TEVA-DICLOFENAC EC TABLET (ENTERIC-COATED)

Canada - English - Health Canada

Buy It Now

Active ingredient:
DICLOFENAC SODIUM
Available from:
TEVA CANADA LIMITED
ATC code:
M01AB05
INN (International Name):
DICLOFENAC
Dosage:
50MG
Pharmaceutical form:
TABLET (ENTERIC-COATED)
Composition:
DICLOFENAC SODIUM 50MG
Administration route:
ORAL
Units in package:
100/500
Prescription type:
Prescription
Therapeutic area:
OTHER NONSTEROIDAL ANTIIMFLAMMATORY AGENTS
Product summary:
Active ingredient group (AIG) number: 0114417002; AHFS: 28:08.04.92
Authorization status:
APPROVED
Authorization number:
00808547
Authorization date:
2010-10-08

Documents in other languages

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PRODUCT MONOGRAPH

TEVA-DICLOFENAC EC

TEVA-DICLOFENAC SR

(diclofenac sodium)

25 mg and 50 mg Enteric Coated Tablets, USP

75 mg and 100 mg Slow Release Tablets, Teva Standard

Acetic Acid Derivatives and Related Substances

Teva Canada Limited

30 Novopharm Court

Toronto, Ontario

Canada M1B 2K9

www.tevacanada.com

Date of Revision:

January 23, 2019

Control no. 222007

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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 ..................................................................................................... 17

DOSAGE AND ADMINISTRATION ................................................................................. 21

OVERDOSAGE ................................................................................................................... 23

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

STORAGE AND STABILITY ............................................................................................ 25

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

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

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

CLINICAL TRIALS ............................................................................................................. 28

DETAILED PHARMACOLOGY ........................................................................................ 32

TOXICOLOGY .................................................................................................................... 32

REFERENCES ..................................................................................................................... 36

PART III: CONSUMER

INFORMATION

.................................................................................. 38

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Pr

TEVA-DICLOFENAC EC

Pr

TEVA-DICLOFENAC SR

(diclofenac sodium)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form

Strength

Clinically Relevant Non-medicinal

Ingredients

Oral

Enteric Coated Tablets, 25

mg and 50 mg

magnesium stearate, microcrystalline

cellulose, povidone, pregelatinized starch,

silicon dioxide, sodium lauryl sulfate and

sodium starch glycolate.

The film coating contains (25mg): D&C

Yellow # 10, hypromellose, iron oxide red,

iron oxide yellow, maltodextrin,

methacrylic acid, polyethylene glycol, talc,

titanium dioxide, triethyl citrate

The film coating contains (50mg):

hypromellose, iron oxide black, iron oxide

red, iron oxide yellow, maltodextrin,

methacrylic acid, polyethylene glycol, talc,

titanium dioxide, triethyl citrate

Printing ink contains: black iron oxide,

lecithin, shellac glaze, simethicone

Slow-release Tablets,

75 mg, 100 mg

colloidal silicon dioxide, lactose

monohydrate, magnesium stearate, and

povidone.

The film coating contains: aquacoat ECD-

30, dibutyl sebacate, FD&C Blue #2,

FD&C Red #40, FD&C Yellow #6,

hypromellose, polyethylene glycol,

polysorbate and titanium dioxide.

Printing ink contains: black iron oxide,

lecithin, shellac glaze, simethicone

INDICATIONS AND CLINICAL USE

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TEVA-DICLOFENAC

(diclofenac

sodium)

TEVA-DICLOFENAC

(diclofenac

sodium) are indicated for:

the symptomatic treatment of rheumatoid arthritis and osteoarthritis, including

degenerative joint disease of the hip.

Throughout this document, the term Nonsteroidal Anti-Inflammatory Drug (NSAID) refers to both

non-selective NSAIDs and selective COX-2 inhibitor NSAIDs, unless otherwise indicated.

Diclofenac, particularly at higher doses, is associated with an increased risk of serious

cardiovascular related adverse events that is comparable to COX-2 inhibitors. For patients

with pre-existing risk factors for cardiovascular disease (including ischemic heart disease,

cerebrovascular disease and/or congestive heart failure NYHA II-IV) other management

strategies that do not include NSAlDs, particularly COX-2 inhibitors and diclofenac,

should

be

considered

first

(see

CONTRAINDICATIONS

and

WARNINGS

AND

PRECAUTIONS).

For

patients

with

increased

risk

of

developing

GI

adverse

events

other

management

strategies

that

do

not

include

NSAlDs

should

be

considered

first

(see

CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS).

Use of TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR 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).

TEVA-DICLOFENAC EC and TEVA-DICLOFENAC SR, as NSAIDs, do NOT treat clinical

disease or prevent its progression.

TEVA-DICLOFENAC EC and TEVA-DICLOFENAC SR, as NSAIDs, only relieve

symptoms and decrease inflammation for as long as the patient continues to take them.

Patients Subsets

Geriatrics

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

Pediatrics (< 16 years of age)

Safety and efficacy have not been established in the pediatric population.

CONTRAINDICATIONS

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43

TEVA-DICLOFENAC EC and TEVA-DICLOFENAC SR are contraindicated in:

peri-operative

setting

coronary

artery

bypass

graft

surgery

(CABG).

Although

diclofenac sodium enteric coated tablets and diclofenac sodium slow release tablets have

NOT been studied in this patient population, a selective COX-2 inhibitor NSAID studied in

such a setting has led to an increased incidence of cardiovascular/thromboembolic events,

deep surgical infections and sternal wound complications.

the third trimester of pregnancy, because of risk of premature closure of the ductus arteriosus,

fetal renal impairment with subsequent oligohydramnios

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 TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR

or to any of the components/excipients.

history of asthma, urticaria, or allergic-type reactions after taking ASA or other NSAIDs (i.e.

complete or partial syndrome of ASA-intolerance - rhinosinusitis, urticaria/ angioedema,

nasal polyps, asthma). Fatal anaphylactoid reactions have occurred in such individuals.

Individuals with the above medical problems are at risk of a severe reaction even if they

have taken NSAIDs in the past without any adverse reaction. The potential for cross-

reactivity

between

different

NSAIDs

must

kept

mind

(see

WARNINGS

AND

PRECAUTIONS

Hypersensitivity Reactions - Anaphylactoid Reactions

active gastric / duodenal / peptic ulcer, active GI bleeding or perforation, regional ulcer,

gastritis or ulcerative colitis (see

WARNINGS AND PRECAUTIONS

ADVERSE

DRUG REACTIONS

cerebrovascular bleeding or other bleeding disorders.

inflammatory bowel disease.

severe hepatic impairment or active liver disease.

severe renal impairment (creatinine clearance <30 mL/min or 0.5 mL/sec) or deteriorating

renal disease (individuals with lesser degrees of renal impairment are at risk of deterioration

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

WARNINGS

AND PRECAUTIONS

Renal

known hyperkalemia (see

WARNINGS AND PRECAUTIONS

Renal - Fluid and

Electrolyte Balance

children and adolescents less than 16 years of age.

WARNINGS AND PRECAUTIONS

Risk of Cardiovascular (CV) Adverse Events: Cardiovascular Disease (including

ischemic heart disease, Cerebrovascular Disease, Congestive Heart Failure (NYHA II-IV))

(See WARNINGS AND PRECAUTIONS - Cardiovascular).

Diclofenac is associated with an increased risk of cardiovascular adverse events (such

as myocardial infarction, stroke or thrombotic events, which can be fatal)

that is

comparable to COX-2 inhibitors. Meta-analyses of randomized clinical trials comparing

several

different

NSAIDs

suggest

that

diclofenac,

particularly

at

higher

doses

,

is

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43

associated with an increased risk of cardiovascular adverse events that is comparable to

COX-2

inhibitors.

Large

population-based

observational

studies

conducted

in

the

general population also support these findings. The risk may increase with the dose and

duration of use. Patients with cardiovascular disease or risk factors for cardiovascular

disease may be at greater risk.

patients

with

high

risk

developing

adverse

event,

other

management

strategies that do NOT include NSAIDs, particularly COX-2 inhibitors and diclofenac, 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.

Treatment

with

TEVA-DICLOFENAC

EC

or

TEVA-DICLOFENAC

SR

is

not

recommended in patients with pre-existing

cardiovascular

disease

(congestive

heart

failure

NYHA

II-IV,

ischemic

heart

disease,

peripheral

arterial

disease)

cerebrovascular disease, uncontrolled hypertension or patients with risk factors for

cardiovascular

disease

(e.g.

hypertension,

hyperlipidemia,

diabetes

mellitus

and

smoking). These patients should be treated with TEVA-DICLOFENAC EC or TEVA-

DICLOFENAC SR only after careful consideration.

Use of NSAIDs, such as TEVA-DICLOFENAC EC and TEVA-DICLOFENAC SR, 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).

Risk of Gastrointestinal (GI) Adverse Events (See WARNINGS AND PRECAUTIONS

Gastrointestinal (GI)).

Use of NSAIDs, such as TEVA-DICLOFENAC EC and TEVA-DICLOFENAC SR, is

associated

with

an

increased

incidence

of

gastrointestinal

adverse

events

(such

as

peptic/duodenal ulceration, perforation, obstruction and gastrointestinal bleeding).

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.

Diclofenac 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

potential

additive

adverse

reactions.

(See

DRUG

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43

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

Diclofenac

sodium

should

not

be

used

concomitantly

with

diclofenac

potassium

(

Pr

TEVA-DICLOFENAC-K) since both exist in plasma as the same active organic ion.

Carcinogenesis and Mutagenesis

(See

TOXICOLOGY

Cardiovascular

TEVA-DICLOFENAC EC and TEVA-DICLOFENAC SR are NSAIDs.

Diclofenac is associated with an increased risk of cardiovascular adverse events (such as

myocardial infarction, stroke or thrombotic events, which can be fatal) that is comparable

to

COX-2

inhibitors.

Patients

with

cardiovascular

disease

or

risk

factors

for

cardiovascular disease may be at greater risk.

As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the

lowest effective daily dose should be used for the shortest duration possible. The patient's need

for symptomatic relief and response to therapy should be re-evaluated periodically.

Patients should remain alert for the signs and symptoms of serious arteriothrombotic events (e.g.

chest

pain,

shortness

breath,

weakness,

slurring

speech),

which

occur

without

warnings. Patients should be instructed to see a physician immediately in case of such an event.

Use of NSAIDs, such as TEVA-DICLOFENAC EC and TEVA-DICLOFENAC SR, can lead to

new hypertension or can worsen pre-existing hypertension, either of which may increase the

risk of cardiovascular events as described below. Thus blood pressure should be monitored

regularly. Consideration should

given

discontinuing

TEVA-DICLOFENAC EC and

TEVA-DICLOFENAC SR should hypertension either develop or worsen with its use.

Use of NSAIDs, such as TEVA-DICLOFENAC EC and TEVA-DICLOFENAC SR, 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

Caution should be exercised in prescribing TEVA-DICLOFENAC EC and TEVA-

DICLOFENAC SR 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 II-IV)

Ischemic heart disease

Peripheral Arterial Disease

Smoking

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Creatinine Clearance < 60 mL/min or 1 mL/sec

Acute myocardial infarction, history of myocardial infarction and/or angina

Stroke, cerebrovascular accident, transient ischemic attacks, and/or amaurosis

fugax

If needed, these patients should be treated only after careful consideration (See

WARNINGS

AND PRECAUTIONS

box).

Endocrine and Metabolism

Corticosteroids:

TEVA-DICLOFENAC EC and TEVA-DICLOFENAC SR are NOT a substitute

for corticosteroids. They do NOT treat corticosteroid insufficiency. Abrupt discontinuation of

corticosteroids

lead

exacerbation

corticosteroid-responsive

illness.

Patients

prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made

discontinue corticosteroids (see

DRUG INTERACTIONS - Drug-Drug Interactions -

Glucocorticoids

Gastrointestinal (GI)

Serious

toxicity

(sometimes

fatal),

such

peptic/duodenal

ulceration,

inflammation,

perforation,

peritonitis,

obstruction,

gastrointestinal

bleeding,

gastrointestinal

stenosis

ischemic colitis

can occur at any time, with or without warning symptoms, in patients treated

with

TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR.

Minor upper GI problems,

such as dyspepsia, commonly occur at any time. Health care providers should remain alert for

ulceration

bleeding

patients

treated

with

TEVA-DICLOFENAC

TEVA-

DICLOFENAC SR, even in the absence of previous GI tract symptoms. Most spontaneous

reports of fatal GI events are in elderly or debilitated patients and therefore special care should

be taken in treating this population.

To minimize the potential risk for an adverse GI event,

the lowest effective dose should be used for the shortest possible duration

. For high risk

patients, alternate therapies that do not involve NSAIDs should be considered (see

WARNINGS

AND PRECAUTIONS – Special Populations – Geriatrics

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

instructed to discontinue using TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR and

seek emergency medical attention

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

approximately

patients treated

months, and

in about

2-4%

patients

treated

one year.

These

trends continue, thus increasing the likelihood of

developing a serious GI event at some time during the course of therapy. Even a short-term

therapy has its risks.

Caution should be taken if prescribing TEVA-DICLOFENAC EC or TEVA-DICLOFENAC

SR 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

bleeding include the following:

Helicobacter pylori

infection, increased age,

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43

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)

There is no definitive evidence that the concomitant administration of histamine H

-receptor

antagonists and/or antacids will either prevent or reduce the occurrence of gastrointestinal

adverse events associated with the use of TEVA-DICLOFENAC SR or the enteric-coated

formulation of TEVA-DICLOFENAC EC. Concurrent administration of histamine H

-receptor

antagonists and/or antacids with the enteric-coated version of TEVA-DICLOFENAC EC might

result in altered absorption.

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 TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR

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 hemophilia or platelet disorders should be carefully observed when

TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR is administered.

Anti-coagulants:

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

coagulants increases the risk of bleeding. Concurrent therapy of TEVA-DICLOFENAC EC or

TEVA-DICLOFENAC

with

warfarin

requires

close

monitoring

international

normalized ratio (INR).

Even with therapeutic INR monitoring, increased bleeding may occur.

Anti-platelet Effects:

NSAIDs inhibit platelet aggregation and have been shown to prolong

bleeding time in some patients. Unlike acetylsalicylic acid (ASA), their effect on platelet

function is quantitatively less, or of shorter duration, and is reversible.

TEVA-DICLOFENAC EC, TEVA-DICLOFENAC SR

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

prophylaxis

cardiovascular

thromboembolic

diseases.

Anti-platelet

therapies (e.g. ASA) should NOT be discontinued. There is some evidence that use of NSAIDs

with

markedly

attenuate

cardioprotective

effects

(see

DRUG

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

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43

Concomitant a d mi n i s t r a t i o n o f TEVA-DICLOFENAC EC o r TEVA-DICLOFENAC S R

with l o w d o s e 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 diclofenac sodium

enteric coated tablets and diclofenac sodium slow release tablets . 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 TEVA-DICLOFENAC EC and T E V A -

DICLOFENAC SR, 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, including TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR,

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.

In post-marketing reports, cases of drug-induced hepatotoxicity have been reported in the first

month, and in some cases, the first 2 months of therapy, but can occur at any time during

treatment with diclofenac.

Post-marketing surveillance has reported cases of severe hepatic

reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and

liver failure. Some of these reported cases resulted in fatalities or liver transplantation.

Physicians

should

regularly

monitor

hepatic

function

patients

receiving

TEVA-

DICLOFENAC EC or TEVA-DICLOFENAC SR. If abnormal liver function tests persist or

worsen, if clinical signs and symptoms consistent with liver disease develop (e.g. nausea, fatigue,

lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and «flu-like» symptoms),

or if other manifestations occur (e.g. eosinophilia, associated with rash etc.), this drug should be

discontinued.

Hepatotoxic

effects

occur

with

diclofenac

without

prodromal

symptoms.

minimize

possibility that

hepatic

injury

will become

severe

between transaminase

measurements,

physicians

should

inform

patients

warning

signs

symptoms

hepatotoxicity and the appropriate action patients should take if these signs and symptoms

appear.

TEVA-DICLOFENAC EC and TEVA-DICLOFENAC SR are contraindicated in severe liver

impairment or active liver disease. If there is a need to prescribe this drug to other patients with

liver impairment, it must be done under strict observation.

Caution is advised when using TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR in

patients with hepatic porphyria, since diclofenac sodium may trigger an attack.

Hypersensitivity Reactions

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43

Anaphylactoid reactions:

As with NSAIDs in general, anaphylactoid reactions have occurred in

patients without known prior exposure to diclofenac sodium. In post- marketing experience,

rare cases of anaphylactic/ anaphylactoid reactions and angioedema have been reported in

patients receiving diclofenac sodium. TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR

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

other

NSAIDs

(see

CONTRAINDICATIONS

ASA-intolerance:

TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR should NOT be

given

patients

with

complete

partial

syndrome

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 any one of the NSAIDs may be sensitive to any of the

other NSAIDs as well.

Serious Skin Reactions:

(See

WARNINGS AND PRECAUTIONS - Skin

Immune

(See

WARNINGS AND PRECAUTIONS - Infection- Aseptic Meningitis

Infection

TEVA-DICLOFENAC EC and TEVA-DICLOFENAC SR, in common with other NSAIDs, may

mask signs and symptoms of an underlying infectious disease.

Aseptic Meningitis:

Rarely, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck,

severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed.

Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissue

diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the health care provider must

be vigilant to the development of this complication.

Neurologic

Some

patients

experience

drowsiness,

dizziness,

blurred

vision,

vertigo,

insomnia,

depression, tinnitus or hearing loss with the use of NSAIDs, such as TEVA-DICLOFENAC EC

and TEVA-DICLOFENAC SR. If patients experience such adverse reaction(s) they should

exercise caution in carrying out activities that require alertness.

Ophthalmologic

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43

Blurred and/or diminished vision has been reported with the use of NSAIDs, which may be

reversible with discontinuation.

If such symptoms develop, TEVA-DICLOFENAC EC or

TEVA-DICLOFENAC

should

discontinued

ophthalmologic

examination

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

patient receiving TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR for an extended

period of time.

Sun exposure in patients using TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR might

cause photosensitivity and vision changes. Patients should be advised to contact their physician

for assessment and advice if this occurs.

Peri-Operative Considerations

(See

CONTRAINDICATIONS -

Coronary Artery Bypass Graft Surgery)

Psychiatric

(See

WARNINGS AND PRECAUTIONS – Neurologic

Renal

Long term administration of NSAIDs to animals has resulted in renal papillary necrosis and other

abnormal renal pathology.

In humans, there have been reports of acute interstitial nephritis,

hematuria, low grade proteinuria and occasionally nephrotic syndrome.

During long-term therapy, kidney function should be monitored periodically (see

ACTION

AND

CLINICAL

PHARMACOLOGY-Special

Populations

and

Conditions-Renal

Impairment

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

glomerular

filtration

rate

(GFR).

these

patients,

administration of a NSAID may cause a reduction in prostaglandin synthesis leading to impaired

renal

function.

Patients

greatest

risk

this

reaction

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, cyclosporine, 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 TEVA-DICLOFENAC

EC or TEVA-DICLOFENAC SR, 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.

(See

WARNING AND PRECAUTIONS

Monitoring and Laboratory Tests - Renal

Page

13

43

Advanced Renal Disease:

(See

CONTRAINDICATIONS

Fluid and Electrolyte Balance:

Use of NSAIDs, such as TEVA-DICLOFENAC EC or TEVA-

DICLOFENAC SR, 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 TEVA-DICLOFENAC

TEVA-DICLOFENAC

patients

with

history

congestive

heart

failure,

compromised cardiac function, hypertension, increased age or other conditions predisposing to

fluid retention (see

WARNINGS AND PRECAUTIONS - Cardiovascular

Use of NSAIDs, such as TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR, 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, cyclosporine, tacrolimus, trimethoprim or

some diuretics. Electrolytes should be monitored periodically (see

CONTRAINDICATIONS

DRUG INTERACTIONS-Drug-Drug Interactions

Respiratory

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

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

Pre-existing asthma:

In patients with asthma, seasonal allergic rhinitis, swelling of the nasal

mucosa (i.e. nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the

respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions on NSAIDs

like asthma exacerbations (so-called intolerance to analgesics / analgesics-asthma), Quincke’s

oedema or urticaria are more frequent than in other patients. Therefore, special precaution is

recommended in such patients (readiness for emergency). This is applicable as well for patients

who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.

Sexual Function / Reproduction

The use of TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR, 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 TEVA-DICLOFENAC EC or TEVA-

DICLOFENAC SR should be considered.

Skin

rare

cases,

serious

skin

reactions

such

Stevens-Johnson

syndrome,

toxic

epidermal

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

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

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

potential development of these serious skin reactions. Thus, causality is NOT clear. These

reactions

potentially

life

threatening

reversible

causative

agent

discontinued

appropriate

treatment

instituted.

Patients

should

advised

that

they

experience a skin rash they should discontinue their NSAID and contact their physician for

Page

14

43

assessment and advice, including which additional therapies to discontinue.

Use of TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR may cause photosensitivity

upon exposure to sunlight or UV light causing symptoms such as sunburn, skin rash, skin

blisters, pruritus, erythema and discolouration.

Special Populations

Pregnant

Women

TEVA-DICLOFENAC

EC

or

TEVA-DICLOFENAC

SR

are

CONTRAINDICATED for use during the third trimester of pregnancy because of risk of

premature

closure

of

the

ductus

arteriosus,

fetal

renal

impairment

with

subsequent

oligohydramnios and the potential to prolong parturition (see TOXICOLOGY)

TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR should not be used during the first

two trimesters of pregnancy unless the expected benefits to the mother outweigh the risks to

the fetus.

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

development. Data from epidemiological studies suggest an increased risk of miscarriage and of

cardiac malformation after use of a prostaglandin synthesis inhibitor (such as NSAIDs) in early

pregnancy.

In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in

increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased

incidences of various malformations, including cardiovascular, have been reported in animals

given a prostaglandin synthesis inhibitor during the organogenetic period. Diclofenac sodium

readily crosses the placental barrier.

Nursing Women

: (see

CONTRAINDICATIONS

Pediatrics:

(see

CONTRAINDICATIONS

Geriatrics:

Patients older than 65 years (referred to in this document as older or elderly) and frail

or debilitated patients are more susceptible to a variety of adverse reactions from NSAIDs; the

incidence of these adverse reactions increases with dose and duration of treatment. In addition,

these patients are less tolerant to ulceration and bleeding. Most reports of fatal GI events are in

this population. Older patients are also at risk of lower esophageal injury including ulceration

and bleeding.

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

recommended,

with

individual

adjustment

when

necessary

under

close

supervision,

especially in frail elderly patients or those with a low body weight.

Monitoring and Laboratory Tests

Cardiovascular (Hypertension):

Blood pressure should be monitored regularly during therapy

with TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR.

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15

43

Hematologic:

Patients on long-term treatment with TEVA-DICLOFENAC EC or TEVA-

DICLOFENAC SR should have their hemoglobin, hematocrit, red blood cells (RBC), white

blood cells (WBC), and platelets checked if they exhibit any signs or symptoms of anemia or

blood loss or blood dyscrasia.

Concurrent therapy of TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR with warfarin

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

Hepatic:

Hepatic function (e.g.serum transaminases, bilirubin) should be monitored regularly

during therapy with TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR.

Ophthalmologic

: Patients on long-term treatment with TEVA-DICLOFENAC EC or TEVA-

DICLOFENAC SR should have an ophthalmologic examination performed periodically, and if

they experience blurred and/or diminished vision.

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 blockers,

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

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

TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR.

Electrolytes,

including

serum

potassium,

should

monitored

periodically,

especially

patients with diabetes mellitus, renal failure, increased age, or those receiving concomitant

therapy

with

adrenergic

blockers,

angiotensin-converting

enzyme

inhibitors,

angiotensin-II

receptor antagonists, cyclosporine, tacrolimus, trimethoprim or some diuretics.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Although not all adverse drug reactions have been reported with diclofenac

sodium, the types of adverse drug reactions are expected to be similar to those of diclofenac

potassium since both formulations exist in the plasma as the same active organic anion.

Gastrointestinal, dermatological, CNS and hepatic adverse reactions are the most commonly

seen with diclofenac. The most severe gastrointestinal adverse reactions observed were

ulceration and bleeding, while the most severe dermatological albeit rare reactions

observed with diclofenac were erythema multiforme (Stevens-Johnson Syndrome and Lyell

Syndrome). Fatalities have occurred on occasion, particularly in the elderly.

This section summarizes adverse drug reaction data pooled from clinical trials, published

investigations

post-marketing

experience

with

diclofenac

potassium

diclofenac

sodium.

Frequency estimate:

Very common:

≥10%

Page

16

43

Common: ≥1% and <10%

Uncommon:

≥0.01% and <1%

Very rare: <0.01%, including isolated reports.

Table 1 Most Common Adverse Drug Reactions ( ≥ 1%)

Gastrointestinal

disorders

Very

common

nausea, vomiting, diarrhea, dyspepsia, abdominal pain,

flatulence, decreased appetite

Nervous system

disorders

Common

dizziness, headache

Hepatic

Common

elevations (≥3 times the upper normal limit) of

serum

aminotransferase

enzymes

(SGOT

AST,

SGPT or ALT).

Skin and

subcutaneous

disorders

Common

rash, pruritus

Ear and

labyrinth disorders

Common

vertigo

Table 2

Less Common Adverse Drug Reactions (<1%)

Gastrointestinal

disorders

Uncommon

gastritis,

gastrointestinal

hemorrhage,

hemorrhagic

diarrhea,

melena,

hematemesis

gastric

intestinal

ulcerations (with or without bleeding or perforation)

Very rare

lower gut disorders (including hemorrhagic colitis

and exacerbation of ulcerative colitis or Crohn's

disease), intestinal diaphragm disease, hyperacidity,

stomatitis, glossitis, coated tongue, esophageal lesions,

constipation, pancreatitis

Nervous system

disorders

Uncommon

somnolence, malaise, impaired concentration, tiredness

Very rare

Sensory

disturbances

including

paresthesia,

memory

impairment,

convulsions,

anxiety,

tremor,

aseptic

meningitis, cerebrovascular accident (including transient

ischemic attack, cerebral hemorrhage), dysgeusia

Eye disorders

Very rare

visual impairment (blurred vision, diplopia)

Ear and labyrinth

disorders

Very rare

hearing impaired, tinnitus

Cardiac disorders

Uncommon

myocardial infarction, cardiac failure, palpitations,

angina, arrhythmias, chest pain

Vascular

disorders

Very rare

hypertension, vasculitis

Skin and

subcutaneous

disorders

Uncommon

urticaria

Very rare

bullous

dermatitis,

erythema,

eczema,

erythema

multiforme, Stevens-Johnson Syndrome, Lyell Syndrome

(toxic

epidermal

necrolysis),

erythroderma

(exfoliative

Page

17

43

dermatitis), alopecia, photosensitivity reactions, purpura,

Henoch-Schonlein purpura

Renal and

urinary disorders

Uncommon

edema (facial, general, peripheral)

Very rare

acute

kidney

injury

(acute

renal

failure),

nephrotic

syndrome,

urinary

abnormalities

(e.g.,

hematuria

proteinuria),

tubulointerstitial

nephritis,

renal

papillary

necrosis

Hematologic

Very rare

thrombocytopenia,

leukopenia,

agranulocytosis,

hemolytic anemia, aplastic anemia, anemia secondary to

gastrointestinal bleeding

Hepatic

Uncommon

liver

function

disorders

including

hepatitis,

hepatic

necrosis, hepatic failure, jaundice

Very rare

hepatitis fulminant

Immune system

disorders

Uncommon

hypersensitivity

anaphylactic

anaphylactoid

systemic reactions (including hypotension and shock)

Very rare

angioedema (including face edema)

Psychiatric

disorders

Very rare

disorientation, depression, insomnia, nightmare,

irritability, psychotic disorder

Respiratory

disorders

Uncommon

asthma (including dyspnea)

Very rare

Pneumonitis

Post-Market Adverse Drug Reactions

Hepatic:

Severe

hepatic

reactions

including liver

necrosis,

fulminant

hepatitis

with

without jaundice, and liver failure, some of them with fatal outcome or requiring liver

transplantation (see

WARNINGS AND PRECAUTIONS – Hepatic/Biliary/Pancreatic

Cardiovascular:

Serious

reactions

including

myocardial

infarction,

cardiac

failure,

palpitations, angina, arrhythmias, chest pain.

Meta-analysis

pharmacoepidemiological

data

point

towards

increased

risk

arteriothrombotic events associated with the use of diclofenac, particularly at a high dose

(see

WARNINGS AND PRECAUTIONS

box).

Gastrointestinal Disorders:

gastrointestinal stenosis, perforation which may lead to peritonitis,

and ischemic colitis (which are sometimes fatal) (see

WARNINGS AND PRECAUTIONS –

Gastrointestinal (GI))

Immune/Hypersensitivity:

Kounis syndrome, a serious allergic reaction that can cause

myocardial infarction.

DRUG INTERACTIONS

Page

18

43

Drug-Drug Interactions

Overview

Effect of Other Drugs on the Metabolism of diclofenac:

Co-prescribing diclofenac with

CYP2C9 inhibitors could result in a significant increase in peak plasma concentrations and

exposure to diclofenac. Although there are no clinical data available on the drug interaction

between diclofenac sodium SR and CYP2C9 inducers, the possibility of decreased efficacy of

diclofenac resulting from concomitant administration with a CYP2C9 inducer cannot be

excluded. Dosage adjustment may be required.

Drugs

known

to

cause

hyperkalemia:

Concomitant

treatment

with

potassium-sparing

diuretics, cyclosporine, tacrolimus, trimethoprim, ACE inhibitors, angiotensin-II receptor

antagonists or adrenergic blockers may be associated with increased serum potassium levels,

which should therefore be monitored frequently (see

WARNINGS AND PRECAUTIONS

- Renal - Fluid and Electrolyte Balance

Table 3 Established Potential Drug-Drug Interactions

Diclofenac

Sodium

enteric

coated tablets or slow release

tablets

Clinical comment

Acetaminophen

There may be an increased risk of adverse renal effects

when administered concomitantly with NSAIDs.

Acetylsalicylic acid

(ASA) or other NSAIDs

TEVA-DICLOFENAC

TEVA-

DICLOFENAC

addition

other

NSAID,

including over the counter ones (such as ASA and ibuprofen)

analgesic

and/or

anti-inflammatory

effects

recommended because of the absence of any evidence

demonstrating

synergistic

benefits

potential

additive adverse reactions.

The exception is the use of low dose ASA for cardiovascular

protection

when

another

NSAID

being

used

analgesic/anti-

inflammatory

effect,

keeping

mind

that

combination

NSAID

therapy

associated

with

additive

adverse reactions.

Some NSAIDs (e.g. ibuprofen) may interfere with the anti-

platelet effects of

low dose

ASA, possibly by

competing

with ASA for access to the active site of cyclooxygenase-1.

Diclofenac sodium should not be used concomitantly with

diclofenac

potassium

since

both

exist in plasma as the

same active organic ion.

Concomitant administration of diclofenac and other

systemic NSAIDs or corticosteroids may

increase

Page

19

43

frequency of gastrointestinal undesirable effects.

Alcohol

There may be an increased risk of gastrointestinal side

effects, including ulceration or hemorrhage, when administered

concomitantly with NSAIDs.

Antacids

Concomitant administration of antacids with NSAIDs may

affect the rate, but generally not the extent of the absorption of

the NSAID.

Anticoagulants

(See

WARNINGS AND PRECAUTIONS – Hematologic -

Anti-coagulants

Anti-hypertensives

NSAIDs may diminish the anti-hypertensive effect of

Angiotensin Converting Enzyme (ACE) inhibitors.

Combinations of ACE inhibitors, angiotensin-II antagonists, or

diuretics with NSAIDs might have an increased risk for acute

renal

failure

hyperkalemia.

Blood

pressure

renal

function (including electrolytes) should be monitored more

closely

this

situation,

occasionally

there

substantial increase in blood pressure (see

WARNINGS AND

PRECAUTIONS – Renal

Therefore the combination should be administered with caution

especially in the elderly (see

WARNINGS AND

PRECAUTIONS - Monitoring and Laboratory Tests

Anti-platelet agents

(including ASA)

There is an increased risk of bleeding, via inhibition of platelet

function, when anti-platelet agents are combined with NSAIDs,

such as TEVA-DICLOFENAC EC and TEVA-DICLOFENAC

SR (see

WARNINGS AND PRECAUTIONS – Hematologic

- Anti-platelet Effects

Cyclosporine

Nephrotoxicity of cyclosporine may be increased because

of the effect of NSAIDs on renal prostaglandins. Therefore,

it should be given at doses lower than those that would be

used in patients not receiving cyclosporine.

CYP2C9 inducers

Caution is recommended when co-prescribing diclofenac with

CYP2C9 inducers (such as rifampin), which could result in a

significant decrease in plasma concentration and exposure to

diclofenac

.

Dosage adjustment may be required.

CYP2C9 inhibitors

Caution is recommended when co-prescribing diclofenac with

CYP2C9 inhibitors (such as voriconazole or sulfinpyrazone),

which could result in a significant increase in peak plasma

concentrations and exposure to diclofenac. Dosage adjustment

may be required.

Digoxin

Diclofenac

increase

plasma concentration

digoxin. Dosage adjustment may be required. Monitoring of

serum digoxin level is recommended

Diuretics

Clinical

studies as well

as post-marketing observations have

shown that NSAIDs can reduce the effect of diuretics. (see

WARNINGS AND PRECAUTIONS – Renal

Class Statement

Concomitant treatment with potassium-sparing diuretics may

Page

20

43

be associated with increased serum potassium, thus making it

necessary to monitor levels. (see

WARNINGS AND

PRECAUTIONS – Monitoring and Laboratory Tests –

Renal

Glucocorticoids

Some studies have shown that

concomitant use of

NSAIDs

and oral glucocorticoids increases the risk of GI adverse events

such as ulceration and bleeding. This is especially the case

in older (>65 years of age) individuals.

Lithium

Monitoring of plasma lithium concentrations is advised when

stopping

starting

NSAID,

increased

lithium

concentrations can occur in patients taking lithium. Dosage

adjustment

of lithium may be required.

Methotrexate

Caution

should

exercised

when

NSAIDs,

including

TEVA-DICLOFENAC

TEVA-

DICLOFENAC SR, are administered less than 24 hours before

after

treatment

with

methotrexate.

Elevated

blood

concentrations of methotrexate may occur, increasing toxicity.

Oral Contraceptives

No drug interaction data are available for diclofenac sodium

co-administered with oral contraceptives.

Oral Hypoglycemics

Pharmacodynamic

studies

have

shown

potentiation

effect

with

concurrent

administration

with

diclofenac;

however, there are isolated reports of both hypoglycemic and

hyperglycemic effects in the presence of diclofenac, which

necessitated changes in the dosage of hypoglycemic agents.

this

reason,

monitoring

blood glucose level is

recommended as a precautionary measure during concomitant

therapy.

There have also been reports of metabolic acidosis when diclofenac

was co-administered with metformin, particularly in the context of

renal impairment. Caution is recommended when co-prescribing

diclofenac with metformin.

Phenytoin

When using phenytoin concomitantly with diclofenac,

monitoring of phenytoin plasma concentrations is

recommended due to an expected increase in exposure to

phenytoin.

Probenecid

decrease

excretion

increase

serum

concentrations

of NSAIDs possibly enhancing effectiveness

and/or increasing potential for toxicity. Concurrent therapy

of NSAIDs with probenecid requires close monitoring to be

certain that no change in dosage is necessary.

Quinolone antibacterials

There have been isolated reports of convulsions which may

have been due to concomitant use of quinolones and NSAIDs.

Selective serotonin reuptake

inhibitors (SSRIs)

Concomitant

administration

NSAIDs,

including

TEVA-

DICLOFENAC EC or TEVA-DICLOFENAC SR, and SSRIs

increase

risk

gastrointestinal

ulceration

bleeding.

(see

WARNINGS

AND

PRECAUTIONS

Gastrointestinal(GI)

Sulfinpyrazone

Caution is recommended when co-prescribing diclofenac with

CYP2C9 inhibitors (such as sulfinpyrazone, which could result

Page

21

43

in a significant

increase in peak plasma concentrations and

exposure to diclofenac. Dosage adjustment may be required.

Tacrolimus

Nephrotoxicity of tacrolimus may be increased because of the

effect of NSAIDs on renal prostaglandins. Therefore, it should

be given at doses lower than those that would be used in

patients not receiving tacrolimus.

Voriconazole

Caution is recommended when co-prescribing diclofenac

with CYP2C9 inhibitors (such as voriconazole), which could

result in a significant increase in peak plasma concentrations and

exposure to diclofenac. Dosage adjustment may be required.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug Laboratory Tests Interactions:

Diclofenac increases platelet aggregation time but does not affect bleeding time, plasma

thrombin clotting time, plasma fibrinogen, or factors V and VII to XII. Statistically significant

changes in prothrombin and partial thromboplastin times have been reported in normal

volunteers. The mean changes were observed to be less than 1 second in both instances, and are

unlikely to be clinically important.

Persistently abnormal or worsening renal, hepatic or hematological test values should be

followed up carefully since they may be related to therapy.

Drug-Lifestyle Interactions

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

system

disturbances

while

taking

TEVA-DICLOFENAC

TEVA-DICLOFENAC

should refrain from driving or using machines.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Geriatrics:

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.

Caution is indicated especially for frail elderly patients or those with a low body weight (See

WARNINGS AND PRECAUTIONS – Special Populations - Geriatrics

Cardiovascular disease or cardiovascular risk factors:

Treatment with TEVA-DICLOFENAC

EC (diclofenac sodium) or TEVA-DICLOFENAC SR is not recommended in patients with pre-

existing cardiovascular disease (congestive heart failure NYHA II-IV, ischemic heart disease,

Page

22

43

peripheral arterial disease), cerebrovascular disease, uncontrolled hypertension, or patients with

risk factors for cardiovascular disease (e.g. hypertension, hyperlipidemia, diabetes mellitus and

smoking).

These

patients

should

treated

with

TEVA-DICLOFENAC

TEVA-

DICLOFENAC SR only after careful consideration (see

WARNINGS AND PRECAUTIONS –

box).

Renal Impairment

TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR is contraindicated in patients with

severe renal impairment or deteriorating renal disease (see

CONTRAINDICATIONS

). Lower

doses

TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR should be considered in

patients with impaired renal function (see

WARNINGS AND PRECAUTIONS – Renal

Hepatic Impairment:

TEVA-DICLOFENAC EC o r T E V A -DICLOFENAC

SR is

contraindicated

patients

with severe hepatic impairment or active liver disease (see

CONTRAINDICATIONS

). Lower

doses of TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR should be considered in

patients

with

impaired

hepatic

function

(see

WARNINGS

AND

PRECAUTIONS

Hepatic/Biliary/Pancreatic

Recommended Dose and Dose Adjustment

As a general recommendation, the dose should be individually adjusted. Adverse effects may be

minimized by using the lowest effective dose for the shortest duration necessary to control

symptoms.

TEVA-DICLOFENAC EC Tablets 25 mg (enteric-coated)

In the treatment of rheumatoid arthritis and osteoarthritis, the recommended starting dose of

TEVA–DICLOFENAC EC (diclofenac sodium) is 25 mg three times daily depending on

the severity of the condition.

TEVA-DICLOFENAC EC 50 mg Tablets, and TEVA-DICLOFENAC SR are to be used for

maintenance therapy only.

TEVA-DICLOFENAC EC Tablets 50 mg (enteric-coated)

Rheumatoid arthritis and osteoarthritis patients may use TEVA-DICLOFENAC EC 50 mg

enteric-coated tablets if:

They were previously initiated at the lowest dose of 75 mg (enteric-coated) per day in

divided doses and required up-titration because they did not respond to that dose.

The maximum recommended daily dose is 100 mg.

TEVA-DICLOFENAC EC should be taken with food and the tablets should be swallowed whole.

Page

23

43

TEVA-DICLOFENAC SR 75 mg and 100 mg (slow-release tablets)

Patients with rheumatoid arthritis or osteoarthritis on a maintenance dose of 75 mg

diclofenac sodium per day may be changed to a once daily dose of TEVA-DICLOFENAC

SR 75 mg administered morning or evening.

Patients on a maintenance dose of 100 mg diclofenac sodium per day may be changed

to a once daily dose of TEVA-DICLOFENAC SR 100 mg, administered morning or

evening.

The maximum recommended daily dose is 100 mg.

TEVA-DICLOFENAC SR tablets should be swallowed whole with liquid, preferably at mealtime.

Missed Dose

Patients who miss one or more doses of TEVA-DICLOFENAC EC 25 mg or 50 mg tablets or

TEVA-DICLOFENAC SR 75 and 100 mg tablets should not increase the dose of TEVA-

DICLOFENAC EC or TEVA-DICLOFENAC SR to compensate for the missed dose or doses,

but should continue with their therapy as soon as possible.

OVERDOSAGE

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

Symptoms

There is no typical clinical picture resulting from diclofenac overdosage. Overdosage can cause

symptoms

such

vomiting,

gastrointestinal

haemorrhage,

diarrhoea,

dizziness,

tinnitus

convulsions. In the event of significant poisoning, acute renal failure and liver damage are

possible.

Therapeutic measures

Management of acute poisoning with NSAIDs, including TEVA-DICLOFENAC EC or TEVA-

DICLOFENAC SR, essentially consists of supportive measures and symptomatic treatment.

Supportive measures and symptomatic treatment should be given for complications such as

hypotension, renal failure, convulsions, gastrointestinal disorder, and respiratory depression.

Special measures such as forced diuresis, dialysis or haemoperfusion are probably of no help in

eliminating NSAIDs, including TEVA-DICLOFENAC EC or TEVA-DICLOFENAC SR, due to

the high protein binding and extensive metabolism. Activated charcoal may be considered

Page

24

43

after ingestion of a potentially toxic overdose, and gastric decontamination (e.g. vomiting,

gastric lavage) after ingestion of a potentially life threatening overdose.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID). The mode of action is

not fully known but it does not act through the pituitary-adrenal axis. Diclofenac sodium inhibits

prostaglandin

synthesis

interfering

with

action

prostaglandin

synthetase.

This

inhibitory effect may partially explain its actions.

Pharmacodynamics

The effects of TEVA-DICLOFENAC EC, TEVA-DICLOFENAC SR are largely mediated by

inhibition of cyclooxygenases (COXs, COX-1, COX-2). These enzymes are found throughout

the body and produce prostaglandins, which are important mediators of pain, fever, and

adaptive and protective reactions in many organs and (inflamed) tissues.

Pharmacokinetics

Absorption

: In humans, orally-administered diclofenac sodium is rapidly and almost completely

absorbed and distributed to blood, liver, and kidneys. The plasma concentrations show a linear

relationship to the amount of drug administered.

No accumulation occurs provided the

recommended dosage intervals are observed.

Enteric coating may delay the onset of absorption from 50 mg tablets. Absorption occurs more

rapidly when the drug is administered on an empty stomach (T

2.5 hours), than with meals

6 hours). The bioavailability remains the same under both conditions. The mean peak

plasma concentration of 1.5 μg/mL (5 μmol/L) is attained, on average, 2 hours after ingestion of

one 50 mg enteric-coated tablet.

Following

administration

slow-release

(SR)

diclofenac

sodium,

reached

approximately 4 hours or later. Significant drug plasma concentrations persist when levels

would have dropped almost to baseline values following enteric-coated tablet administration.

Mean plasma concentrations of 13 ng/mL (40 nmol/L) were produced 24 hours after diclofenac

sodium 100 mg slow release tablets, or 16 hours after diclofenac sodium 75 mg slow release

tablets (single dose).

Trough levels are approximately 22-25 ng/mL (70-80 nmol/L) during

treatment with diclofenac sodium 100 mg slow release tablets once daily or diclofenac sodium 75

mg slow release tablets twice daily. In pharmacokinetic studies no accumulation of diclofenac

sodium was found following repeated once daily administration of diclofenac sodium 100 mg

slow release tablets or repeated twice daily administration of diclofenac sodium 75 mg slow

release tablets.

Distribution

: Diclofenac sodium is extensively bound (99%) to serum albumin. The apparent

volume of distribution is 0.12 to 0.17 L/kg. Single-dose (P.O. or I.M) studies in rheumatoid

patients with joint effusions have shown that diclofenac is distributed to the synovial fluid, where

occurs 2 to 4 hours after plasma T

. Synovial fluid concentrations exceed plasma levels

Page

25

43

within 4 to 6 hours of administration.

This elevation above plasma concentrations can be

maintained for up to 12 hours. The synovial fluid elimination half-life is at least 3 times greater

than that for plasma.

Diclofenac was detected in a low concentration (100 ng/mL) in breast milk in one nursing

mother. The estimated amount ingested by an infant consuming breast milk is equivalent to a

0.03 mg/kg/day dose (see

CONTRAINDICATIONS

Metabolism:

Diclofenac

undergoes

single

multiple

hydroxylation

methoxylation,

producing 3'-, 4'-, 5-hydroxy, 4'- 5-hydroxy and 3'-hydroxy-4'-methoxy derivatives of diclofenac.

These phenolic metabolites are largely inactive, and (along with the parent compound) are

mostly converted to glucuronide conjugates.

Excretion

: Plasma clearance of diclofenac is 263 ± 56 mL/min. The mean terminal drug

half-life in plasma is 1.8 hours after oral doses.

In humans about 60% of the drug and its

metabolites are eliminated in the urine and the balance through bile in the feces. More than 90%

of an oral dose is accounted for in elimination products within 72 hours. About 1% of an oral

dose is excreted unchanged in urine.

Special Populations and Conditions

Renal Impairment

In patients suffering from renal impairment, no accumulation of the

unchanged active substance can be inferred from the single-dose kinetics when applying the

usual dosage schedule. At a creatinine clearance of <10 mL/min, the calculated steady-state

plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects.

However, the metabolites are ultimately cleared through the bile. Although no accumulation of

pharmacologically

active

substance

seem

occur,

caution

advised

while

administering

diclofenac sodium to patients with impaired kidney function (ie GFR <60 mL/min or 1 mL/sec)

(see

WARNINGS

AND

PRECAUTIONS

-

Renal

TEVA-DICLOFENAC

TEVA-

DICLOFENAC SR are contraindicated in patients with severely impaired or deteriorating renal

function (creatinine clearance < 30 mL/min (0.5 mL/s) (see

CONTRAINDICATIONS

Hepatic impairment

: In a study of ten patients with impaired hepatic function (chronic hepatitis

and non-decompensated cirrhosis) receiving a single oral dose of 100 mg diclofenac sodium, the

kinetics and metabolism of diclofenac, were the same as in patients without liver disease.

Pediatrics:

TEVA-DICLOFENAC EC and TEVA-DICLOFENAC SR are contraindicated in

children and adolescents less than 16 years of age (see

CONTRAINDICATIONS

Geriatrics

: The ability of elderly subjects to absorb, metabolize and excrete TEVA-

DICLOFENAC EC or TEVA-DICLOFENAC SR does not appear to differ significantly from

those of younger subjects.

STORAGE AND STABILITY

Store between 15°-30°C.

Page

26

43

DOSAGE FORMS, COMPOSITION AND PACKAGING

TEVA-DICLOFENAC EC (diclofenac sodium) 25 mg:

Yellowish, tan coloured, round, bi-

convex , enteric film coated tablets, printed with black ink modified

N/25

on one side and plain on

the reverse. Supplied in bottles of 100.

TEVA-DICLOFENAC EC (diclofenac sodium) 50 mg:

Tan coloured, round, bi-convex, enteric

film coated tablets, printed with black ink modified

N/50

on one side and plain on the reverse.

Supplied in bottles of 100 and 500.

TEVA-DICLOFENAC SR (diclofenac sodium) 75 mg:

Light pink triangular standard bi-convex

bevel-edged film coated slow release tablets. Printed with black ink

N

on one side and

SR /75

the reverse. Supplied in bottles of 100.

TEVA-DICLOFENAC SR (diclofenac sodium) 100mg:

Pink round bi-convex bevel-edged film

coated slow release tablets. Printed

N

on one side and

SR/100

on the reverse. Supplied in bottles of

100.

Composition:

TEVA-DICLOFENAC EC (diclofenac sodium) 25 mg and 50 mg enteric coated tablets:

Each tablet contains the medicinal ingredient diclofenac sodium and non-medicinal ingredients:

magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, silicon dioxide,

sodium lauryl sulfate and sodium starch glycolate.

The film coating contains (25mg): D&C Yellow # 10, hypromellose, iron oxide red, iron oxide

yellow, maltodextrin, methacrylic acid, polyethylene glycol, talc, titanium dioxide, triethyl citrate

The film coating contains (50mg): hypromellose, iron oxide black, iron oxide red, iron oxide

yellow, maltodextrin, methacrylic acid, polyethylene glycol, talc, titanium dioxide, triethyl citrate

Printing ink contains: black iron oxide, lecithin, shellac glaze, simethicone

TEVA-DICLOFENAC SR (diclofenac sodium) 75 mg and 100 mg slow release tablets:

Each tablet contains the medicinal ingredient diclofenac sodium and non-medicinal ingredients:

colloidal silicon dioxide, lactose monohydrate, magnesium stearate, and povidone.

The film coating contains: aquacoat ECD-30, dibutyl sebacate, FD&C Blue #2, FD&C Red #40,

FD&C Yellow #6, hypromellose, polyethylene glycol, polysorbate and titanium dioxide.

Printing ink contains: black iron oxide, lecithin, shellac glaze, simethicone

Page

27

43

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance:

Proper name:

Diclofenac sodium

Chemical Name:

Sodium-[o-[2,6-dichloroanilino)phenyl]acetate.

Molecular formula:

NNaO

Molecular mass:

318.13 g/mol

Structural formula:

Physicochemical properties:

Diclofenac Sodium is white to off-white powder with a salty

bitter taste. At 25 ° C, diclofenac sodium is 2% soluble in water

(pH 7.7). It is practically insoluble in aqueous acidic solutions

Page

28

43

CLINICAL TRIALS

ENTERIC-COATED TABLETS:

A comparative bioavailability study was performed on three diclofenac sodium enteric coated

tablet products, TEVA–DICLOFENAC EC 25 mg tablets, TEVA–DICLOFENAC EC 50 mg

tablets and Voltaren

50 mg tablets. Diclofenac sodium tablets were administered as a single dose

(2 x 25 mg and 1 x 50 mg TEVA-DICLOFENAC EC versus 1 x 50 mg Voltaren

) under fasting

conditions. Eighteen volunteers completed the randomized, three–way crossover study. The

pharmacokinetic plasma data (mean ± standard deviation) calculated for the TEVA–

DICLOFENAC EC and Voltaren

Tablet formulations is tabulated below:

Diclofenac Sodium (enteric-coated)

(2 x 25 mg) and (1 x 50 mg)

From measured data

Arithmetic Mean (± standard deviation)

Parameter

TEVA-

DICLOFENAC

EC

*

25 mg

(A):

2 x 25 mg

TEVA-

DICLOFENAC

EC

**

50 mg

(B):

50 mg

VOLTAREN

50 mg

(C):

1 x 50 mg

% Ratio of

Geometric Means

(0-24)

(ng

hours/mL)

1277.45 ± 316.70

1251.16 ± 287.46

1348.41 ± 327.13

96.02 ± 18.44 (A)

94.68 ± 18.32 (B)

(ng/mL)

1151.88 ± 362.55

1185.77 ± 328.32

1308.69 ± 394.63

91.48 ± 28.54 (A)

101.14 ± 57.98 (B)

2.03 ± 0.83

1.78 ± 0.75

2.64 ± 1.29

0.70 ± 0.20

0.66 ± 0.16

0.69 ± 0.21

Test: TEVA-DICLOFENAC EC 25 mg (enteric-coated tablets)

Test: TEVA-DICLOFENAC EC 50 mg (enteric-coated tablets)

Reference: VOLTAREN

50 mg tablets, Ciba Geiby Canada, Streetsville, Ontario

Statistical evaluation by analysis of variance (ANOVA) of 0-24 hour AUC, C

and T

showed

no significant differences among the three formulations. The T

values for both TEVA-

DICLOFENAC EC formulations were significantly shorter than the T

for Voltaren

Page

29

43

Therefore, the maximum plasma diclofenac concentration occurred sooner for both TEVA-

DICLOFENAC EC formulations relative to Voltaren

SLOW RELEASE TABLETS:

A comparative bioavailability study was performed on two 100 mg diclofenac sodium slow release

products under fed conditions in normal, healthy, male volunteers. The pharmacokinetic plasma

data calculated for the TEVA-DICLOFENAC SR and VOLTAREN

SR tablet formulations is

tabulated below:

Diclofenac Sodium SR

( 1 x 100 mg)

From measured data

Geometric Mean

Arithmetic Mean (CV %)

Paramet

er

TEVA-

DICLOFENAC

SR

*

(1 x 100 mg)

VOLTAREN

®

(1 x 100 mg)

% Ratio of

Geometric

Means

90% Confidence

Interval

(0-t)

(ngh/mL

2416

2531 (35)

2566

2924 (75)

94.18%

83.44% – 106.31%

(0-∞)

(ngh/mL

2322

2362 (19)

2465

2523 (24)

92.32%

84.36% – 101.03%

(ng/mL)

763 (42)

761 (64)

112.92%

85.78% – 148.65%

7.56 (4.93)

8.37 (6.18)

2.08 (1.54)

2.25 (1.32)

Test: TEVA-DICLOFENAC SR 100mg (sustained release tablets).

Reference: VOLTAREN

SR 100mg tablets, Geigy Pharmaceuticals, Mississauga, ON,

Canada

Expressed as the arithmetic mean (standard deviation)

A comparative bioavailability study was performed on two 100 mg diclofenac sodium slow release

products under fasting state in normal, healthy, male volunteers. The pharmacokinetic plasma data

calculated for the TEVA-DICLOFENAC SR and VOLTAREN

SR tablet formulations is

tabulated below:

Page

30

43

Diclofenac Sodium SR

(1 x 100 mg)

From measured data

Geometric Mean

Arithmetic Mean (CV %)

Paramete

r

TEVA-

DICLOFENAC

SR

*

(1 x 100 mg)

VOLTAREN

®

(1 x 100 mg)

% Ratio of

Geometric

Means

90% Confidence

Interval

(0-t)

(ngh/mL)

1998

2066 (23)

2122

2155 (19)

97.77%

88.19% – 106.93%

(0-∞)

(ngh/mL)

2143

2179 (19)

2276

2322 (18)

97.11%

91.21% – 103.39%

(ng/mL)

606 (63)

535 (52)

112.82%

91.51% – 139.11%

5.17 (2.3)

4.83 (2.24)

4.23 (7.45)

5.40 (4.71)

Test: TEVA-DICLOFENAC SR 100mg (sustained release tablets).

Reference: VOLTAREN

SR 100mg tablets, Geigy Pharmaceuticals, Mississauga, ON,

Canada

Expressed as the arithmetic mean (standard deviation)

Randomized clinical trials with diclofenac sodium enteric coated tablets and slow release tablets

have NOT been designed to detect differences in cardiovascular adverse events in a chronic

setting.

However, large population-based observational studies, meta-analyses and systematic reviews

suggest that diclofenac use is associated with an increased risk of cardiovascular thrombotic

events, including myocardial infarction and ischemic stroke. Results of some studies suggest

that the CV risk is related to the dose and duration of diclofenac exposure and is greater in

patients with risk factors for CV disease.

Large meta-analyses of randomized clinical trials show that diclofenac is associated with an

increased risk of stroke, cardiovascular death, and death from any cause when compared with

placebo. Data also suggest that diclofenac, particularly when used at a high dose (150 mg daily)

may have a higher risk of thrombotic CV events than other NSAIDs.

The

information

provided

below

supported

the

original

registration

and

its

subsequent

amendments. These studies were conducted in accordance with the standards and regulations in

force at the time of conduct of these studies.

Page

31

43

Enteric coated tablets

The therapeutic safety and efficacy of diclofenac sodium enteric coated tablets in arthritic

conditions has been investigated in both short and long-term (three months) controlled clinical

studies, followed by extended controlled

non-controlled

studies. The

majority of

comparative studies were double blind, within patient or between patient design, using placebo

indomethacin

controls.

Acetylsalicylic

acid

(ASA),

ibuprofen,

phenylbutazone

acetaminophen were also used as comparative standards.

At time of approval, the safety and efficacy of diclofenac sodium enteric coated tablets for

relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis was demonstrated in

short-term prospective comparative clinical trials conducted in 105 patients with osteoarthritis

and 654 patients with rheumatoid

arthritis. The

controls

used

these

trials

included:

indomethacin, acetylsalicylic acid, acetaminophen and ibuprofen.

Several of the long-term double-blind, between patient studies comparing a three times daily

dosing of diclofenac sodium enteric coated to that of indomethacin were of three months

duration. Patients received either drug at dosages ranging from 50 to 125 mg. In the

treatment

patients

with rheumatoid arthritis there was no clear difference between the

treatment groups for therapeutic effect.

The safety and efficacy of diclofenac sodium enteric coated tablets compared to indomethacin for

relief of the signs and symptoms of rheumatoid arthritis was also studied in longer-term studies

of 6 to 30 months.

Slow release tablets

Bioavailability studies have demonstrated that the absorption of active drug from the diclofenac

sodium

slow

release

(SR)

tablets

similar

that

reported

from

diclofenac sodium

enteric

coated

tablets

with

being

attained

approximately

four

hours

after

administration

single

diclofenac

sodium

slow

release

tablet.

Repeated

administration of the diclofenac sodium slow release tablets for seven days or longer did not

result in any accumulation of active drug and food intake did not alter absorption from the

diclofenac sodium slow release tablet.

A regimen of multiple doses of the 75 mg diclofenac sodium slow release tablet (every 12

hours) provided an equivalent AUC

0-24

to that of the 50 mg diclofenac sodium enteric coated

tablet dosed every eight hours; an indication that the 75 mg diclofenac sodium slow release

tablet is an effective and desirable alternate to the 50 mg diclofenac sodium enteric coated

tablet for the treatment of rheumatoid arthritis or osteoarthritis.

Safety and efficacy of diclofenac sodium 100 mg slow release tablets were demonstrated

in a randomized, double-blind, parallel, short-term (two weeks) clinical study when compared to

diclofenac sodium enteric coated tablets and placebo in patients suffering from adult onset

rheumatoid arthritis. A second comparative clinical trial was conducted in patients with

established osteoarthritis of the hip and knee. No statistically significant differences were

seen between the 2 diclofenac sodium regimens.

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32

43

DETAILED PHARMACOLOGY

Diclofenac sodium is a phenyl-acetic acid derivative possessing anti-inflammatory activities

as shown in various pharmacological models.

In vitro

diclofenac sodium does not suppress proteoglycan biosynthesis in cartilage

at concentrations equivalent to the concentrations reached in humans.

Anti-Inflammatory Activity in Rats

The anti-inflammatory potency was assessed by testing inhibition of paw edema (carrageenin

solution and kaolin suspension) and reduction of adjuvant arthritis (Freund's adjuvant).

Preparation

Inhibition of edema induced by

Carrageenin

mg/kg)

P.O.*

Kaolin

mg/kg)

P.O.*

Diclofenac sodium

*determined by graphic interpolation from 3 or more doses.

Inhibition of Prostaglandin

A close correlation exists between certain febrile reactions and increased prostaglandin levels in

the brain. Diclofenac (0.5

µ g/mL) reduces prostaglandin E

formation which parallels

antipyresis

does

induce

hypothermia

afebrile

animal.

inhibition

prostaglandin synthesis

in vitro

µ M/L) is 1.6.

Platelet Adhesiveness

At 15

µ g/mL, diclofenac reduces collagen-induced aggregation in rabbit platelets by 50%.

ADP- induced adhesiveness at the same dosage is similarly affected. At 10 mg/kg P.O.,

diclofenac protected rabbits against the lethal action of thrombokinase without untoward effects.

Gastrointestinal Tolerability

In rats, oral doses of 17 mg/kg diclofenac sodium caused a blood loss of 150 µ L in 72 hours, as

measured by the administration of

Cr-labelled erythrocytes.

TOXICOLOGY

Acute Toxicity

Page

33

43

Species

Route

LD

50

mg/kg

95% Confidence Limits

(mg/kg)

Mouse

P.O.

I.V.

197 - 595

126 - 140

P.O.

I.V.

133 - 213

80 - 132

Guinea-pig

P.O.

I.V.

950 - 1270

123 - 132

Rabbit

P.O.

151 - 259

The symptoms included bradycardia and convulsions.

The most frequent autopsy findings in animals that died were gastric irritation, perforation and

their sequelae.

Long-Term Toxicity Studies

SPECIES

PERIOD

DAILY DOSE mg/kg/day P.O.

No signs of

intoxication

Reversible signs

of toxicity, mainly GI

Tract

Minimum

lethal dose

3 months

6 months

98 weeks

0.25

3 months

Rhesus Monkey

6 months

5-15

Baboon

12 months

Diclofenac sodium was given orally to male and female rats in doses of 0.25, 1.0 and

2.0 mg/kg/day from 59 weeks (high-dose groups) to 98 weeks (low- and intermediate-dose

groups). High dose-related mortality rates resulted in termination of the high-dose

administration after 59 weeks; the high mortality rate was caused by severe dose-dependent

ulceration of the gastrointestinal tract, with perforated ulcers leading to peritonitis and sequelae.

Body-weight gains and feed consumption of the treated groups were close to the controls.

Hematologic patterns showing neutrophilic leucocytosis and anemia were seen in the high- and

intermediate-dose groups, particularly females at weeks 52 and 98, respectively. Female animals

tended to develop enlarged adrenals and eventually experienced depressed glucose and elevated

alkaline phosphatase levels. Histology studies carried out on the tissues of the control, low- and

intermediate-dose groups showed drug-related changes including mucosal ulceration of the small

intestine, lymphangiectasis, lymphoid hypoplasia, and plasma cell hypoplasia of the mesenteric

lymph nodes, foci of hepatocytic hyperplasia, adrenal cortical atrophy and prostatitis. No

increase in tumour incidence was observed in the drug-treated groups as compared to the control

group.

Page

34

43

Diclofenac sodium was administered orally in gelatin capsules once daily to baboons

(Papio

spp.)

at dose levels of 0, 5, 15 (reduced to 10 on day 254) and 50 (reduced to 30 on day 38)

mg/kg/day for up to 52 weeks. At all dose levels studied, diclofenac caused ulceration of the

gastrointestinal tract. Ulceration was confined to the colon in the low-dose group but was

present in the stomach and small intestine also in the other two groups. Body weights were

below controls. Constipation, with occasional episodes of diarrhea, was a marked feature. In all

treated groups, there was a dose-related fall in serum albumin levels. Anemia and an increased

ESR were observed in the high-dose group.

In the recovery groups (control, low, and

intermediate), no intestinal lesions were present. Food consumption and body-weight gains were

within normal limits. Hematology parameters were comparable to controls and serum albumin

levels returned towards normal values.

Reproduction Studies

Rats

: Doses of 2 and 4 mg/kg/day were given orally to male and female rats with no noticeable

effect on fertility. Dosing was carried out during premating, mating, gestation, and lactation

periods. At the higher dose, prolonged gestation and dystocia were observed. Embryotoxicity

(low birth weight, failure to survive) was observed at both doses but it was minimal at

2 mg/kg/day. Post-natal survival and growth of pups from drug-treated animals were

comparable to those of controls except for slightly retarded growth at the higher dose.

Mice and Rats

Teratology studies at oral doses of 2, 3, 10, and 20 mg/kg/day showed no

teratogenic effects on fetuses.

At the higher doses, pronounced gastrointestinal effects were

observed in the dams and a marked toxic effect noted in fetuses (reduced birth weights and

increased fetal deaths).

Rabbits

: Pregnant females treated with oral doses of 5 or 10 mg/animal/day throughout the

gestation period showed a dose-dependent increase in resorption rates, diminished fetus weights,

and abnormal skeletal findings. Definite embryotoxicity was observed at the highest dose

although there was no evidence to suggest teratogenicity.

Administration

NSAIDs

(including

diclofenac)

inhibited

ovulation

rabbit

implantation and placentation in the rat, and led to premature closure of the ductus arteriosus in

the pregnant rat. Maternally toxic doses of diclofenac were associated with dystocia, prolonged

gestation, decreased fetal survival, and intrauterine growth retardation in rats. The slight effects

of diclofenac on reproduction parameters and delivery as well as constriction of the ductus

arteriosus in utero are pharmacologic consequences of this class of prostaglandin synthesis

inhibitors (see

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Special

Populations

Mutagenicity Studies

Mutagenicity studies were carried out

in vitro

using bacteria with, and without microsomal

activation, and in mammalian cells. Studies

in vivo

were also performed. Diclofenac sodium

was not mutagenic in any of these test systems.

Carcinogenicity Studies

Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day have

Page

35

43

revealed no significant increases in tumour incidence. There was a positive dose-related trend

with respect to adrenal medullary hyperplasia, mammary fibroadenomas and subcutaneous tissue

fibromas in females, as well as of C-cell adenomas of the thyroid in males. The differences in

the incidence between the various groups, including control, were small and were considered to

reflect the variation in the spontaneous occurrence of these incidental lesions, common in old

laboratory rats.

In a 2-year mouse study, only controls and animals at the two lower daily doses of 0.1 and

0.3 mg/kg showed survival sufficient for assessment of carcinogenic potential. The two higher

daily doses of 1 and 2 mg/kg resulted in a shortening of lifespan, particularly in males, as a

consequence of ulceration and/or perforation of the small intestine and therefore prevented

evaluation. The known susceptibility of rodents to non-steroidal anti-inflammatory drugs,

resulting in high mortality at dose levels close to the therapeutic dose, is considered to be a

rodent-specific effect. Diclofenac sodium was not carcinogenic to mice under the conditions of

this study.

Page

36

43

REFERENCES

Bijlsma A. The long-term efficacy and tolerability of VOLTAREN* (diclofenac

sodium) and indomethacin in rheumatoid arthritis. Scand J Rheumatol Supp 1978; 22:

74-80

Bodem H, Haringer E, Maier-Lenz H. Open multicentre study comparing the

efficacy and tolerability of diclofenac sodium and piroxicam in degenerative joint

diseases. IN: VOLTAREN* - new findings. Proceedings of an International

Symposium on VOLTAREN* held in Paris on 22nd June 1981 during the 15th

International Congress of Rheumatology. Hans Huber Publishers, Bern Stuttgart,

Vienna 1982, pp 66-67.

Brogden RN, Heel RC, Pakes GE, Speight TM, Avery GS. Diclofenac sodium: A

review of its pharmacological properties and therapeutic use in rheumatic diseases and

pain of varying origin. Drugs 1980; 20: 24-48

Ciccolunghi SN, Chaudri HA, Schubiger BI, Reddrop R. Report on a long-

term tolerability study of up to two years with diclofenac sodium (VOLTAREN*).

Scand J Rheumatol (Suppl) 1978; 22: 86-96

Dittrich P, Kohler G, Braun H-D. Concentration of nonsteriodal anti-inflammatory

drugs in inflamed tissue and in plasma. Naunyn Schmiedeberg Arch Pharmacol 1982;

Fowler PD. Voltarol: Diclofenac sodium. Clin Rheum Dis 1979; 5 (2): 427-464

Hartman AP, Astorga G, Badia J, Gentiletti R, Loizzi I, Pucaar I, et al..

Comparison of VOLTAREN* slow release once daily and VOLTAREN* twice daily

with placebo in rheumatoid patients. IXth Europ Congr Rheumatol, Wiesbaden,

2nd-8th September, 1979. Abstract

Menasse R, Hedwall PR, Krawtz J, Pericin C, Riesterer L, Sallmann A, et

al. Pharmacological properties of diclofenac sodium and its metabolites. Scand J

Rheumatol (Suppl) 1978; 22: 5-15

Osnes M, Larsen S, Eidsaunet W, Thom E. Effect of diclofenac and naproxen

on gastroduodenal mucosa. Clin Pharmacol Ther 1979; 26 (3): 399-405

Riess W, Stierlin H. Pharmacokinetics and metabolism of the anti-inflammatory

agent VOLTAREN*. Scand J Rheumatol (Suppl) 1978; 22: 17-29

Rossi FA, Baroni L. A double-blind comparison between diclofenac sodium

and ibuprofen in osteoarthritis. J Int Med Res 1975; 3: 267-274

Schubiger BI, Ciccolunghi SN, Tanner K. Once daily dose treatment with a non-

steroidal anti-rheumatic drug (diclofenac) in osteoarthrosis. J Int Med Res 1980; 8:

167-174

Siraux P. Diclofenac (VOLTAREN*) for the treatment of osteo-arthrosis: A double-

blind comparison with naproxen. J Int Med Res 1977; 5: 169-174

Srivastava DN, Bhattacharya SK, Sanyal AK. Effect of some prostaglandin

synthesis inhibitors on the antinociceptive action of morphine in albino rats. Clin Exp

Pharmacol Physiol 1978; 5: 503-509

Stierlin H, Faigle JW, Colombi A. Pharmacokinetics of diclofenac

sodium (VOLTAREN*) and metabolites in patients with impaired renal function.

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37

43

Scand J Rheumatol (Suppl) 1978; 22: 30-35

Tausch G, Ebner W. Results of a multicentre clinical study of VOLTAREN*

slow- release in patients with osteoarthritis. Verh Dtsch Ges Rheumatol 1980; 6:

350-353 Abstract

Information Letter, Health Protection Branch. Non-steroidal Anti-inflammatory

Drugs. DD-33; August 21, 1985

Health Canada GUIDANCE DOCUMENT: Basic Product Monograph Information

for Nonsteroidal; Anti-Inflammatory Drugs (NSAIDs). Effective date: November 23,

2006

A comparative three-way, single dose bioavailability study (study #159) of diclofenac

sodium enteric coated tablets in normal volunteers. Completed March 18, 1986. On

file at Teva Canada Limited.

A two-way, single dose fasting bioavailability study (study # 1243) of sustained-

release diclofenac sodium 100mg tablets in normal healthy male volunteers.

Compeleted January 22, 1993. On file at Teva Canada Limited.

A two-way, single dose food effect bioavailability study (study # 1189) of sustained-

release diclofenac sodium 100mg tablets in normal healthy male volunteers.

Completed March 10, 1992. On file at Teva Canada Limited.

Voltaren

, Voltaren

SR, Product Monograph. Novartis Pharmaceuticals Canada

Inc., Dorval, Quebec. July 18, 2018 (control# 215251).

IMPORTANT: PLEASE READ

Page

38

43

PART III: CONSUMER

INFORMATION

Pr

TEVA-DICLOFENAC EC

Pr

TEVA-DICLOFENAC SR

(diclofenac

sodium)

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

TEVA-

DICLOFENAC EC and TEVA-DICLOFENAC

SR were approved for sale in Canada and is

designed specifically for Consumers.

This

leaflet is a

summary and will NOT

tell

you

everything about TEVA-DICLOFENAC EC or

TEVA-DICLOFENAC

SR.

Contact

your

doctor or pharmacist if you have any questions

about the drug.

ABOUT THIS MEDICATION

ABOUT THIS MEDICATION

What

the Medication is used for:

Your health care provider has prescribed TEVA-

DICLOFENAC EC

TEVA-DICLOFENAC

SR for

to relieve pain and

swelling in

rheumatoid

arthritis

osteoarthritis,

including

degenerative joint disease of the hip.

What it does:

TEVA-DICLOFENAC

TEVA-

DICLOFENAC

(diclofenac

sodium),

nonsteroidal

anti-inflammatory

drugs

(NSAIDs),

can reduce the chemicals prostaglandins produced

by your body which cause pain and swelling.

TEVA-DICLOFENAC

TEVA-

DICLOFENAC

nonsteroidal

anti-

inflammatory drugs (NSAIDs) do NOT cure your

illness or prevent it from getting worse. TEVA-

DICLOFENAC EC or TEVA-DICLOFENAC SR

can only relieve pain and reduce swelling as long

as you continue to take it.

When it should not be used:

DO NOT TAKE TEVA-DICLOFENAC EC or

TEVA-DICLOFENAC SR if you have any of the

following conditions:

Heart bypass surgery (planning to have

or recently had)

Severe, uncontrolled heart failure

Bleeding in the brain or other

bleeding disorders

Current pregnancy (after 28 weeks of

pregnancy)

Currently breastfeeding (or planning to

breastfeed)

Allergy

(hypersensitivity)

to

diclofenac

sodium, or

ASA (Acetylsalicylic Acid)

or

other

NSAIDs

(Nonsteroidal

Anti-

Inflammatory

Drugs),

or

any

of

the

nonmedicinal

ingredients

in

TEVA-

DICLOFENAC EC or TEVA-DICLOFENAC

SR

Ulcer (active)

Bleeding or perforation from the stomach

or gut (active)

Inflammatory bowel disease (Crohn’s Disease

or Ulcerative Colitis)

Liver disease (active or severe)

Kidney problems (severe or worsening)

High potassium in the blood

Patients who took a drug in the same class as

TEVA-DICLOFENAC

EC

and

TEVA-

DICLOFENAC SR 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.

TEVA-DICLOFENAC

TEVA-

DICLOFENAC

should

used

patients under 16 years of age since the safety

and effectiveness have NOT been established.

What the medicinal ingredient is:

diclofenac sodium.

What the non-medicinal ingredients are:

TEVA-DICLOFENAC

(diclofenac

sodium)

25 mg and 50 mg enteric coated tablets:

Each

tablet

contains

medicinal

ingredient

diclofenac

sodium

non-medicinal

ingredients: magnesium stearate, microcrystalline

cellulose, povidone, pregelatinized starch, silicon

dioxide, sodium lauryl sulfate and sodium starch

glycolate.

The film coating contains (25mg): D&C Yellow

# 10, hypromellose, iron oxide red, iron oxide

yellow,

maltodextrin,

methacrylic

acid,

IMPORTANT: PLEASE READ

Page

39

43

polyethylene

glycol,

talc,

titanium

dioxide,

triethyl citrate

The film coating contains (50mg): hypromellose,

iron

oxide

black,

iron

oxide

red,

iron

oxide

yellow,

maltodextrin,

methacrylic

acid,

polyethylene

glycol,

talc,

titanium

dioxide,

triethyl citrate

Printing ink contains: black iron oxide, lecithin,

shellac glaze, simethicone

TEVA-DICLOFENAC

(diclofenac

sodium)

75 mg and 100 mg slow release tablets:

Each

tablet

contains

medicinal

ingredient

diclofenac

sodium

non-medicinal

ingredients:

colloidal

silicon

dioxide,

lactose

monohydrate, magnesium stearate and povidone.

The film coating contains: aquacoat ECD-30,

dibutyl

sebacate,

FD&C

Blue

FD&C

#40,

FD&C

Yellow

hypromellose,

polyethylene

glycol,

polysorbate

titanium

dioxide.

What dosage forms it comes in:

TEVA-DICLOFENAC EC (diclofenac sodium) 25

mg: Yellowish, tan coloured, round, bi-convex ,

enteric film coated tablets, printed with black ink

modified N/25 on one side and plain on the reverse.

TEVA-DICLOFENAC EC (diclofenac sodium) 50

mg: Tan coloured, round, bi-convex, enteric film

coated

tablets,

printed

with

black

modified

N/50 on one side and plain on the reverse.

TEVA-DICLOFENAC SR (diclofenac sodium) 75

mg: Light pink triangular standard bi-convex bevel-

edged film coated slow release tablets. Printed with

black ink N on one side and SR /75 on the reverse.

TEVA-DICLOFENAC

(diclofenac

sodium)

100 mg: Pink round bi-convex bevel-edged film

coated slow release tablets. Printed N on one side

and SR/100 on the reverse.

Check

with

your

pharmacist

identifying

markings or colour appear different.

WARNINGS AND

PRECAUTIONS

If

you have, or previously had, any of

the

following conditions, see your health care

provider to discuss treatment options other

than TEVA-DICLOFENAC EC or TEVA-

DICLOFENAC SR:

Heart Attack or Angina

Stroke or Mini-stroke

Loss of Vision

Current Pregnancy (less than 28 weeks)

Congestive Heart Failure

High blood pressure

Diabetes

High levels of fats in your blood

Smoking

It

is

important

to

take

the

lowest

dose

of

TEVA-DICLOFENAC

EC

and

TEVA-

DICLOFENAC

SR

that

relieves

your

pain

and/or

swelling

and

for

the

shortest

time

possible

in

order

to

keep your risk of

side

effects on the heart and blood vessels as small

as possible.

Use

of

NSAIDS,

such

as

TEVA-

DICLOFENAC

EC

and

TEVA-

DICLOFENAC

SR

can

result

in

increased

blood pressure and /or worsening of congestive

heart failure.

Use

of

NSAIDs,

such

as

TEVA-

DICLOFENAC EC and TEVA-DCLOFENAC

SR, may cause stomach and bowel problems

(such as ulceration, perforation, obstruction

and bleeding).

Before taking this medication, tell your health care

provider if you have any of the following:

Disease

heart

blood

vessels

(also

called

cardiovascular

disease,

including

uncontrolled high blood pressure, congestive

heart

failure,

established

ischemic

heart

disease,

peripheral

arterial

disease),

treatment

with

TEVA-DICLOFENAC

TEVA-DICLOFENAC SR in these cases is not

recommended.

Risk factors

for cardiovascular

disease

(see

above)

such

high

blood

pressure,

abnormally

high

levels

(cholesterol,

triglycerides) in your blood, diabetes, or if you

smoke.

Diabetes mellitus or on a low sugar diet

Atherosclerosis

Poor circulation to your extremities

Kidney disease or urine problems

Previous ulcer or bleeding from the stomach

or gut

Previous bleeding in the brain

IMPORTANT: PLEASE READ

Page

40

43

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

sinus

(chronic

sinusitis) or hives

Also, before taking this medication, tell your

health care provider if you are pregnant or 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;

drink

alcoholic

beverages

while

taking this medication because you would

be more likely to develop stomach problems;

Fertility may be decreased. The use of

TEVA-DICLOFENAC

TEVA-

DICLOFENAC

recommended

women trying to get pregnant. In women who

have

difficulty

conceiving,

stopping

TEVA-

DICLOFENAC EC or TEVA-DICLOFENAC

SR should be considered.

If you have cardiovascular disease or risks for

cardiovascular

disease,

your

doctor

will

periodically

re-evaluate

whether

should

continue treatment with TEVA-DICLOFENAC

EC or TEVA-DICLOFENAC SR.

Your doctor will monitor your kidney

function, your liver function and your

blood count to decide if TEVA-

DICLOFENAC EC or TEVA-DICLOFENAC

SR needs to be discontinued or if the dose

needs to be changed.

time

while

taking

TEVA-

DICLOFENAC or TEVA-DICLOFENAC SR you

experience any signs or symptoms of problems

with your heart or blood vessels such as chest

pain, shortness of breath, weakness, or slurring of

speech, contact your doctor immediately.

Long-term use of TEVA-DICLOFENAC EC or

TEVA-DICLOFENAC

SR

might

increase

the

risk of heart attacks or strokes.

TEVA-DICLOFENAC

EC

or

TEVA-

DICLOFENAC SR is NOT recommended

for

use

in

patients

under

16

years of age since

safety

and

effectiveness

have

NOT

been

established.

I INTERACTIONS WITH THIS MEDICATION

TERACTIONS WITH THIS MEDICATION

What

About

Taking

Other

Drugs

At

The

Same Time?

See 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):

Acetaminophen

Acetylsalicylic Acid (ASA) or other NSAIDs

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

indomethacin, ketorolac, meloxicam, naproxen

Alcohol

Antacids

Anti-depressants

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-blockers e.g. metoprolol

Blood thinners (medicine used to prevent blood-

clotting)

e.g. warfarin, ASA, clopidogrel

Corticosteroids

(including

glucocorticoids)

(medicines used to provide relief for inflamed

areas of the body) e.g. prednisone

Cyclosporine

medicine

primarily

used

patients who have received organ transplants)

Digoxin (a medicine used for heart problems)

Diuretics

(medicines

used

increase

amount

urine)

e.g.

furosemide,

hydrochlorothiazide

Lithium

Methotrexate (a medicine used to treat some

kinds of cancer or arthritis)

Oral hypoglycemics (diabetes medications such

as metformin)

Phenytoin (a medicine used to treat seizures).

Probenecid

Quinolone

antibacterials

(medicines

used

against infection)

Rifampin (an antibiotic medicine used to treat

bacterial infections)

Sulfinpyrazone (a medicine used to treat gout)

Tacrolimus

medicine

primarily

used

patients who have received organ transplants)

Trimethoprim (a medicine used to prevent or

treat urinary tract infection)

Voriconazole (a medicine used to treat fungal

IMPORTANT: PLEASE READ

Page

41

43

infections)

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

taking

TEVA-

DICLOFENAC EC or TEVA-DICLOFENAC SR.

Take

only

amount

prescribed

your health care provider. You are more likely to

upset or damage your stomach if you take both

TEVA-DICLOFENAC

TEVA-

DICLOFENAC SR

than

you took

TEVA-DICLOFENAC

TEVA-

DICLOFENAC SR alone.

PROPER USE OF THIS MEDICATION

TEVA-DICLOFENAC EC, TEVA-DICLOFENAC

SR is used for maintenance therapy only.

Usual Dose for patients 16 years of age and

older:

Medical Condition

Starting

Dose

(per

day)

TEVA-DICLOFENAC EC 25 mg enteric-coated

tablets

Rheumatoid

Arthritis

25 mg 3 times a day.

Osteoarthritis

25 mg 3 times a day.

Medical

Conditio

n

Maintenanc

e Dose

Maximu

m Dose

(per day)

TEVA-DICLOFENAC EC 50 mg enteric-coated

tablets

Rheumatoid

Arthritis

50 mg twice

daily

100 mg

Osteoarthriti

s

50 mg twice

daily

100 mg

TEVA-DICLOFENAC SR 75 & 100 mg slow-

release tablets

Rheumatoid

Arthritis

once

daily

100 mg

Osteoarthriti

s

once

daily

100 mg

Take

TEVA-DICLOFENAC

TEVA-

DICLOFENAC SR 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 TEVA-

DICLOFENAC EC or TEVA-DICLOFENAC SR

increase

your

chances

unwanted

sometimes dangerous side effects, especially if you

are elderly and frail or if you have a low body

weight,

have

other

diseases

take

other

medications.

If you will be using TEVA-DICLOFENAC EC or

TEVA-DICLOFENAC SR for more than 7

days, see your health care provider regularly to

discuss whether this medicine is working for you

and if it is causing you any unwanted effects.

Swallow the tablet whole with water, do not chew

or divide the tablet. It is best to take your dose at

the same time each day.

To help reduce the possibility of stomach upset you

should take TEVA-DICLOFENAC EC or TEVA-

DICLOFENAC SR immediately after a meal or

with

food

milk.

Also,

should

remain

standing or sitting upright (i.e. do not lie down) for

about

15-30

minutes

after

taking

medicine.

This helps to prevent irritation that may lead to

trouble

swallowing.

stomach

upset

(indigestion,

nausea,

vomiting,

stomach

pain

diarrhea) occurs and continues, contact your doctor.

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.

Missed dose:

If you forget to take your scheduled dose, you

should not double the next scheduled dose to make

up for the missed dose.

Overdose:

If you think you have taken too much TEVA-

DICLOFENAC EC or TEVA-DICLOFENAC SR,

contact

your

healthcare

professional,

hospital

emergency

department

or

regional

poison

control centre immediately, even if there are no

symptoms.

SIDE EFFECTS AND WHAT TO DO ABOUT

THEM

TEVA-DICLOFENAC

TEVA-

DICLOFENAC SR 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

TEVA-DICLOFENAC

TEVA-

DICLOFENAC

cause

become

drowsy

tired.

careful

about

driving

participating in activities that require you to be

alert. If you become drowsy, dizzy or light-headed

after taking TEVA-DICLOFENAC EC or TEVA-

IMPORTANT: PLEASE READ

Page

42

43

DICLOFENAC

drive

operate

machinery.

TEVA-DICLOFENAC

TEVA-

DICLOFENAC

cause

become

more

sensitive

sunlight.

exposure

sunlight

sunlamps

cause

sunburn,

skin

blisters,

skin

rash,

redness,

itching

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

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

SERIOUS

ALLERGIC

REACTION to this medication.

SERIOUS SIDE EFFECTS AND WHAT TO DO

ABOUT THEM

Symptom

STOP taking

TEVA-

DICLOFENAC

EC or

TEVA-

DICLOFENAC

SR and get

emergency

medical attention

IMMEDIATELY

STOP taking

TEVA-

DICLOFENAC-

EC or

TEVA-

DICLOFENAC

SR and talk to

your physician

or pharmacist

Bloody or black

tarry stools,

vomiting blood

Spontaneous

bleeding or

bruising (signs of

thrombocytopenia

Shortness of

breath, wheezing,

any trouble

breathing or chest

tightness

Skin rash, hives,

swelling or itching

Skin rash with

flacking or peeling

(signs of

dermatitis

exfoliative

SERIOUS SIDE EFFECTS AND WHAT TO DO

ABOUT THEM

Purple skin

patches (signs of

purpura or

Henoch-Schonlein

purpura if caused

by an allergy).

Blurred vision, or

any visual

disturbance

Any change in the

amount or colour

of your

urine (red or

brown)

Any pain or

difficulty

experienced while

urinating

Swelling of the

feet, lower legs;

weight gain

Swelling mainly

of the face, throat,

lips, tongue,

and/or extremities

(signs of

angioedema)

Vomiting or

persistent

indigestion,

nausea,

stomach pain or

diarrhea

Chest pain and

allergic reactions

happening at the

same time (signs

of Kounis

syndrome)

Yellow

discolouration of

the skin or eyes

(signs of liver

failure), with or

without itchy skin

Malaise, fatigue,

loss of appetite or

« flu-like »

symptoms

Headaches, stiff

neck, fever,

nausea, vomiting

(signs of aseptic

meningitis)

IMPORTANT: PLEASE READ

Page

43

43

SERIOUS SIDE EFFECTS AND WHAT TO DO

ABOUT THEM

Mental confusion,

depression

Dizziness,

lightheadedness

Hearing problems

Rectal itching or

bleeding

Right upper

abdominal

discomfort or pain

This is NOT a complete list of side effects. If you

develop any other symptoms while taking TEVA-

DICLOFENAC EC and/or TEVA-DICLOFENAC

SR, see your health care provider.

HOW TO STORE IT

Store between 15°-30°C.

Do NOT keep outdated medicine or medicine no

longer needed.

Any outdated or unused medicine

should be returned to your pharmacist.

Keep this and all medication out of the reach of

children.

REPORTING SUSPECTED SIDE EFFECTS

Reporting Side Effects

You can report any suspected side effects

associated with the use of health products to Health

Canada by:

Visiting the Web page on Adverse Reaction

Reporting (https://www.canada.ca/en/health-

canada/services/drugs-health-

products/medeffectcanada/adverse-reaction-

reporting.html) for information on how to

report online, by mail or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you

need information about how to manage your side

effects. The Canada Vigilance Program does not

provide medical advice.

MORE INFORMATION

want

more

information

about

TEVA-

DICLOFENAC

TEVA-DICLOFENAC

Talk to your healthcare professional

Find

full

Product

Monograph

that

prepared

healthcare

professionals

includes

this

Consumer

Information

visiting

Health

Canada

website

(https://health-products.canada.ca/dpd-

bdpp/index-eng.jsp);

manufacturer’s

website

http://www.tevacanada.com;

calling

1-800-268-4127

ext.

email

druginfo@tevacanada.com.

This leaflet was prepared by:

Teva Canada Limited

30 Novopharm Court

Toronto, Ontario

Canada, M1B 2K9

Last revised: January 23, 2019

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