Apo-Tiaprofenic Tablets-200mg 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 ....................................................... 6

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

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

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

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ...................................... 7

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

7.1 Special Populations .............................................................................................. 15

7.1.1 Pregnant Women ................................................................................................ 15

7.1.2 Breast-feeding ..................................................................................................... 16

7.1.3 Pediatrics ............................................................................................................. 16

7.1.4 Geriatrics ............................................................................................................. 16

8 ADVERSE REACTIONS ..................................................................................................... 16

8.1 Adverse Reaction Overview ................................................................................. 16

8.2 Clinical Trial Adverse Reactions ........................................................................... 16

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ................................................................................................ 18

8.5 Post-Market Adverse Reactions ........................................................................... 18

9 DRUG INTERACTIONS ..................................................................................................... 19

9.2 Drug Interactions Overview ................................................................................. 19

9.4 Drug-Drug Interactions ........................................................................................ 19

9.5 Drug-Food Interactions ........................................................................................ 23

9.6 Drug-Herb Interactions ........................................................................................ 23

9.7 Drug-Laboratory Test Interactions ....................................................................... 23

10 CLINICAL PHARMACOLOGY ............................................................................................ 24

10.1 Mechanism of Action ........................................................................................... 24

10.2 Pharmacodynamics.............................................................................................. 24

10.3 Pharmacokinetics: ............................................................................................... 24

11 STORAGE, STABILITY AND DISPOSAL .............................................................................. 25

12 SPECIAL HANDLING INSTRUCTIONS ................................................................................ 25

PART II:SCIENTIFIC INFORMATION ........................................................................................ 26

13 PHARMACEUTICAL INFORMATION ................................................................................. 26

14 CLINICAL TRIALS ............................................................................................................. 26

14.2 Comparative Bioavailability Studies ..................................................................... 26

15 MICROBIOLOGY ............................................................................................................. 27

16 NON-CLINICAL TOXICOLOGY ........................................................................................... 27

17 SUPPORTING PRODUCT MONOGRAPHS ......................................................................... 30

PATIENT MEDICATION INFORMATION .................................................................................. 31

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

APO-TIAPROFENIC (tiaprofenic acid) is indicated for:

• The relief of signs and symptoms of rheumatoid arthritis and osteoarthritis (degenerative joint disease).

Throughout this document, the term NSAIDs refers to both non-selective NSAIDs and selective COX-2 inhibitor NSAIDs, unless otherwise indicated.

For patients with an increased risk of developing CV and/or GI adverse events, other management strategies that do NOT include the use of should be considered first. (See 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS).

Use of APO-TIAPROFENIC 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-TIAPROFENIC, as a NSAID, does NOT treat clinical disease or prevent its progression.

APO-TIAPROFENIC, 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): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of tiaprofenic acid in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use. See 2 CONTRAINDICATIONS.

1.2 Geriatrics

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 7.1.4 Geriatrics.

2 CONTRAINDICATIONS

APO-TIAPROFENIC is contraindicated in:

• the peri-operative setting of coronary artery bypass graft surgery (CABG). Although tiaprofenic acid 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
• 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
• history of asthma, urticaria, or allergic-type reactions after taking ASA or other (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 in the past without any adverse reaction. The potential for cross-reactivity between different must be kept in mind (see 7 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 and must be monitored) (see 7 WARNINGS AND PRECAUTIONS - Renal)
• known hyperkalemia (see 7 WARNINGS AND PRECAUTIONS - Renal - Fluid and Electrolyte Balance)
• children and adolescents less than 18 years of age.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Use of APO-TIAPROFENIC should be limited to the lowest effective dose for the shortest possible duration of treatment. See 1 INDICATIONS

4.2 Recommended Dose and Dosage Adjustment

Rheumatoid Arthritis: The usual initial and maintenance dose is 600 mg daily in 3 divided doses. Some patients may do well on 300 mg twice daily. The maximum daily dose is 600 mg.

Osteoarthritis: The usual initial and maintenance dose is 600 mg daily in 2 or 3 divided doses. In rare cases patients may be maintained on 300 mg daily in divided doses. The maximum maintenance daily dose is 600 mg.

Pediatrics (< 18 years of age): Health Canada has not authorized an indication for pediatric use. See 2 CONTRAINDICATIONS

Geriatrics (>65 years of age): In the elderly, frail and debilitated, the dosage should be reduced to the lowest level providing control of symptoms, and adjusted when necessary. See 7.1.4 Geriatrics

Renal impairment: A lower dose should be considered in patients with mild and moderate renal impairment. APO-TIAPROFENIC is contraindicated in 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 2 CONTRAINDICATIONS

Hepatic impairment: A lower dose should be considered in patients with mild and moderate hepatic impairment. APO-TIAPROFENIC is contraindicated in severe liver impairment or active liver disease. See 2 CONTRAINDICATIONS

4.4 Administration

APO-TIAPROFENIC should be administered with food.

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

There have been no reports of overdosage with tiaprofenic acid. No specific antidote is known, therefore, the patient should be observed carefully and given symptomatic and supportive treatment.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 Dosage Forms, Strengths, Composition and Packaging

Description

APO-TIAPROFENIC 200 mg Tablets:

Each round, white, film-coated, biconvex tablet, bisected and engraved "APO" over "200" on one side contains 200 mg of tiaprofenic acid.

Available in bottles of 100 and 250, unit dose packages of 100 (10x 10), 620 (nursing cards of 20 x 31) and 700 (nursing cards of 20 x 35).

APO-TIAPROFENIC 300 mg Tablets:

Each round, white, film-coated, biconvex tablet, bisected and engraved "APO" over "300" on one side contains 300 mg of tiaprofenic acid.

Available in bottles of 100 and 500, unit dose packages of 100 (10 x 10), 620 (nursing cards of 20 x 31) and 700 (nursing cards of 20 x 35).

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, 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 should be considered.

APO-TIAPROFENIC is NOT recommended for use with other, 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 9.4 Drug-Drug Interactions - Acetylsalicylic acid (ASA) or other)

Carcinogenesis and Mutagenesis

See 16 NON-CLINICAL TOXICOLOGY

Cardiovascular

APO-TIAPROFENIC is a non-steroidal anti-inflammatory drug (NSAID). Use of some 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-TIAPROFENIC 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-TIAPROFENIC), 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-TIAPROFENIC) should hypertension either develop or worsen with its use.

Use of, such as APO-TIAPROFENIC, can induce fluid retention and edema, and may exacerbate congestive heart failure, through a renally-mediated mechanism. See 7 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 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.

Endocrine and Metabolism

Corticosteroids: APO-TIAPROFENIC 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 peptic / duodenal ulceration, inflammation, perforation, obstruction and gastrointestinal bleeding, can occur at any time, with or without warning symptoms, in patients treated with, such as tiaprofenic acid. 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 tiaprofenic acid, 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 should be considered. (see 7.1.4 Geriatrics)

Patients should be informed about the signs and/or symptoms of serious GI toxicity and instructed to discontinue using APO-TIAPROFENIC 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, appear to occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 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-TIAPROFENIC 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 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-TIAPROFENIC should be stopped to ascertain if symptoms disappear. This should be done before urological investigations or treatments are carried out.

Hematologic

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-TIAPROFENIC is administered.

Anti-coagulants: Numerous studies have shown that the concomitant use of and anti- coagulants increases the risk of bleeding. Concurrent therapy of APO-TIAPROFENIC with warfarin requires close monitoring of the international normalized ratio (INR).

Even with therapeutic INR monitoring, increased bleeding may occur.

Anti-platelet Effects: 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-TIAPROFENIC and other 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 with ASA can markedly attenuate the cardioprotective effects of ASA. See 9.4 Drug-Drug Interactions - Acetylsalicylic Acid (ASA) or other)

Concomitant administration of APO-TIAPROFENIC 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 non-steroidal anti-inflammatory drugs are rare, but could occur with severe consequences.

Anemia is sometimes seen in patients receiving, including APO-TIAPROFENIC. 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-TIAPROFENIC, 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.

Immune

In common with other anti-inflammatory drugs, APO-TIAPROFENIC may mask the usual signs of infection.

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-TIAPROFENIC should have their blood pressure monitored regularly.

Hematology: Hemoglobin, hematocrit, red blood cells (RBCs), white blood cells (WBCs), and platelets should be checked in patients on long-term treatment with APO-TIAPROFENIC. Additionally, concurrent therapy with warfarin requires close monitoring of the international normalized ratio (INR).

Hepatic: Serum transaminase and bilirubin should be monitored regularly during APO-TIAPROFENIC therapy.

Ophthalmologic: Ophthalmic examination should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.

Renal: Serum creatinine, creatine clearance and serum urea should be checked in patient during APO-TIAPROFENIC therapy. Electrolytes including serum potassium should be monitored periodically.

Pregnancy: If APO-TIAPROFENIC is administered in the middle (approximately 20 weeks) to the end of the second trimester, it is recommended that pregnant women on APO-TIAPROFENIC be closely monitored for amniotic fluid volume since APO-TIAPROFENIC may result in reduction of amniotic fluid volume and even oligohydramnios. See 7.1.1 Pregnant Women

APO-TIAPROFENIC is contraindicated for use in the third trimester of pregnancy.

Neurologic

Some patients may experience drowsiness, dizziness, blurred vision, vertigo, tinnitus, hearing loss, insomnia or depression with the use of NSAIDs, such as tiaprofenic acid. 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 should be discontinued and an ophthalmologic examination performed.

Ophthalmologic examination should be carried out at periodic intervals in any patient receiving tiaprofenic acid for an extended period of time.

Peri-Operative Considerations

See 2 CONTRAINDICATIONS - Coronary Artery Bypass Graft Surgery

Psychiatric

See 7 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.

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-II 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 tiaprofenic acid 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-TIAPROFENIC, 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-TIAPROFENIC 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 - Cardiovascular).

Use of NSAIDs, such as APO-TIAPROFENIC, 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).

Reproductive Health: Female and Male Potential

Fertility

The use of tiaprofenic acid, 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-TIAPROFENIC 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 tiaprofenic acid. In post-marketing experience, rare cases of anaphylactic/ anaphylactoid reactions and angioedema have been reported in patients receiving APO-TIAPROFENIC. Tiaprofenic acid 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: Tiaprofenic acid 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-TIAPROFENIC, 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,
• toxic epidermal necrolysis,
• exfoliative dermatitis and
• 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-TIAPROFENIC 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 16 NON-CLINICAL TOXICOLOGY). Caution is recommended in prescribing APO-TIAPROFENIC 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-TIAPROFENIC 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 embryo-fetal 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-fetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenesis period.

7.1.2 Breast-feeding

APO-TIAPROFENIC 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 tiaprofenic acid 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 on occasion, 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

The following side effects were encountered in clinical trials with tiaprofenic acid in 1,361 patients.

Table 2

Rare incidents of gastric or duodenal ulceration have been reported although not seen in this series of patients.

Table 3

Less than 1% (range 0.1 to 0.5%).

Eye itching/conjunctivitis/red eyes, minor eye ulcers, blurred vision, anorexia, weight gain, cramps, dyspnea, intermenstrual bleeding/vaginal spotting, paresthesia of fingers, sneezing, sweating.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Laboratory and Biochemical Tolerance

Combined decrease of hematocrit and hemoglobin: 2.8% of patients. Decrease of hemoglobin: 2.8% of patients. Increased white blood cell count 0.6%; decreased count 0.3%.

Increased gammaglutamic transferase and AST(SGOT): less than 1%. Increased alkaline phosphatase from previously normal levels: less than 1%. In patients with initially high alkaline phosphatase the levels remained high or increased.

Increase in blood urea nitrogen (BUN): 2.5% of total patients (11.8% in the elderly). Increase in BUN and creatinine: 0.4% of patients.

Hyperkalemia: 2.4% of patients.

8.5 Post-Market Adverse Reactions

Gastrointestinal: Disorders of intestinal transit, ulcer, perforation, overt or occult gastrointestinal haemorrhage resulting in anaemia.

Muco-cutaneous: Purpura, urticaria, very rarely erythema multiforme and bulbous eruptions (Stevens-Johnson syndrome or exceptionally toxic epidermal necrolysis); very rarely photosensitivity reactions.

Hypersensitivity Reactions: Asthmatic attacks, especially in subjects allergic to aspirin and other non-steroidal anti-inflammatory agents, angio-oedema, anaphylactic shock.

Haematological: thrombocytopenia, prolongation of bleeding time.

Urinary System: Urinary symptoms (bladder pain, dysuria, and frequency), haematuria or cystitis may occur. When treatment with tiaprofenic acid has been continued for months after onset of the urinary symptoms, inflammatory changes to the urinary tract, sometimes severe, have been observed and a few patients have undergone surgical procedures. Therefore, should any urinary symptom occur, treatment with tiaprofenic acid must be discontinued immediately, Complete recovery after discontinuation is the rule (See 7 WARNINGS AND PRECAUTIONS - Renal).

Nervous System: Vertigo, tinnitus, tremor.

Renal: Sodium and water retention (see 7 WARNINGS AND PRECAUTIONS - Renal). As with other NSAIDS, isolated cases of acute interstitial nephritis have been reported with tiaprofenic acid.

Hepatic: Liver test abnormalities.

Other: Palpebral oedema, palpitations.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

Tiaprofenic acid is highly bound to serum albumin (98%). This may lead to interaction with anticoagulants, sulfonylurea, hypoglycemic agents, sulfonamides, phenytoin, lithium and certain chemotherapeutic agents such as methotrexate. Therefore, caution should be used when these drugs are used concurrently.

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; 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 tiaprofenic acid.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

APO-TIAPROFENIC (tiaprofenic acid), is a non-steroidal, anti-inflammatory agent with analgesic and antipyretic properties. It is a propionic acid derivative. The exact mechanism of action responsible for the anti–inflammatory, analgesic action is unknown. Tiaprofenic acid inhibits the enzyme prostaglandin synthetase which may be responsible for the reduction in inflammation and pain. The therapeutic effect of tiaprofenic acid does not result from pituitary– adrenal stimulation.

10.2 Pharmacodynamics

Tiaprofenic acid did not depress the biosynthesis of proteoglycans nor alter the differentiation of proteoglycans secreted in different experimental models with cartilage and cultures of human chondrocytes. The degradation of proteoglycan aggregates was also inhibited. These in vitro results suggest a positive effect of tiaprofenic acid on the joint cartilage. The clinical significance of these findings has to be further investigated.

10.3 Pharmacokinetics

Absorption

Tiaprofenic acid is rapidly absorbed at the gastric and duodenal levels after oral administration. Peak serum levels are obtained in 30 to 90 minutes. Food delays the absorption and the time to reach peak plasma concentrations by 10%. Tiaprofenic acid is approximately 98% protein bound. The plasma half–life is approximately 2 hours, following a single dose of 200 mg tiaprofenic acid.

Elimination

Tiaprofenic acid is primarily eliminated in the urine, 50% as unchanged tiaprofenic acid and two metabolites (II & Ill) accounting for less than 10%. The metabolites are inactive.

Chronic administration at a dosage of 200 mg tid demonstrated rapid elimination and absence of accumulation. Steady state was attained after one day's treatment and plasma levels approached zero within 24 hours of the last dose.

The times to reach mean peak serum levels were tested in two groups of arthritic patients treated with 200 mg tid and 300 mg bid for 7 days or more. The times were found to be 78 and 50 minutes, respectively. In synovial fluid, the mean time to peak levels was approximately 4 hours for both dosages. Following a 200 mg dose, peak serum and synovial fluid levels reached 26 mcg/mL and 5 mcg/mL respectively and 50 mcg/mL and 7.7 mcg/mL after a 300 mg dose. At 8 hours serum blood levels were lower than those of synovial fluids but by 11 hours these levels were approximately the same.

In another study, rheumatoid arthritis patients were given tiaprofenic acid 200 mg tid for 7 days. After the first dose, a fall in the synovial PGE₂ level occurred inversely to a rise in drug level. The level of PGE₂ remained low after one week's continuous medication. These results indicate that tiaprofenic acid reaches its target organ and is retained within the joint. It also suggests that reduction in PGE₂ production is one of the ways in which tiaprofenic acid acts. The clinical significance of the relative serum and synovial fluid levels has, however, not been elucidated.

A pharmacokinetic study conducted in elderly patients receiving tiaprofenic acid 300 mg bid for 3 months showed no significant differences for all pharmacokinetic parameters (C_max, T_max, C₉, AUC_{0-9 h}, t_½) measured at weeks 0, 4, 8 and 12, thus suggesting lack of accumulation.

Fecal blood loss at the therapeutic dose range was less than with usual clinical doses of ASA.

Special Populations and Conditions

Pediatrics: The pharmacokinetics of tiaprofenic acid have not been investigated in pediatric patients.

Hepatic Insufficiency: Patients with acute and chronic hepatic disease may require reduced doses of tiaprofenic acid compared to patients with normal hepatic function.

Renal Insufficiency: Tiaprofenic acid and its metabolites are eliminated primarily by the kidneys, therefore the drug should be used with great caution in patients with impaired renal function. In these cases utilization of lower doses of tiaprofenic acid should be considered and patients carefully monitored.

11 STORAGE, STABILITY AND DISPOSAL

Store at room temperature 15 to 30°C. Protect from excessive heat, light and humidity.

Keep out of reach and sight of children.

12 SPECIAL HANDLING INSTRUCTIONS

Not Applicable.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Tiaprofenic acid

Chemical name: alpha-(5-benzoyl-2-thienyl) propionic acid or

5-benzoyl-alpha-methyl-2 thiophene acetic acid.

Molecular formula and molecular mass: C₁₄H₁₂O₃S and 260.3 g/mol

Structural formula:

Physicochemical properties: Tiaprofenic acid is a white microcrystalline powder with a melting point of about 95°C. It is readily soluble in alcohol, chloroform and acetone, but is only sparingly soluble in water. The pKa is approximately 3.0.

14 CLINICAL TRIALS

The clinical trial data on which the original indication was authorized is not available.

14.2 Comparative Bioavailability Studies

A randomized, two-treatment, two-period, single dose (1 x 300 mg), crossover comparative bioavailability study of APO-TIAPROFENIC (Apotex Inc.) and SURGAM (Roussel Canada Inc.) was conducted in healthy male subjects under fasting conditions. A summary of the data from the 19 subjects that were included in the pharmacokinetic and statistical analyses is presented in the following table.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology

Comparative Non-Clinical Pharmacology and Toxicology

Acute Toxicity: LD₅₀ (95% confidence limits) mg/kg.

Table 5:

Signs of toxicity observed in mice, rats and rabbits included respiratory distress, bradypnea, cyanosis, convulsions, excitability, depression, tremors, motor incoordination, writhing, prostration, ptosis and weight loss. Necropsies showed ascites, peritonitis, hypertrophy and congestion of the mesenteric ganglia.

Long-Term Toxicity:

Tiaprofenic acid was administered orally to rats (35 animals/group/sex) at doses of 0, 10, 20 and 30 mg/kg/day, 6 days a week for 24 consecutive weeks. Signs of toxicity observed were dose and sex–related; the 10 mg/kg/day dose was well tolerated. At 20 mg/kg/day jejunoileal ulcerations with perforations and peritonitis were identified and a few cases of hepatic abscesses and pancreatitis were observed. At a dose of 30 mg/kg/day, anemia and splenic myeloid metaplasia were also observed. A higher death rate from anemia in females was evident.

In a six month study conducted in 32 beagle dogs (4 animals/group/sex) at daily oral doses of 0, 10, 20 and 40 mg/kg. Four animals treated with 10 and 20 mg/kg showed a slight to moderate erosion of the gastric mucosa. At 4 weeks, at a dose of 20 mg/kg, a transient reduction in red blood cell count in females was observed. The following toxic signs in animals receiving 40 mg/kg were observed. Weight loss, anemia, reticulocytosis, transient leucocytosis, reactive polycythaemia, fecal occult blood, jejunum and gastric ulceration, increased megakaryocyte and erythrocyte count and splenic myeloid metaplasia. These effects had been observed after 2 to 1/2 months.

In another study conducted in baboons (3 animals/group/sex), tiaprofenic acid was orally administered at 0, 10, 30 and 90 mg/kg/day for 6 months. No histological changes occurred in the gastrointestinal tract in the 0, 10 and 30 mg/kg/day groups. At 90 mg/kg/day there was: increased BUN, diarrhea, fecal occult blood, vomiting, weight loss, anemia, leucocytosis, decreased LAP, transient increased SGPT, gastric and ileum lesions. Slight degeneration of the renal tissue and hyalin areas in cortical tubuli were also observed. One female was sacrificed after 8 weeks of treatment due to a general deteriorating condition of unknown cause.

In a one year study, baboons (5 animals/group/sex) were given tiaprofenic acid orally at doses of 0, 10, 25, 50 and 75 mg/kg/day. At the highest dose of 75 mg/kg/day there were microscopic changes in the gastrointestinal tract, especially in the stomach, indicating minor erosions of the mucosa. Similar lesions, confined to the intestines, were noted, in 3 animals at 50 mg/kg/day and 2 female baboons at 25 mg/kg/day. There was no evidence of such lesions in animals killed after a recovery period of 16 weeks.

Carcinogenicity

No evidence of carcinogenicity of tiaprofenic acid was found in mice (60 male and 60 female/group) and in rats (50 male and 50 female/main group; 35 male and 35 female/supplementary group) at oral doses of 0 (control), 10, 20 and 30 mg/kg/day for 80 weeks and 104 weeks, respectively.

Mutagenicity

No evidence of mutagenicity of tiaprofenic acid was observed in the diffusion method, the Ames Test in bacterial strains, or in the mouse using the micronucleus test.

Reproductive and Developmental Toxicology

Mice (24 animals/group) were treated with doses of 0, 25, 50 and 100 mg/kg/day from days 0 to 17 of pregnancy. No treatment–related effects on pregnancy were observed except for a small increase in the rate of fetal loss at the 100 mg/kg dose.

Rats (24 animals/group) were administered tiaprofenic acid at 0, 5, 10 and 25 mg/kg/day from days 0 to 20 of gestation. At the 10 mg/kg and 25 mg/kg, a slight increase in fetal loss was observed.

Rabbits (20 animals/group) received doses of 0, 25, 50 and 75 mg/kg/day from days 0 to 27 of pregnancy. At the 75 mg/kg/day dose, the number of implantation sites were reduced. The rate of fetal loss was also increased at this dose.

Rats (20 males and 24 females per group) were given daily oral doses of 0, 5, 10 and 20 mg/kg, prior to pairing and during the mating period. Mated females were treated throughout gestation (21 days) except for the last 3 days before parturition. A second group was treated during the lactation period (21 days). There was no effect observed on the fertility and the reproductive performance of rats at all doses; however, at the 20 mg/kg/day, the pre and post implantation losses were slightly increased. There was no effect or influence on development and reproduction of the two subsequent generations (F₁ and F₂ off–spring).

In another study in rats (24 animals/group), tiaprofenic acid was administered orally at daily doses of 0, 8, 16 and 24 mg/kg, from day 15 of gestation until day 21 post partum. At doses of 16 and 24 mg/kg, 9 females in each group showed a delayed or lengthened parturition. Means of the length of gestation were 22.42 ± .16 and 22.73 ± 0.18 days on 16 and 24 mg/kg, respectively, versus 21.62 ± 0.16 for the control group. Another group of pregnant rats (12 animals) received 16 mg/kg orally from day 0 to 18 of gestation and from parturition until day 21 post partum. There were no adverse effects observed during gestation, parturition or lactation on mothers or pups.

17 SUPPORTING PRODUCT MONOGRAPHS

1 TEVA–TIAPROFENIC ACID Tablets, 200 mg and 300 mg, submission control: 261587, Product Monograph, Teva Canada Limited (AUG 15, 2022)