APO PIROXICAM CAP 20MG CAPSULE

Canada - English - Health Canada

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Active ingredient:
PIROXICAM
Available from:
APOTEX INC
ATC code:
M01AC01
INN (International Name):
PIROXICAM
Dosage:
20MG
Pharmaceutical form:
CAPSULE
Composition:
PIROXICAM 20MG
Administration route:
ORAL
Units in package:
100/500
Prescription type:
Prescription
Therapeutic area:
OTHER NONSTEROIDAL ANTIIMFLAMMATORY AGENTS
Product summary:
Active ingredient group (AIG) number: 0114612001; AHFS: 28:08.04.92
Authorization status:
MARKETED
Authorization number:
00642894
Authorization date:
1986-12-31

Documents in other languages

Page 1 of 37

PRODUCT MONOGRAPH

APO-PIROXICAM

Piroxicam, USP

10 mg and 20 mg Capsules

Apotex Standard

Nonsteroidal Anti-inflammatory Drug (NSAID)

APOTEX INC.

DATE OF REVISION:

150 Signet Drive

June 23, 2010

Weston, Ontario

M9L 1T9

Control Number: 137970

Page 2 of 37

Table of Contents

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

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

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

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

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

ADVERSE REACTIONS....................................................................................................... 15

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

DOSAGE AND ADMINISTRATION ................................................................................... 23

OVERDOSAGE...................................................................................................................... 24

ACTION AND CLINICAL PHARMACOLOGY.................................................................. 24

STORAGE AND STABILITY............................................................................................... 26

DOSAGE FORMS, COMPOSITION AND PACKAGING .................................................. 26

PART II: SCIENTIFIC INFORMATION ............................................................................. 27

PHARMACEUTICAL INFORMATION............................................................................... 27

CLINICAL TRIALS ............................................................................................................... 27

DETAILED PHARMACOLOGY .......................................................................................... 29

TOXICOLOGY ...................................................................................................................... 29

REFERENCES........................................................................................................................ 32

PART III: CONSUMER INFORMATION............................................................................ 34

Page 3 of 37

APO-PIROXICAM

Piroxicam, USP

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form /

Strength

Clinically Relevant Nonmedicinal

Ingredients

Oral

Capsules

10 mg and 20 mg

Lactose and Gelatin

For a complete listing see Dosage Forms,

Composition and Packaging section.

INDICATIONS AND CLINICAL USE

APO-PIROXICAM (piroxicam) is indicated for the symptomatic treatment of:

rheumatoid arthritis,

osteoarthritis (degenerative joint disease), and

ankylosing spondylitis.

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 NSAIDs should be considered first.

(See Contraindications and Warnings and Precautions)

Use of APO-PIROXICAM should be limited to the lowest effective dose for the shortest

possible duration of treatment in order to minimize the potential risk for cardiovascular or

gastrointestinal adverse events. (See Contraindications and Warnings and Precautions)

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

APO-PIROXICAM, as a NSAID, only relieves symptoms and decreases inflammation for as

long as the patient continues to take it.

Geriatrics (> 65 years of age):

Evidence from clinical studies and post-market experience

suggests that use in the geriatric population is associated with differences in safety (See

Warnings and Precautions

Page 4 of 37

Pediatrics (< 16 years of age):

Safety and efficacy have not been established in the pediatric

population.

CONTRAINDICATIONS

APO-PIROXICAM is contraindicated in:

the peri-operative setting of coronary artery bypass graft surgery (CABG). Although

APO-PIROXICAM 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

known hypersensitivity to Piroxicam or to any of the components/excipients of APO-

PIROXICAM.

history of asthma, urticaria, or allergic-type reactions after taking acetylsalicylic acid

(ASA) or other NSAIDs (i.e. complete or partial syndrome of ASA-intolerance -

rhinosinusitis, urticaria/ angioedema, nasal polyps, asthma). Fatal anaphylactoid reactions

have occurred in such individuals. Individuals with the above medical problems are at

risk of a severe reaction even if they have taken NSAIDs in the past without any adverse

reaction. The potential for cross-reactivity between different NSAIDs must be kept in

mind (see

Warnings and Precautions

Hypersensitivity Reactions Anaphylactoid

Reactions

active gastric / duodenal /peptic ulcer or active inflammatory disease of the

gastrointestinal system, active GI bleeding or patients with a recent or recurrent history of

these conditions

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

Page 5 of 37

of deterioration of their renal function when prescribed NSAIDs and must be monitored)

(see

Warnings and Precautions

Renal

known hyperkalemia (see

Warnings and Precautions

Renal - Fluid and Electrolyte

Balance

children and adolescents less than 16 years of age

WARNINGS AND PRECAUTIONS

Risk of Cardiovascular (CV) Adverse Events: Ischemic Heart Disease, Cerebrovascular

Disease, Congestive Heart Failure (NYHA II-IV) (See Warnings and Precautions -

Cardiovascular).

APO-PIROXICAM is a non-steroidal anti-inflammatory drug (NSAID). 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-PIROXICAM to any patient with

ischemic heart disease (including but NOT limited to acute myocardial infarction, history

of myocardial infarction and/or angina), cerebrovascular disease (including but NOT

limited to stroke, cerebrovascular accident, transient ischemic attacks and/or amaurosis

fugax) and/or congestive heart failure (NYHA II-IV).

Use of APO-PIROXICAM, can promote sodium retention in a dose-dependent manner,

through a renal mechanism, which can result in increased blood pressure and/or

exacerbation of congestive heart failure. (see also Warnings and Precautions - Renal –

Fluid and Electrolyte Balance)

Randomized clinical trials with APO-PIROXICAM have not been designed to detect

differences in cardiovascular events in a chronic setting. Therefore, caution should be

exercised when prescribing APO-PIROXICAM.

Risk of Gastrointestinal (GI) Adverse Events (see Warnings and Precautions –

Gastrointestinal)

Use of APO-PIROXICAM, is associated with an increased incidence of gastrointestinal

adverse events (such as peptic/duodenal ulceration, perforation, obstruction and

gastrointestinal bleeding).

Page 6 of 37

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-PIROXICAM is NOT recommended for use with other NSAIDs, with the exception of

low-dose ASA for cardiovascular prophylaxis, because of the absence of any evidence

demonstrating synergistic benefits and the potential for additive adverse reactions. (See

Drug

Interactions - Drug/Drug Interactions - Acetylsalicylic acid (ASA) or other NSAIDs

Carcinogenesis and Mutagenesis

See Toxicology Section.

Cardiovascular

APO-PIROXICAM is a non-steroidal anti-inflammatory drug (NSAID). 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-PIROXICAM 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-PIROXICAM, can lead to new hypertension or can worsen

preexisting 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-PIROXICAM should hypertension either develop or worse with its

use.

Page 7 of 37

Use of NSAIDs, such as APO-PIROXICAM, can induce fluid retention and edema, and may

exacerbate congestive heart failure, through a renally-mediated mechanism. (See

Warnings and

Precautions - Renal - Fluid and Electrolyte Balance

For patients with a high risk of developing an adverse CV event, other management strategies

that do NOT include the use of NSAIDs should be considered first.

To minimize the potential

risk for an adverse CV event, the lowest effective dose should be used for the shortest

possible duration.

Endocrine and Metabolism:

Corticosteroids:

APO-PIROXICAM (piroxicam) is NOT a substitute for corticosteroids. It does NOT treat

corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to

exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid

therapy should have their therapy tapered slowly if a decision is made to discontinue

corticosteroids. (see

Drug Interactions - Drug-Drug Interactions - Glucocorticoids

Gastrointestinal (GI)

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 NSAIDs, including APO-PIROXICAM. 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-PIROXICAM, even in the

absence of previous GI tract symptoms. Most spontaneous reports of fatal GI events are in

elderly or debilitated patients and therefore special care should be taken in treating this

population.

To minimize the potential risk for an adverse GI event, the lowest effective dose

should be used for the shortest possible duration

. For high risk patients, alternate therapies

that do not involve NSAIDs should be considered. (see

Warnings and Precautions - Special

Populations - Geriatrics

Evidence from epidemiological studies suggests that APO-PIROXICAM (piroxicam) is

associated with a high risk of gastrointestinal toxicity relative to some other NSAIDs.

Patients should be informed about the signs and/or symptoms of serious GI toxicity and

instructed to discontinue using APO-PIROXICAM 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.

Page 8 of 37

Caution should be taken if prescribing APO-PIROXICAM 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)

Gastrointestinal side effects are dose-related and doses of piroxicam greater than 20 mg daily

should not be used. The minimum maintenance dose needed to control symptoms is

recommended.

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 an NSAID. Should urinary symptoms occur, in the absence of an

alternate explanation, treatment with APO-PIROXICAM 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-

PIROXICAM is administered.

Anti-coagulants:

Piroxicam is highly protein-bound, and therefore, might be expected to displace other

protein- bound drugs. The physician should closely monitor dosage requirements of

coumarin anticoagulants and other drugs that are highly protein-bound when these are

administered concomitantly with piroxicam.

Numerous studies have shown that the concomitant use of NSAIDs and anti-coagulants

increases the risk of bleeding. Concurrent therapy of APO-PIROXICAM with warfarin

requires close monitoring of the international normalized ratio (INR). Even with

therapeutic INR monitoring, increased bleeding may occur.

Page 9 of 37

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-PIROXICAM and other NSAIDs have no proven efficacy as anti-platelet agents

and should NOT be used as a substitute for ASA or other anti-platelet agents for

prophylaxis of cardiovascular thromboembolic diseases. Anti-platelet therapies (e.g.

ASA) should NOT be discontinued. There is some evidence that use of NSAIDs with

ASA can markedly attenuate the cardioprotective effects of ASA. (see

Drug Interactions

- Drug-Drug Interactions - Acetylsalicylic Acid (ASA) or other NSAIDs

Concomitant administration of APO-PIROXICAM 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-PIROXICAM.

This may be due to fluid retention, GI blood loss, or an incompletely described effect

upon erythropoiesis. In clinical trials with piroxicam hematologic adverse reactions

occurred very commonly (15%) (See

Adverse Reactions – Clinical Trial Adverse Drug

Reactions –Hematologic

). At the recommended dose of 20 mg/day of piroxicam,

reductions in hemoglobin and hematocrit values are observed in about 4% of the patients

treated with piroxicam alone or concomitantly with ASA. These observations occurred in

the absence of fecal blood loss due to gastrointestinal irritation. Therefore, hematocrit and

hemoglobin values should be determined periodically.

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. Elevations of

ALT and AST 3 times the upper limit of normal, occurred in controlled clinical trials in less than

1% of patients. Hepatitis and jaundice occurred in less than 1% of patients.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal

liver 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 piroxicam.

Page 10 of 37

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 presc

be this drug in the presence of impaired liver function, it must be done

under st

ct observation.

Hypersensitivity Reactions:

Anaphylactoid Reactions:

As with NSAIDs in general, anaphylactoid reactions have occurred in patients without

known prior exposure to APO-PIROXICAM. In post-marketing experience, rare cases of

anaphylactic/ anaphylactoid reactions and angioedema have been reported in patients

receiving APO-PIROXICAM. APO-PIROXICAM should NOT be given to patients with

the ASA-triad. This symptom complex typically occurs in asthmatic patients who

experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal

bronchospasm after taking ASA or other NSAIDs (see

Contraindications

ASA-Intolerance:

APO-PIROXICAM should NOT be given to patients with complete or partial syndrome

of ASA-intolerance (rhinosinusitis, urticaria/angioedema, nasal polyps, asthma) in whom

asthma, anaphylaxis, urticaria/angioedema, rhinitis or other allergic manifestations are

precipitated by ASA or other NSAIDs. Fatal anaphylactoid reactions have occurred in

such individuals. As well, individuals with the above medical problems are at risk of a

severe reaction even if they have taken NSAIDs in the past without any adverse reaction

(see

Contraindications

Cross-sensitivity:

Patients sensitive to one NSAID may be sensitive to any of the other NSAIDs as well.

Serious skin reactions:

(See

Warnings and Precautions - Skin

Evidence from epidemiological studies suggests that piroxicam is associated with a high

risk of serious skin reactions compared to other non-oxicam NSAIDs.

Immune

(See Warnings and Precautions -

Infection

Aseptic Meningitis

Page 11 of 37

Infection:

APO-PIROXICAM, in common with other NSAIDs, may mask signs and symptoms of an

underlying infectious disease.

Aseptic Meningitis:

Rarely, with some NSAIDs including APO-PIROXICAM, the symptoms of aseptic

meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of

consciousness) have been observed. Patients with autoimmune disorders (systemic lupus

erythematosus, mixed connective tissue diseases, etc.) seem to be pre-disposed.

Therefore, in such patients, the health care provider must be vigilant to the development

of this complication.

Neurologic

Some patients may experience drowsiness, dizziness, blurred vision, vertigo, tinnitus, hearing

loss, insomnia or depression with the use of NSAIDs, such as APO-PIROXICAM. 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 piroxicam and other NSAIDs.

If such symptoms develop this drug should be discontinued and an ophthalmologic examination

performed. Ophthalmologic examination should be carried out at periodic intervals in any patient

receiving APO-PIROXICAM for an extended period of time.

Peri-Operative Considerations

(See Contraindications – Coronary Artery Bypass Graft Surgery)

Psychiatric:

(See Warnings and Precautions – Neurologic)

Renal

Long-term administration of piroxicam to

imals has resulted in renal papilla

necrosis and

other abnormal renal pathology. In hum

s, there have been repo

s of acute interstitial neph

with hematuria, proteinu

d occasionally nephrotic syndrome.

Acute renal failure and hyperkalemia as well as reversible elevations of BUN and serum

creatinine have been reported with piroxicam.

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

Page 12 of 37

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 lifethreatening 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 pretreatment state.

Caution should be used when initiating treatment with APO-PIROXICAM 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. Because of the

extensive renal excretion of APO-Piroxicam and its biotransformation products (less than 5% of

the daily dose excreted unchanged), lower doses of APO-PIROXICAM should be anticipated in

patients with impaired renal function and they should be carefully monitored.

Kidney function should be monitored periodically.

Advanced Renal Disease:

(See

Contraindications

Fluid and Electrolyte Balance:

Use of NSAIDs, including APO-PIROXICAM, 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-PIROXICAM in patients with a history of

congestive heart failure, compromised cardiac function, hypertension, increased age or

other conditions predisposing to fluid retention (See

Warnings and Precautions -

Cardiovascular

Use of NSAIDs, including APO-PIROXICAM, can increase the risk of hyperkalemia,

especially in patients with diabetes mellitus, renal failure, increased age, or those

receiving concomitant therapy with adrenergic blockers, angiotensin-converting enzyme

inhibitors, angiotensin-II receptor antagonists, cyclosporin, or some diuretics.

Electrolytes should be monitored periodically (see

Contraindications

Respiratory

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

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

Page 13 of 37

Sexual Function / Reproduction:

The use of APO-PIROXICAM, 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-PIROXICAM should be considered.

Skin

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

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

some NSAIDs, including APO-PIROXICAM. Because the rate of these reactions is low, they

have usually been noted du

ng post-marketing surveillance in patients taking other medications

also associated with the potential development of these se

ous skin reactions. Thus, causality is

not clear. These reactions are potentially life threatening but may be reversible if the causative

agent is discontinued

d approp

ate treatment instituted. Patients should be advised that if they

experience a skin rash they should discontinue their NSAID and contact their physici

assessment and advice, including which additional therapies to discontinue.

Evidence from epidemiological studies suggests that piroxicam is associated with a higher risk of

serious skin reactions compared to other non-oxicam NSAIDs.

Photosensitivity has been occasionally associated with the use of piroxicam.

A combination of dermatological and/or allergic signs and symptoms suggestive of serum

sickness has occasionally occurred in conjunction with the use of APO-PIROXICAM. These

include arthralgias, pruritus, fever, fatigue, and rash including vesiculo bullous reactions and

exfoliative dermatitis.

Special Populations

Pregnant Women:

APO-PIROXICAM is CONTRAINDICATED for use during the third trimester of

pregnancy because of risk of premature closure of the ductus arteriosus and the potential

to prolong parturition (see Toxicology)

The use of APO-PIROXICAM during the first and second trimester of pregnancy is not

recommended as its safety in this condition has not been established. Based on animal data

caution should be exercised in prescribing APO-PIROXICAM during the first and second

trimesters of pregnancy (see Toxicology)

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or the embryofoetal

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.

Page 14 of 37

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.

Nursing Women:

(See

Contraindications

Pediatrics:

(See

Contraindications

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, especially those with cardiovascular disease. Older patients are also at risk of

lower esophageal ulceration and bleeding.

For such patients, consideration should be given to a starting dose lower than the one usually

recommended, with individual adjustment when necessary and under close supervision.

Monitoring and Laboratory Tests

Cardiovascular:

Blood Pressure should be monitored regularly during treatment with APO-

PIROXICAM (See

Warnings and Precautions

Cardiovascular

Hematologic:

Patients should have their hemoglobin or hematocrit checked periodically.

Concurrent therapy of APO-PIROXICAM with warfarin requires close monitoring of the

international normalilized ratio (INR) (See

Warnings and Precautions

Haematology

Hepatic:

Liver function tests should be monitored periodically (See

Warnings and Precautions

Hepatic/Biliary/Pancreatic

Opthalmologic:

Opthalmic examination should be performed at periodic intervals. (See

Warnings and Precautions

Ophthalmologic

Renal:

Patients 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 blocker,

cyclosporin, diuretics, and the elderly should have their renal function monitored (e.g. urine

output, serum creatinine, creatinine clearance and serum urea) during therapy with APO-

PIROXICAM (See

Warnings and Precautions

Renal

Page 15 of 37

Serum electrolytes should be monitored periodically, especially in those patients who are at risk

Warnings and Precautions

Renal – Fluid and Electrolyte Balance

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most common adverse reactions encountered with NSAIDs are gastrointestinal, of which

peptic ulcer, with or without bleeding is the most severe. Fatalities have occurred, particularly in

the elderly. Evidence from epidemiological studies suggests that piroxicam is associated with a

high risk of gastrointestinal toxicity relative to some other NSAIDs (

Warnings and Precautions

Gastrointestinal

Serious skin reactions have been associated with NSAID use. Evidence from epidemiological

studies suggests that piroxicam is associated with higher risk of serious skin reactions compared

to other non-oxicam NSAIDs (

Warnings and Precautions

Skin

Use of some NSAIDs is associated with an increased incidence of cardiovascular adverse events

Warnings and Precautions

Cardiovascular

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates

observed in the clinical trials may not reflect the rates observed in practice and should not be

compared to the rates in the clinical trials of another drug. Adverse drug reaction information

from clinical trials is useful for identifying drug-related adverse events and for approximating

rates.

In approximately 2300 patients receiving a daily dose of 20 mg or less of piroxicam in clinical

trials, the most frequent side effects observed have been gastrointestinal (approximately 20% of

the patients). Of the patients experiencing gastrointestinal side effects, approximately 5%

discontinued therapy with an overall incidence of peptic ulceration of about 1% and

gastrointestinal bleeding of approximately 0.1%. Very Common (≥10%) and Common (>1% and

10%) adverse drug reactions are summarized in Tables 1 and 2, respectively.

Table 1. Very Common (≥10%) Clinical Trial Adverse Drug Reactions

Body System

Frequency

(N≈2300)

(%)

Gastrointestinal

17.4

epigastric distress

nausea

constipation

abdominal discomfort

Page 16 of 37

flatulence

diarrhea

abdominal pain

indigestion

anorexia

peptic ulceration

About 1

stomatitis

< 1

vomiting

< 1

hematemesis

< 1

melena

< 1

perforation

< 1

dry mouth

< 1

pancreatitis

< 1

Hematologic 15.0

15.0

decrease in hemoglobin

decrease in hematocrit

thrombocytopenia

eosinophilia

leukocytosis

basophilia

leukopenia

petechial rash

< 1

ecchymosis

< 1

bone marrow depression

< 1

including aplastic anemia and

epistaxis < 1

< 1

Table 2. Common (≥1% and ≤10%) Clinical Trial Adverse Drug Reactions

Adverse Reactions

Frequency

(N≈2300)

(%)

Central Nervous System

5

headache

1 .8

malaise

1 .0

dizziness

< 1

drowsiness/sedation (somnolence)

< 1

vertigo

< 1

depression

< 1

hallucinations

< 1

insomnia

< 1

nervousness

< 1

paresthesia

< 1

personality change

< 1

Page 17 of 37

dream abnormalities

< 1

mental confusion

< 1

Dermatologic (2.0%)

2.0

rash

pruritus

< 1

erythema

< 1

bruising

< 1

desquamation

< 1

exfoliative dermatitis

< 1

erythema multiforme

< 1

toxic epidermal necrolysis

< 1

vesiculo bullous reaction

< 1

onycholysis

< 1

Stevens-Johnson syndrome

< 1

photoallergic skin reactions

< 1

Renal

1

(See Warnings and Precautions)

oedema

dysuria

< 1

hematuria

< 1

proteinuria

< 1

interstitial nephritis

< 1

renal failure

< 1

hyperkalemia

< 1

glomerulitis

< 1

nephrotic syndrome

< 1

Special Populations: Patients older than 65 years 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.

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

Allergic (<1%): anaphylaxis, bronchospasm, urticaria/ angioedema, vasculitis, serum sickness

(see

Warning and Precautions

), each in less than 1% of patients.

Cardiovascular (<1%): hypertension, palpitations, worsening of congestive heart failure (see

Warning and Precautions,

Cardiovascular), exacerbation of angina, each in less than 1% of

patients.

Special senses: Eyes, ears, nose and throat reactions (<1%): tinnitus (about 1%); blurred vision,

eye irritation/swelling, each in less than l% of patients.

Page 18 of 37

Hepatic (<1%): jaundice, hepatitis (See

Warnings and Precautions,

Hepatic/Biliary/Pancreatic

), each in less than 1% of patients.

Respiratory (<1%): dyspnea

Metabolic (<1%): hypoglycemia, hyperglycemia, weight increase/decrease, each in less than 1%

of patients

Miscellaneous (<1%): sweating, pain (colic), fever, flu-like syndrome (see

Warning and

Precautions, Skin, Infection / Aseptic Meningitis

), weakness, each in less than 1% of patients

Other: Isolated reports have included delayed wound healing, thrombophlebitis, pemphigus,

alopecia, mastodynia, reduction or loss of libido, impotence, urinary frequency, oliguria,

menorrhagia, amnesia, anxiety, tremor, hearing impairment, deafness, thirst, chills, increased

appetite, akathisia, tachycardia, flushing, tooth discolouration, glossitis, chest pain, anemia,

hemolytic anemia and positive antinuclear factor (ANA); a causal relationship has not been

established for these rarely reported events.

Abnormal Hematologic and Clinical Chemistry Findings

Hematologic (15.0%): See

Table 1, Very common (≥10%) Clinical Trial Adverse Drug

Reactions.

Warnings and Precautions, Hematologic

Laboratory Parameters: Changes in laboratory parameters observed during APO-PIROXICAM

therapy have included an elevation of BUN, creatinine (See

Warnings and Precautions,

Renal

), uric acid and liver enzymes LDH, AST, ALT and alkaline phosphatase.

Post-Market Adverse Drug Reactions

Evidence from epidemiological studies suggests that piroxicam is associated with high risk of

gastro-intestinal toxicity relative to some other NSAIDs.

Evidence from epidemiological studies suggests that piroxicam is associated with higher risk of

serious skin reaction compared to other non-oxicam NSAIDs.

In patients taking piroxicam the most frequently reported adverse experiences occurring

commonly (in 1-10% of patients) are:

Cardiovascular System

Oedema

Digestive System

Anorexia, abdominal pain, constipation, diarrhoea,

dyspepsia, elevated liver enzymes, flatulence, gross

bleeding/perforation, heartburn, nausea, ulcers,

(gastric/duodenal), vomiting

Hemic and Lymphatic System

Anaemia, increased bleeding time

Nervous System

Dizziness, headache

Page 19 of 37

Skin and Appendages

Pruritus, rash

Special Senses

Tinnitus

Urogenital System

Abnormal renal function

Adverse experiences reported in 0.1% -1% of patients include:

Body as a Whole

Fever, infection, sepsis

Cardiovascular System

Congestive heart failure, hypertension, tachycardia,

syncope

Digestive System

Dry mouth, esophagitis, gastritis, glossitis, hematemesis,

hepatitis, jaundice, melena, rectal bleeding, stomatitis

Hemic and Lymphatic System

Ecchymosis, eosinophilia, epistaxis, leukopenia, purpura,

petechial rash, thrombocytopenia

Metabolic and Nutritional

Weight changes

Nervous System

Anxiety, asthenia, confusion, depression, dream

abnormalities, drowsiness, insomnia, malaise, nervousness,

paresthesia, somnolence, tremors, vertigo

Respiratory System

Asthma, dyspnoea

Skin and Appendages

Alopecia, bruising, desquamation, erythema,

photosensitivity, sweat

Special Senses

Blurred vision

Urogenital System

Cystitis, dysuria, hematuria, hyperkalemia, interstitial

nephritis, nephritic syndrome, oliguria/polyuria,

proteinuria, renal failure

Other adverse reactions, which occur rarely (0.01% -<0.1%) are:

Body as a Whole

Anaphylactic reactions, appetite change, death, flu-like

syndrome, pain (colic), serum sickness

Cardiovascular System

Arrhythmia, exacerbation of angina, hypotension,

myocardial infarction, palpitations, vasculitis

Digestive System

Eructation, liver failure, pancreatitis

Hemic and Lymphatic System

Agranulocytosis, haemolytic anemia, aplastic anemia,

lymphadenopathy, pancytopenia

Metabolic and Nutritional

Hyperglycemia, hypoglycemia

Nervous System

Akathisia, convulsions, coma, hallucinations, meningitis,

mood alterations

Respiratory System

Respiratory depression, pneumonia

Skin and Appendages

Angioedema, toxic epidermal necrosis, erythema

multiforme, exfoliative dermatitis, onycholysis, Stevens-

Johnson syndrome, urticaria, vesiculobullous reaction

Special Senses

Conjunctivitis, hearing impairment, swollen eyes

DRUG INTERACTIONS

Highly Protein Bound Drugs:

Page 20 of 37

APO-PIROXICAM is highly protein bound, and therefore might be expected to displace other

proteinbound drugs. The physician should closely monitor dosage requirement of coumarin

anticoagulants and other drugs that are highly protein-bound when these are administered

concomitantly with APO-PIROXICAM.

Acetylsalicylic acid (ASA) or other NSAIDs:

The use of APO-PIROXICAM in addition to

y other NSAID including over the counter one

(such as ASA and ibuprofen) for analgesic and /or anti-inflammatory effects is NOT

recommended because of the absence of

y evidence demonstrating synergistic benefits

d the

potential for additive side reactions.

The exception is the use of low dose ASA for cardiovascular protection, when another NSAID is

being used for its analgesic/anti-inflammatory effect, keeping in mind that combination NSAID

therapy is associated with additive adverse reactions, and that NSAIDs may interfere with the

antiplatelet effects of low dose ASA, possibly by competing with ASA for access to the active

site of cyclooxygenase-I.

Anticoagulants:

(

Warnings and Precautions -Hematologic – Anti-coagulants

Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases

the risk of GI adverse events such as ulceration and bleeding.

Because prostaglandins play an important role in hemostasis, and NSAIDs affect platelet

function, concurrent therapy of APO-PIROXICAM with warfarin requires close monitoring to be

certain that no change in anticoagulant dosage is necessary.

APO-PIROXICAM is highly protein-bound, and therefore, might be expected to displace other

protein-bound drugs. The physician should closely monitor dosage requirements of coumarin

anticoagulants and other drugs that are highly protein-bound when these are administered

concomitantly with APO-PIROXICAM.

Anti-hypertensives:

NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE)

inhibitors.

Combinations of ACE inhibitors, angiotensin-II antagonists, or diuretics

d NSAIDs might have

increased risk for acute renal failure

d hyperkalemia. Blood pressure and renal function

(including electrolytes) should be monitored more closely in this situation, as occasionally there

can be a substantial increase in blood pressure.

Concomitant administration of APO-PIROXICAM with propranolol can reduce the hypotensive

effect. Patients should be

monitored

for altered antihypertensive or antianginal response to

betablockers when APO-PIROXICAM is initiated or discontinued.

Page 21 of 37

Anti-Platelet Agents (including ASA):

There is an increased risk of bleeding, via inhibition of platelet function, when antiplatelet agents

are combined with NSAIDs, such as APO-PIROXICAM (see

Warnings and Precautions –

Hematologic - Anti-platelet Effects

Cholestyramine:

In healthy subjects co-administration of cholestyramine to piroxicam results in enhanced

elimination of piroxicam (i.e. reduction in half-life by 40% and increase in clearance by 52%).

Although the magnitude of these changes in piroxicam disposition appears sufficient to inhibit its

therapeutic effects, studies in patients are needed to confirm this. It is suggested that the doses of

APO-PIROXICAM and cholestyramine be separated as much as possible, and that the patients

be monitored for inadequate response to piroxicam therapy. If an inadequate anti-inflammatory

response appears to be related to the concomitant use of cholestyramine, consideration should be

given to the use of alternative hypolipidemic therapy.

Cimetidine:

Results of two separate studies indicate a slight increase in absorption of piroxicam following

cimetidine administration but no significant changes in elimination parameters. Cimetidine

increases the area under the curve (AUC 0-120 hrs) and Cmax of piroxicam by approximately 13

to 15%. Elimination rate constants and half-life show no significant differences. The clinical

significance of this small but significant increase in absorption is yet unknown.

Cyclosporin:

Inhibition of renal prostaglandin activity by NSAIDs may increase the plasma concentration of

cyclosporin and/or the risk of cyclosporin induced nephrotoxicity. Patient should be carefully

monitored during concurrent use.

Diuretics:

Clinical studies as well as post-marketing observations have shown that NSAIDs can reduce the

effect of diuretics. During concomitant therapy with NSAIDs, the patient should be closely

observed for signs and symptoms of renal failure (

Warnings and Precautions

Renal

) as well

as to assess diuretic efficacy.

Glucocorticoids:

Some studies have shown that the concomit

t use of NSAIDs

d oral glucoco

icoids increases

sk of GI adverse events such as ulceration

d bleeding. This is especially the case in older

(>65 years of age) individuals.

Page 22 of 37

Lithium:

Piroxicam has been reported to increase steady state plasma lithium concentrations. It is

recommended that these concentrations are monitored when initiating, adjusting and

discontinuing APO-PIROXICAM treatment.

Methotrexate:

Although up to date there have been no reports of an interaction with APO-PIROXICAM,

isolated cases indicate that the concomitant use of some NSAIDs in patients receiving

methotrexate may be associated with severe or sometimes fatal methotrexate toxicity.

Until more information is available on this interaction, caution should be used if APO-

PIROXICAM is administered concomitantly with methotrexate, particularly in patients with

preexisting renal impairment, who may be more susceptible.

Selective Seretonin Reuptake Inhibitors (SSRIs):

Concomitant administration of NSAIDs and SSRIs may increase the risk of gastrointestinal

ulceration and bleeding (see

Warnings and Precautions - Gastrointestinal

Tacrolimus:

Inhibition of renal prostaglandin activity by NSAIDs may increase the plasma concentration of

tacrolimus and/or the risk of tacrolimus induced nephrotoxicity. Patient should be carefully

monitored during concurrent use.

Oral Contraceptives:

No drug interaction information is available for APO-PIROXICAM co-administered with oral

contraceptives.

Oral Hypoglycemics:

An interaction has been noted with some NSAIDs, however no interaction data are available for

the co-administration of these agents with APO-PIROXICAM.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Page 23 of 37

Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

Concurrent use of alcohol with APO-PIROXICAM may increase the risk of gastrointestinal side

effects, including ulceration and haemorrhage.

Smoking has been associated with an increased risk of gastrointestinal side effects, including

ulceration and bleeding.

Patients experiencing visual disturbances, dizziness, vertigo, somnolence or other central

nervous system disturbances while taking APO-PIROXICAM should exercise caution in

carrying out activities that require alertness and should refrain from driving or using machines.

DOSAGE AND ADMINISTRATION

Dosing Considerations:

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, hepaticor cardiac function. Consideration should be given to a

starting dose that is lower than usual and to an increase of the dose only if symptoms remain

uncontrolled. Such patients must be carefully supervised. For high risk patients, alternate

therapies that do not involve NSAIDs should be considered.

Hepatic Insufficiency:

A substantial portion of piroxicam elimination occurs by hepatic

metabolism. Consequently, patients with hepatic disease may require reduced doses of APO-

PIROXICAM. APO-PIROXICAM is contraindicated in severe liver impairment or active liver

disease.

Renal Insufficiency:

Because of the extensive renal excretion of APO-PIROXICAM and its

biotransformation products (less than 5% of the daily dose excreted unchanged), lower doses of

APO-PIROXICAM should be anticipated in patients with impaired renal function and they

should be carefully monitored. APO-PIROXICAM is contraindicated in severe renal impairment

and in deteriorating renal disease (See

Contraindications

Recommended Dose and Dose Adjustment

Use of APO-PIROXICAM should be limited to the lowest effective dose for the shortest

possible duration of treatment (See Contraindications and Warnings and Precautions)

The recommended starting dose is a single daily dose of 20 mg, or 10 mg b.i.d.

Page 24 of 37

In rheumatoid arthritis and ankylosing spondylitis most patients will be maintained on 20 mg

daily. Some patients may be maintained on 10 mg daily.

In osteoarthritis the usual maintenance dose is 10-20 mg daily.

APO-PIROXICAM should not be given in doses greater than 20 mg daily.

APO-PIROXICAM capsules should be taken immediately after a meal or with food or milk. If

stomach upset (indigestion, nausea, vomiting, stomach pain or diarrhea) occurs and continues, a

doctor should be consulted.

Hepatic Insufficiency: (

Dosing Considerations).

Renal Insufficiency: (

Dosing Considerations).

Geriatrics (>65 years of age), Frail or Debilitated: (

Dosing Considerations).

Pediatrics (<16 years of age): (

Contraindications).

Missed Dose

If a dose of APO-PIROXICAM is taken once a day and a dose of this medicine is missed, a dose

of APO-PIROXICAM should be taken right away if remembered by the patient within 8 hours of

the missed dose. If APO-PIROXICAM is taken twice a day and a dose is missed, which the

patient remembers within 2 hours of the missed dose then the dose should be taken right away

and the patient should go back to the regular dosing schedule.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Cases of overdose, up to 1800 mg piroxicam, have been reported. Recovery was complete

without sequelae. In the event of overdosage with APO-PIROXICAM (piroxicam) supportive

and symptomatic therapy is indicated. Studies indicate that administration of activated charcoal

may result in reduced absorption and reabsorption of piroxicam thus reducing the total amount of

active drug available.

Piroxicam is highly protein bound, therefore dialysis of this drug is not feasible as a course of

action due to an overdosage.

ACTION AND CLINICAL PHARMACOLOGY

Page 25 of 37

Mechanism of Action

APO-PIROXICAM inhibits the activity of prostaglandin synthetase. The resulting decrease in

prostaglandin biosynthesis may partially explain its anti-inflammatory action. APO-

PIROXICAM does not act by pituitary-adrenal stimulation.

In rheumatoid arthritis the efficacy of piroxicam 20 mg daily has been found to be similar to 4.2

g daily of ASA.

Pharmacodynamics

APO-PIROXICAM is a non-steroidal anti-inflammatory agent with analgesic and antipyretic

properties. Its mechanism of action is incompletely known. (See

Action and Clinical

Pharmacology, Mechanism of Action)

Pharmacokinetics

Absorption:

Piroxicam is well-absorbed following oral or rectal administration.

After a single

oral dose of 20 mg, peak plasma levels of piroxicam are achieved in about 4 hours. When the

drug is administered daily, plasma concentrations increase for seven to twelve days during which

a steady state is reached. Concentrations attained are not exceeded following further constant

daily drug intake. The plasma half-life is approximately 50 hours in man. The extent and rate of

absorption are not influenced by administration with food or antacids.

Metabolism:

Piroxicam is extensively metabolized and less than 5% of the daily dose is

excreted unchanged in urine and feces. The main metabolic pathway is hydroxylation of the

pyridyl ring, followed by conjugation with glucuronic acid and urinary elimination.

Approximately 5% of the dose is metabolized to and excreted as saccharin.

Excretion:

Approximately 5% of the dose is metabolized to and excreted as saccharin.

Over a four day period of observation, twenty healthy men, taking piroxicam 20 mg daily in

single or divided doses, showed significantly less mean daily fecal blood loss than did ten

healthy male controls taking 3.9 g of ASA daily.

Special Populations and Conditions

Gender / Geriatrics:

The effects of age and sex on the pharmacokinetics of piroxicam have

been examined in three single-dose, three multiple dose, and five therapeutic drug monitoring

studies. Although not consistent across all studies, some indicated a tendency towards a modest

decrease in total body clearances and an increase in elimination half-life and steady-state plasma

Page 26 of 37

concentrations in the elderly, particularly elderly females. Irrespective of age, some patients had

plasma concentration levels that are substantially greater than the mean.

Hepatic Insufficiency:

A substantial portion of piroxicam elimination occurs by hepatic

metabolism. Consequently, patients with hepatic disease may require reduced doses of APO-

PIROXICAM. APO-PIROXICAM is contraindicated in severe liver impairment or active liver

disease.

Renal Insufficiency:

Because of the extensive renal excretion of APO-PIROXICAM and its

biotransformation products, lower doses of APO-PIROXICAM should be anticipated in patients

with impaired renal function and they should be carefully monitored. APO-PIROXICAM is

contraindicated in severe renal impairment and in deteriorating renal disease.

STORAGE AND STABILITY

Store between 15°C and 30°C.

DOSAGE FORMS, COMPOSITION AND PACKAGING

APO-PIROXICAM (piroxicam) hard gelatin capsules, 10 mg each, are opaque No. 2 maroon and

blue printed APO 10.

APO-PIROXICAM (piroxicam) hard gelatin capsules, 20 mg each, are opaque No. 2 maroon

printed APO 20.

Each capsule contains 10 or 20 mg of piroxicam, USP. Available in bottles of 100 and 500

capsules.

In addition to the active ingredient, piroxicam, each capsule also contains the non-medicinal

ingredients, D&C Red #28, FD&C Blue #1, FD&C Red #40, gelatin, lactose, microcrystalline

cellulose, sodium lauryl sulfate, sorbitan monolaurate, starch, stearic acid, talc and titanium

dioxide.

Page 27 of 37

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name:

Piroxicam, USP

Chemical Name:

4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-

carboxamide 1,1-dioxide

Molecular formula and molecular weight:

331.35

Structural Formula:

Physicochemical properties:

Piroxicam is a white crystalline, hygroscopic solid which melts in the range 196 to 200

It is poorly soluble in water, dilute acids, and most organic solvents. It is slightly soluble in

alcohols and aqueous alkaline solutions.

CLINICAL TRIALS

Comparative Bioavailability Studies

A comparative bioavailability studies were performed using normal human volunteers. The rate

and extent of absorption after a single 20 mg dose of Feldene 10 mg, APO-PIROXICAM 10 mg,

Feldene 20 mg and APO-PIROXICAM 20 mg was measured and compared. The results from

measured data are summarized as follows:

Page 28 of 37

Summary Table of the Comparative Bioavailability Data

Piroxicam

(A single 20 mg dose: 2 x 10 mg Capsules)

From measured data

Geometric Mean

Arithmetic Mean (CV%)

Parameter

Apo-Piroxicam

Feldene®

% Ratio of

Geometric Means

90% Confidence Interval

(mcg.h/mL)

113.66 (22.0)

112.96 (18.5

100.0

96.2 – 104.0

(mcg.h/mL)

145.20 (33.1)

138.20 (25.8)

103.5

97.2 – 110.2

(mcg/mL)

2.05

2.08 (16.9)

2.11

2.13 (13.5)

97.4

93.7 – 101.1

2.7 (46.5)

1.8 (95.9)

55.1 (25.3)

50.8 (25.7)

Feldene® is manufactured by Pfizer Canada Inc., and was purchased in Canada.

Expressed as the arithmetic mean (CV %) only.

Summary Table of the Comparative Bioavailability Data

Piroxicam

(A single 20 mg dose: 1 x 20 mg Capsule)

From measured data

Geometric Mean

Arithmetic Mean (CV%)

Parameter

Apo-Piroxicam

Feldene®

% Ratio of

Geometric Means

90% Confidence Interval

(mcg.h/mL)

113.84 ( 19.2)

119.42 (18.3)

95.1

91.7 – 98.7

(mcg.h/mL)

140.80 (27.8)

149.80 (32.6)

94.3

87.8 – 101.2

(mcg/mL)

2.10

2.13 (16.5)

2.17

2.17 (8.5)

97.0

91.9 – 102.4

2.4 (38.6)

2.6 (50.6)

52.1 (22.5)

52.3 (30.9)

Feldene® is manufactured by Pfizer Canada Inc., and was purchased in Canada.

Expressed as the arithmetic mean (CV %) only.

Page 29 of 37

DETAILED PHARMACOLOGY

Animal Studies

The anti-inflammatory activity of piroxicam, given orally, has been demonstrated in rats, guinea

pigs and dogs. A 4.0 mg/kg dose given to rats produced 50% inhibition of carrageenan-induced

foot edema. Piroxicam at doses of 0.3 to 3.3 mg/kg also caused inhibition of adjuvant-induced

arthritis in rats. At doses of 10 and 18 mg/kg, an inhibition of cotton string-induced granuloma

formation in rats was observed. A 0.3 mg/kg dose of piroxicam given to guinea pigs produced

50% inhibition of the erythema induced by ultraviolet light. Intravenous administration of

piroxicam (5 mg/kg) to dogs inhibited urate-induced inflammation of knee joints.

The analgesic activity of piroxicam, at an oral dose of 1.85 mg/kg, was demonstrated in mice

using the phenylquinone-induced writhing test. Piroxicam at 1.0, 3.2 and 10 mg/kg orally was

active in the Randall-Sellito test in which painful pressure is applied to the inflamed foot pad of

the rat. It was inactive in hot-plate and tail-flick tests at oral doses up to 100 mg/kg. The

antipyretic activity of piroxicam at 10 mg/kg orally was demonstrated in the hyperpyrexia

induced in rats by intramuscular injections of

E. coli

lipopolysaccharide.

Piroxicam inhibits prostaglandin synthetase, thereby reducing the biosynthesis of prostaglandins.

The drug also inhibits collagen-induced platelet aggregation. The anti-inflammatory activity of

piroxicam does not depend upon adrenal stimulation. Its activity was demonstrated in

adrenalectomized rats. Piroxicam has no significant cardiovascular or central nervous system

activity

Human Studies:

See Actions and Clinical Pharmacology section.

TOXICOLOGY

Acute Toxicity:

LD50 (95% Confidence Limits) mg/kg

Species

Oral

Mice

360 (321-404)

360 (305-425)

approx. 360

270 (231-316)

220 (197-241)

Toxic effects observed in mice and rats included ataxia, depression, laboured respiration,

prostration, weight gain inhibition and weight loss. Necropsy of these animals revealed marked

visceral adhesions and erosions of the stomach and intestines.

In the dog, repeated emesis, chronic anorexia, and diarrhea occurred at dosage levels of 5, 25,

50, 400 and 700 mg/kg; fecal occult blood was observed 24 hours after dosing. A weight loss of

about 15% and bloody diarrhea occurred with the 50, 400 and 700 mg/kg doses. Necropsy of the

dogs receiving 5 mg/kg revealed mucosal erosions and hemorrhage. These lesions, together with

ulcerations of the pyloric antrum and/or sphincter, were also observed at the higher dose level.

Page 30 of 37

Subacute and Chronic Toxicity: Piroxicam administered orally to beagle dogs at a dose of 1.0

mg/kg/day for 373 consecutive days caused signs of gastrointestinal and renal toxicity. These

included emesis, diarrhea, duodenal and gastric ulceration or erosion, fecal occult blood, anemia,

proteinuria, hematuria, renal papillary necrosis and one case of pyelonephritis. Other effects

considered to be related to the primary pathology were integumental signs, leukocytosis and

decreased serum calcium levels.

A one year study in the rhesus monkey at daily oral doses of 2.5, 5.0 and l0.0 mg/kg revealed

epithelial casts within the collecting tubules of the kidneys in 67% of high dose females. There

was no evidence of gastrointestinal toxicity at any dose. Another study in rhesus monkeys was

conducted over 90 days at the same dose levels. Occasional erosions of the gastrointestinal

mucosa were observed only in the animals receiving the highest dose. However, one female

monkey, receiving 2.5 mg/kg/day, did develop an acute gastric ulcer.

In an 18-month rat study, daily oral doses of 0.3, 1.0 and 3.0 mg/kg gave dose- and duration-

related renal papillary necrosis, elevation of BUN and necrotizing gastrointestinal lesions. At the

highest dose, gastrointestinal lesions and renal papillary necrosis were present in more females

than males. Dose-related anemia in males also occurred.

An 18-month mouse study was conducted at daily oral doses of 2, 4 and 8 mg/kg. There was

increased mortality at 8 mg/kg. Dose-related renal papillary necrosis with secondary chronic

diffuse interstitial nephritis, elevated BUN and necrotizing gastrointestinal lesions were

observed.

Reproduction and Teratology Studies: Consistent with its inhibitory effect on prostaglandin

biosynthesis, piroxicam prolongs the gestational period of the rat. The effects are dependent on

dose and time.

When piroxicam was administered in oral doses of 2, 5 and 10 mg/kg daily to pregnant rats from

day 15 post-coitum onwards, a dose-dependent increase in mortality and prolongation of

gestation and parturition occurred. Parturition was completely inhibited by piroxicam at l0 mg/kg

administered for 8 days. The dystocia, together with the gastrointestinal toxicity of the drug,

caused weakness and death of dams and offspring. When treatment was stopped after 5 days of

drug administration, deaths and prolonged labour still occurred.

When pregnant rats received 10 mg/kg/day of piroxicam orally from day 1 post-coitum to day

16, 17, 18, 19 or 20 post-coitum, all groups displayed gestational prolongation and the delay

increased with length of treatment. Prolongation of parturition and increased mortality of the

offspring occurred. There was dose-related suppression of lactation.

Piroxicam was administered in oral doses of 2, 5 and 10 mg/kg/day to male and female rats for

81 and 14 days respectively, before mating. Dosing in females was continued to day 6

postcoitum. Neither sex exhibited a modification of sexual behaviour or diminished fertility.

Fetal development was normal. Viability and growth of pups were comparable to controls, and

no drug-induced malformation or lesion was seen.

Page 31 of 37

Oral administration of piroxicam to pregnant rats and rabbits, during the critical period of

organogenesis, induced no embryotoxic or teratogenic effect at doses of 2, 5 and 10 mg/kg/day.

Oral administration of piroxicam to female rats on days 1-12 of the lactation period inhibited

postnatal body weight gain in pups owing to suppression of lactation in dams. This effect was

explored at doses of 2, 5 and 10 mg/kg/day and was dose-related.

Mutagenicity: Piroxicam demonstrated no mutagenic activity in any of the test systems.

Carcinogenicity: In a 24-month rat study, piroxicam administered in the diet to provide doses of

0.3 and l.0 mg/kg, induced the same spectrum, but higher incidence at l mg/kg, of non-neoplastic

lesions than in the l8-month rat study. The principal drug-induced pathologic changes consisted

of renal papillary necrosis, suppurative pyelonephritis and pyloric ulceration. Except for

suppurative pyelonephritis, females were more often affected than males.

Page 32 of 37

REFERENCES

Dessain P, Estabrooks TF, Gordon AJ. Piroxicam in the treatment of osteoarthritis: a

multi-centre study in general practice involving 1218 patients. J Int Med Res 1979;

7:335-34.

FELDENE (piroxicam) 10 and 20 mg Capsules and Suppositories Product Monograph.

Pfizer Canada Inc. Kirkland, Quebec. June 18, 1991.

Hobbs D.C., Twomey TM. Piroxicam pharmacokinetics in man: aspirin and antacid

interaction studies. J Clin Pharmacol 1979; 219:270-281.

Hobbs D.C., Gordon A.J.: Absense of an effect of age on the pharmacokinetics of

piroxicam. Roy. Soc. Med. Int. Congr. Symp. Series 67:270-281, 1979.

Information Letter, Health Protection Branch. Nonsteroidal Anti-inflammatory Drugs

DD-33; August 21, 1985.

Nuotio P. and Makisara P.: Pharmacokinetic and clinical study of piroxicam. Royal

Society of Medicine International Congress and Symposium Series No. 1:25-30 (1978).

Physician’s Desk Reference 1989; Edition 43.

Pisko EJ, Rahman MA, Turner RA, Agudelo CA. Long-term efficacy and safety or

piroxicam in the treatment of rheumatoid arthritis. Curr Ther Res 1980; 27:852-859.

Pitts N.E.: Efficacy and safety of piroxicam. Am. J. Med. 72(2A):77-78, 1982.

Radi I.; Matoso L.; Posmantir A. and Papalexiou P.: Safety and efficacy of piroxicam in

the treatment of ankylosing spondylitis. Eur. J. Rheum. Inflam., 1:346-351 (1978).

Richardson JC, Block KLN, Ross SG, Verbeeck RK. Effects of age and sex on piroxicam

disposition. Clin Pharmacol Ther 1985; 37:13-18.

Steigerwald J.C.: Piroxicam and rheumatoid arthritis: a double blind 16-week study

comparing piroxicam and indométhacine. Royal Society of Medicine International

Congress and Symposium Series No. 1:47-52 (1978).

Ward J.R.; Willkens R.F.; Louie J.S; McAdam L.P.: Piroxicam and rheumatoid arthritis:

A multi-center 14 week controlled double-blind study comparing aspirin and piroxicam.

Roy. Soc. Med. Int. Congr. Symp. Series 1:31-39 (1978).

Wiseman E.H. and Boyale J.A.: Piroxicam (Feldene). Clinics in Rheumatic Diseases

6:585-613 (1980).

Page 33 of 37

Wiseman E.H., Chang Y-H, Lombardino JG. Piroxicam, a novel anti-inflammatory

agent. Arzneim-Forsch 1976; 26:1300-1303.

Wiseman E.H.: Review of preclinical studies with piroxicam, pharmacokinetics, and

toxicology. Roy. Soc. Med. Int. Congr. Symp. Series 1:11-23 (1978).

Woolf AD, Rogers HJ, Bradbrook ID, Corless D. Pharmacokinetic observations on

piroxicam in young adult, middle-aged and elderly patients. Br J Clin Pharmac 1983;

16:433-437.

Basic Product Monograph Information for Nonsteroidal Anti-Inflammatory Drugs

(NSAIDs), Guidance Document, Health Products and Food Branch, November 23, 2006.

IMPORTANT: PLEASE READ

Page 34 of 37

PART III: CONSUMER INFORMATION

APO-PIROXICAM

Piroxicam Capsules

Apotex Standard

Read this information each time you refill your

prescription in case new information has been

added.

This leaflet is part III of a three-part “Product

Monograph” published when APO-PIROXICAM

was approved for sale in Canada and is designed

specifically for Consumers.

This leaflet is a summary and will not tell you

everything about APO-PIROXICAM. Contact

your doctor or pharmacist if you have any

questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

Your health care provider has prescribed APO-

PIROXICAM Capsules for you for symptomatic

relief of one or more of the following medical

conditions:

rheumatoid arthritis;

osteoarthritis (degenerative joint disease);

ankylosing spondylitis.

What it does:

APO-PIROXICAM (piroxicam) Capsules, as a

nonsteroidal anti-inflammatory drug (NSAID), can

reduce the chemicals produced by your body, which

cause pain and swelling.

APO-PIROXICAM Capsules does NOT cure your

illness or prevent it from getting worse. APO-

PIROXICAM can only relieve the pain and reduce

swelling as long as you continue to take it.

When it should not be used:

DO NOT TAKE APO-PIROXICAM if you have

any of the following medical conditions:

Heart bypass surgery (planning to have or

recently had)

Severe uncontrolled heart failure

Bleeding in the brain or other bleeding

disorder

Current pregnancy (after 28 weeks of

pregnancy)

Currently breastfeeding (or planning to

breastfeed)

Allergy to ASA (Acetylsalicylic Acid) or other

NSAIDs (Nonsteroidal Anti-Inflammatory

Drugs)

Ulcer (active)

Bleeding from the stomach or gut (active)

Inflammatory bowel disease (Crohn’s Disease

or Ulcerative Colitis)

Liver disease (active or severe)

Kidney disease (severe or worsening)

High potassium in the blood

Allergy to piroxicam or any other component

of APO-PIROXICAM capsules.

Patients who took a drug in the same class as

APO-PIROXICAM after a type of heart surgery

(coronary artery bypass grafting (CABG)) were

more likely to have heart attacks, strokes, blood

clots in the leg(s) or lung(s), and infections or

other complications than those who did NOT take

that drug.

APO-PIROXICAM should NOT be used in patients

under 16 years of age since the safety and

effectiveness have NOT been established.

What the medicinal ingredient is:

Piroxicam

What the important nonmedicinal ingredients are:

Non-medicinal ingredients include: D&C Red #28,

FD&C Blue #1, FD&C Red #40, gelatin, lactose,

microcrystalline cellulose, sodium lauryl sulfate,

sorbitan monolaurate, starch, stearic acid, talc and

titanium dioxide.

What dosage forms it comes in:

APO-PIROXICAM is available as capsules of 10 mg

and 20 mg.

WARNINGS AND PRECAUTIONS

If you have, or previously had, any of the following

medical conditions, see your health care provider to

discuss treatment options other than APO-

PIROXICAM:

Heart Attack or Angina

Stroke or Mini-stroke

Page 35 of 37

Loss of Vision

Current Pregnancy (less than 28 weeks)

Congestive Heart Failure

Gastrointestinal conditions such as ulcers, stomach

bleeding, obstruction

Kidney problems (i.e. sodium retention) leading to

increase blood pressure

Before taking this medication, tell your health care

provider if you have any of the following:

High blood pressure

High cholesterol

Diabetes mellitus or on a low sugar diet

Atherosclerosis

Poor circulation to your extremities

Smoker or ex-smoker

Kidney disease or urine problems

Previous ulcer or bleeding from the stomach or

Previous bleeding in the brain

Bleeding problems

Family history of allergy to NSAIDs, such as

acetylsalicylic acid (ASA), celecoxib, diclofenac,

diflunisal, etodolac, fenoprofen, flurbiprofen,

ibuprofen, indomethacin, ketoprofen, ketorolac,

mefenamic acid, meloxicam, nabumetone,

naproxen, oxaprozin, piroxicam, rofecoxib,

sulindac, tenoxicam, tiaprofenic acid, tolmetin,

or valdecoxib (NOT a complete list)

Family history of asthma, nasal polyps, long-

term swelling of the sinus (chronic sinusitis) or

hives

Any other medical problem.

Also, before taking this medication, tell your health

care provider if you are planning to get pregnant.

While taking this medication:

tell any other doctor, dentist, pharmacist or other

health care professional that you see, that you are

taking this medication, especially if you are

planning to have heart surgery;

do NOT drink alcoholic beverages while taking

this medication because you would be more

likely to develop stomach problems;

fertility may be decreased. The use of APO-

PIROXICAM is not recommended in women

trying to get pregnant. In women who have

difficulty conceiving, stopping APO-

PIROXICAM should be considered;

Check with your doctor if you are not getting

any relief or if any problems develop;

Your regular medical checkups are essential.

INTERACTIONS WITH THIS MEDICATION

Talk to your health care provider and pharmacist if

you are taking any other medication (prescription or

non-prescription) such as any of the following (NOT

a complete list):

Acetylsalicylic Acid (ASA) or other NSAIDs

- e.g. ASA, celecoxib, diclofenac, ibuprofen,

indomethacin, ketorolac, meloxicam,

naproxen

Antacids

Antidepressants

-Selective Serotonin Reuptake Inhibitors

(SSRIs)

e.g. citalopram, fluoxetine,

paroxetine, sertraline

Blood pressure medications

-ACE (angiotensin converting enzyme)

inhibitors

e.g. enalapril, lisinopril,

perindopril, ramipril

-ARBs (angiotensin II receptor blockers)

e.g. candesartan, irbesartan,

losartan, valsartan

-Beta-adrenergic blockers

e.g. propranolol

Blood thinners

- e.g. warfarin, ASA, clopidogrel

Cholestyramine

Cimetidine

Corticosteroids (including glucocorticoids)

- e.g. prednisone

Cyclosporin

Diuretics

- e.g. furosemide, hydrochlorothiazide

Lithium

Methotrexate

Oral contraceptives

Oral hypoglycemics (diabetes medications)

Tacrolimus

Your health care provider may prescribe low dose

ASA (acetylsalicylic acid) as a blood thinner to

reduce your risk of having a heart attack or stroke

while you are taking APO-PIROXICAM. Take only

the amount of ASA prescribed by your health care

provider. You are more likely to upset or damage

your stomach if you take both APO-PIROXICAM

and ASA than if you took APO-PIROXICAM alone.

Page 36 of 37

PROPER USE OF THIS MEDICATION

Usual dose:

Medical

Condition

Starting Dose

Maximum

Dose (per

day)

Rheumatoid

Arthritis,

20 mg once daily or 10 mg

twice daily. According to

therapeutic response, the dose

may be reduced to 10 mg

once daily.

20 mg

Ankylosing

Spondylitis

20 mg once daily or 10 mg

twice daily. According to

therapeutic response, the dose

may be reduced to 10 mg

once daily.

20 mg

Osteoarthritis

20 mg once daily or 10 mg

twice daily. According to

therapeutic response, the dose

may be reduced to 10 mg

once daily.

20 mg

Take APO-PIROXICAM only as directed by your

health care provider.

Do NOT take more of it, do

NOT take it more often and do NOT take it for a

longer period of time than your health care

provider recommended. If possible, you should

take the lowest dose of this medication for the

shortest time period

. Taking too much APO-

PIROXICAM may increase your chances of

unwanted and sometimes dangerous side effects,

especially if you are elderly, have other diseases or

take other medications.

See your health care provider regularly to discuss

whether this medicine is working for you and if it is

causing you any unwanted effects.

This medication has been prescribed specifically

for you. Do NOT give it to anyone else. It may

harm them, even if their symptoms seem to be

similar to yours.

APO-PIROXICAM is NOT recommended for use

in patients under 16 years of age since safety and

effectiveness have NOT been esetablished.

APO-PIROXICAM should be taken immediately

after a meal or with food or milk.

Missed Dose:

If you take APO-PIROXICAM once a day and if you

miss a dose of this medicine and remember within 8

hours of the missed dose, take it right away. If you

take APO-PIROXICAM twice a day and if you miss

a dose and remember within 2 hours of the missed

dose take it right away. Then go back to your regular

dosing schedule.

Overdose:

If you take more than the prescribed dose, contact a

health care practitioner, hospital emergency

department or regional Poison Control Center

immediately, even if there are no symptoms.

SIDE EFFECTS AND WHAT TO DO ABOUT

THEM

APO-PIROXICAM may cause some side effects,

especially when used for a long time or in large

doses. When these side effects occur, you may

require medical attention. Report all symptoms or

side effects to your health care provider.

APO-PIROXICAM may cause you to become

drowsy or tired. Be careful about driving or

participating in activities that require you to be alert.

If you become drowsy, dizzy or light-headed after

taking APO-PIROXICAM, do NOT drive or operate

machinery.

APO-PIROXICAM may cause you to become more

sensitive to sunlight. Any exposure to sunlight or

sunlamps may cause sunburn, skin blisters, skin rash,

redness, itching or discolouration, or vision changes.

If you have a reaction from the sun, check with your

health care provider.

Check with your health care provider

IMMEDIATELY if you develop chills, fever, muscle

aches or pains, or other flu-like symptoms, especially

if they occur before or together with a skin rash.

These symptoms may be the first signs of a

SERIOUS ALLERGIC REACTION to this

medication.

SERIOUS ADVERSE EFFECTS AND WHAT TO

DO ABOUT THEM

Symptom

STOP taking

APO-

PIROXICAM

and get

emergency

medical attention

IMMEDIATELY

STOP taking

APO-

PIROXICAM

and talk to

your

physician or

pharmacist

Bloody or black tarry

stools

Shortness of breath,

wheezing, any trouble

breathing, chest tightness,

Skin rash, hives, swelling

or itching

Blurred vision, or any

visual disturbance

Any change in the amount

or colour of urine (red or

brown)

Page 37 of 37

SERIOUS ADVERSE EFFECTS AND WHAT TO

DO ABOUT THEM

Any pain or difficulty

experienced while

urinating

Swelling of the feet, lower

legs; weight gain

Vomiting or persistent

indigestion, nausea

stomach

pain or diarrhea

Yellow discoloration of

the skin or eyes, with or

without itchy skin

Malaise, fatigue, loss of

appetite

Headaches, stiff neck

Mental confusion,

depression

Dizziness, lightheadedness

Hearing problems

This is NOT a complete list of side effects. For any

unexpected effects while taking APO-PIROXICAM,

contact your doctor or pharmacist.

HOW TO STORE IT

Store between 15°C and 30°C.

REPORTING SUSPECTED SIDE EFFECTS

You can report any suspected adverse reactions

associated with the use of health products to the

Canada Vigilance Program by one of the following 3

ways:

Report online at

www.healthcanada.gc.ca/medeffect

Call toll-free at 1-866-234-2345

Complete a Canada Vigilance Reporting Form

and:

Fax toll-free to 1-866-678-6789, or

Mail to : Canada Vigilance Program

Health Canada

Address Locator: 0701D

Ottawa, ON K1A 0K9

Postage paid labels, Canada Vigilance Reporting

Form and the adverse reaction reporting guidelines

are available on the MedEffect

Canada Web site at

www.healthcnada.gc.ca/medeffect.

NOTE: Should you require information related to the

management of side effects, contact your health

professional. The Canada Vigilance Program does

not provide medical advice.

MORE INFORMATION

For more information, please contact your doctor,

pharmacist or other healthcare professional.

This leaflet plus the full product monograph,

prepared for health professionals, can be obtained by

contacting DISpedia, Apotex's Drug Information

Service at:

1-800-667-4708

This leaflet can also be found at:

http://www.apotex.ca/products.

This leaflet was prepared by Apotex Inc., Toronto,

Ontario,

M9L 1T9.

Last revised: June 23, 2010

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