.1 Special Populations

7.1.1 Pregnant Women

APO-NAPRO-NA or APO-NAPRO-NA DS is contraindicated for use during the third trimester of pregnancy because of risks of premature closure of the ductus arteriosus and the potential to prolong parturition. See 2 CONTRAINDICATIONS and 16 NON-CLINICAL TOXICOLOGY). Caution is recommended in prescribing APO-NAPRO-NA or APO-NAPRO-NA DS during the first and second trimesters of pregnancy, particularly from the middle to end of the second trimester of pregnancy (onset at approximately 20 weeks) due to possible fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment or failure.

Published studies and postmarketing reports describe maternal NSAID use at approximately 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment or failure. NSAIDs were shown to cause significant reduction in fetal urine production prior to reduction of amniotic fluid volume. There have also been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction and renal impairment without oligohydramnios, some of which were irreversible, even after treatment discontinuation.

These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Complications of prolonged oligohydramnios may for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If after careful consideration of the benefit-risk, NSAID treatment is considered necessary to be administered anywhere from the middle (onset at approximately 20 weeks) to the end of the second trimester of pregnancy, the use should be limited to the lowest effective dose and shortest duration possible. It is also recommended that ultrasound monitoring of amniotic fluid be considered if APO-NAPRO-NA or APO-NAPRO-NA treatment extends beyond 48 hours and that NSAIDs treatment be discontinued if oligohydramnios occurs, followed by appropriate medical follow up.

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 and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage.

7.1.2 Breast-feeding

APO-NAPRO-NA or APO-NAPRO-NA DS is contraindicated in breast-feeding women. See 2 CONTRAINDICATIONS

7.1.3 Pediatrics

Pediatrics (< 18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of APO-NAPRO-NA or APO-NAPRO-NA in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use. See 2 CONTRAINDICATIONS

7.1.4 Geriatrics

Geriatrics (> 65 years of age): 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.

8 ADVERSE REACTIONS

8.1 Adverse 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.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Adverse reactions reported in controlled clinical trials are listed below.

Table 2: Most Common Clinical Trial Adverse Drug Reactions (3%-9% and 1%-3%)

8.3 Less Common Clinical Trial Adverse Reactions

Table 3: Less Common Clinical Trial Adverse Drug Reactions (<1%)

8.5 Post-Market Adverse Reactions

Additional reports of serious adverse events temporally associated with naproxen and naproxen sodium during worldwide post-marketing experience are included below. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or clearly establish a causal relationship to naproxen exposure.

9 DRUG INTERACTIONS

9.3 Drug-Behavioural 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.

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 4 -Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical; GI = Gastrointestinal; CV = Cardiovascular; INR = International normalized ratio; PD = Pharmacodynamic; ASA = Acetylsalicylic acid; NSAID = Non-Steroidal Anti-Inflammatory Drug; ACE = Angiotensin converting enzyme; ARB = Angiotensin Receptor Blockers; RI = Renal impairment

9.5 Drug-Food Interactions

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

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

See 7 WARNINGS AND PRECAUTIONS - Monitoring and Laboratory Tests

10 CLINICAL PHARMACOLOGY

10.1 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.

10.2 Pharmacodynamics

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 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.

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.

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.

10.3 Pharmacokinetics

Formula A= 2x275 mg naproxen sodium tablets

Formula B=one 550 mg naproxen sodium tablet

¹=p-values resulting from Analysis of Variance

Absorption

Naproxen sodium is freely soluble in water and is completely absorbed from the gastrointestinal tract.

Distribution:

Plasma levels are obtained in patients within 20 minutes and peak levels in approximately 1 hour.

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.

Metabolism:

It is extensively bound to plasma protein and has a plasma half-life of approximately 13 hours. 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.

Elimination:

The preferred route of excretion is via the urine with only 1% of the dose excreted in the feces.

Special Populations and Conditions

Pediatrics: Pharmacokinetic studies of naproxen were not performed in children less than 5 years of age. Health Canada has not authorized an indication for pediatric use. See 2 CONTRAINDICATIONS

Geriatric: Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects.

Hepatic Impairment: Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency.

Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased.

Renal impairment: Given that naproxen and its metabolites are primarily excreted by the kidney, the potential exists for accumulation in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. See 2 CONTRAINDICATIONS

11 STORAGE, STABILITY AND DISPOSAL

Store at controlled room temperature, 15 to 30°C. Protect from moisture. Keep out of reach and sight of children.

12 SPECIAL HANDLING INSTRUCTIONS

N/A

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Naproxen sodium

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

Molecular formula and molecular mass: C₁₄H₁₃NaO₃; 252.24 g/mol

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.

14 CLINICAL TRIALS

14.3 Comparative Bioavailability Studies

A randomized, single dose, double-blinded, 2-way crossover comparative bioavailability study of Apo-Napro-NA Tablets, 275 mg (Apotex Inc.) and ^PrAnaprox® Tablets (Hoffmann-La Roche Ltd.), administered as a 2 x 275 mg dose was conducted in healthy male subjects under fasting conditions. A summary of the bioavailability data from the 16 subjects who completed the study is presented in the following table.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ Apo-Napro-Na (naproxen sodium) Tablets, 275 mg (Apotex Inc.).

^{2 Pr}Anaprox® (naproxen sodium) Tablets, 275 mg (Hoffmann-La Roche Limited, Canada).

³ Expressed as arithmetic mean (CV%) only.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

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.

Acute Animal Toxicity

The oral LD₅₀ 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 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. 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.

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.

Genotoxicity:

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.

Reproductive and Developmental Toxicology:

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 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.

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.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. ANAPROX, ANAPROX DS Tablet, 275 mg and 550 mg, Submission Control No 253450, Product Monograph, Atnahs Pharma UK Limited, (JAN 18, 2022)