Nu-Diclo Rapide Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

NU-DICLO RAPIDE (diclofenac potassium) is indicated for the following:

• the short-term (up to one week) treatment of acute, mild to moderately severe pain that may be accompanied by inflammation, in conditions such as: musculoskeletal and/or soft tissue trauma including sprains, post-operative pain following dental extraction, episiotomy, or dysmenorrhea.

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

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

Use of NU-DICLO RAPIDE 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).

NU-DICLO RAPIDE, as a NSAID, does NOT treat clinical disease or prevent its progression.

NU-DICLO RAPIDE, as a NSAID, only relieves symptoms and decreases inflammation for as long as the patient continues to take it.

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

NU-DICLO RAPIDE is contraindicated in:

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

  DICLO RAPIDE has NOT been studied in this patient population, a selective COX-2 inhibitor NSAID studied in such a setting has led to an increased incidence of cardiovascular/thromboembolic events, deep surgical infections and sternal wound complications

• the third trimester of pregnancy, because of risk of premature closure of the ductus arteriosus and prolonged parturition
• women who are breastfeeding, because of the potential for serious adverse reactions in nursing infants
• severe uncontrolled heart failure
• known hypersensitivity to NU-DICLO RAPIDE or to any of the components/excipients

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

  complete or partial syndrome of ASA-intolerance - rhinosinusitis, urticaria/ angioedema, nasal polyps, asthma). Fatal anaphylactoid reactions have occurred in such individuals. Individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse reaction. The potential for cross-reactivity between different NSAIDs must be kept in mind (see WARNINGS AND PRECAUTIONS _—- Hypersensitivity Reactions - Anaphylactoid Reactions).

• active gastric / duodenal / peptic ulcer, active GI bleeding or perforation, gastritis or ulcerative colitis, regional enteritis, recurrent ulceration
• cerebrovascular bleeding or other bleeding disorders
• inflammatory bowel disease
• severe liver impairment or active liver disease
• severe renal impairment (creatinine clearance <30 mL/min or 0.5 mL/sec) or deteriorating renal disease (individuals with lesser degrees of renal impairment are at risk of deterioration of their renal function when prescribed NSAIDs and must be monitored) (see WARNINGS AND PRECAUTIONS - Renal)

• known hyperkalemia (see WARNINGS AND PRECAUTIONS - Renal - Fluid and

  Electrolyte Balance)

• children and adolescents less than 16 years of age

WARNINGS AND PRECAUTIONS

Risk of Cardiovascular (CV) Adverse Events: Ischemic Heart Disease, Cerebrovascular Disease, Congestive Heart Failure (NYHA II-IV) (See WARNINGS AND PRECAUTIONS -

Cardiovascular).

Diclofenac potassium is a non-steroidal anti-inflammatory drug (NSAID). Use of some NSAIDs is associated with an increased incidence of cardiovascular adverse events (such as myocardial infarction, stroke or thrombotic events) which can be fatal. The risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

Caution should be exercised in prescribing diclofenac potassium to any patient with ischemic heart disease (including but NOT limited to acute myocardial infarction, history of myocardial infarction and/or angina), cerebrovascular disease (including but NOT limited to stroke, cerebrovascular accident, transient ischemic attacks and/or amaurosis fugax) and/or congestive heart failure (NYHA II-IV).

Use of NSAIDs, such as diclofenac potassium, can promote sodium retention in a dose-dependent manner, through a renal mechanism, which can result in increased blood pressure and/or exacerbation of congestive heart failure. (See also WARNINGS AND PRECAUTIONS - Renal - Fluid and Electrolyte Balance)

Randomized clinical trials with diclofenac potassium have not been designed to detect differences in cardiovascular events in a chronic setting. Therefore, caution should be exercised when prescribing diclofenac potassium.

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

Use of NSAIDs, such as diclofenac potassium, 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 potassium is NOT recommended for use with other NSAIDs, with the exception of low-dose ASA for cardiovascular prophylaxis, because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions. (See DRUG INTERACTIONS – Drug/Drug Interactions - Acetylsalicylic acid (ASA) or other NSAIDs)

Diclofenac potassium should not be used concomitantly with diclofenac sodium (e.g. Nu-Diclo or Nu-Diclo SR) since both exist in plasma as the same active organic anion.

Carcinogenesis and Mutagenesis

(See TOXICOLOGY)

Cardiovascular

Diclofenac potassium is a non-steroidal anti-inflammatory drug (NSAID). Use of some NSAIDs is associated with an increased incidence of cardiovascular adverse events (such as myocardial infarction, stroke or thrombotic events) which can be fatal. Large population-based observational studies, meta-analyses and systematic reviews suggest an increased risk of myocardial infarction and stroke also in association with the use of diclofenac. 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.

Caution should be exercised in prescribing diclofenac potassium to patients with risk factors for cardiovascular disease, cerebrovascular disease or renal disease, such as any of the following (NOT an exhaustive list):

• Hypertension
• Dyslipidemia / Hyperlipidemia
• Diabetes Mellitus
• Congestive Heart Failure (NYHA I)
• Coronary Artery Disease (Atherosclerosis)
• Peripheral Arterial Disease
• Smoking
• Creatinine Clearance < 60 mL/min or 1 mL/sec

Use of NSAIDs, such as diclofenac potassium, can lead to new hypertension or can worsen pre-existing hypertension, either of which may increase the risk of cardiovascular events as described above. Thus blood pressure should be monitored regularly. Consideration should be given to discontinuing diclofenac potassium should hypertension either develop or worsen with its use.

Use of NSAIDs, such as diclofenac potassium, can induce fluid retention and edema, and may exacerbate congestive heart failure, through a renally-mediated mechanism. (See WARNINGS AND PRECAUTIONS - Renal - Fluid and Electrolyte Balance).

For patients with a high risk of developing an adverse CV event, other management strategies that do NOT include the use of NSAIDs should be considered first. To minimize the potential risk for an adverse CV event, the lowest effective dose should be used for the shortest possible duration.

Endocrine and Metabolism

Corticosteroids: Diclofenac potassium is NOT a substitute for corticosteroids. It does NOT treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids (see DRUG INTERACTIONS - Drug-Drug Interactions -Glucocorticoids).

Gastrointestinal (GI)

Serious GI toxicity (sometimes fatal), such as peptic / duodenal ulceration, inflammation, perforation, obstruction and gastrointestinal bleeding, can occur at any time, with or without warning symptoms, in patients treated with NSAIDs, such as diclofenac potassium. Minor upper GI problems, such as dyspepsia, commonly occur at any time. Health care providers should remain alert for ulceration and bleeding in patients treated with diclofenac potassium, 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 diclofenac potassium and seek emergency medical attention if they experience any such symptoms. The utility of periodic laboratory monitoring has NOT been demonstrated, nor has it been adequately assessed. Most patients who develop a serious upper GI adverse event on NSAID therapy have no symptoms. Upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. Even a short-term therapy has its risks.

Caution should be taken if prescribing diclofenac potassium to patients with a prior history of peptic / duodenal ulcer disease or gastrointestinal bleeding as these individuals have a greater than 10-fold higher risk for developing a GI bleed when taking a NSAID than patients with neither of these risk factors. Other risk factors for GI ulceration and bleeding include the following: Helicobacter pylori infection, increased age, prolonged use of NSAID therapy, excess alcohol intake, smoking, poor general health status or concomitant therapy with any of the following:

• Anti-coagulants (e.g. warfarin)
• Anti-platelet agents (e.g. ASA, clopidogrel)
• Oral corticosteroids (e.g. prednisone)
• Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. citalopram, fluotexine, paroxetine, sertraline)

There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent or reduce the occurrence of gastrointestinal adverse events associated with the use of diclofenac potassium.

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 diclofenac potassium 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 diclofenac potassium 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 diclofenac potassium with warfarin requires close monitoring of the international normalized ratio (INR).

Even with therapeutic INR monitoring, increased bleeding may occur.

Anti-platelet Effects: NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike acetylsalicylic acid (ASA), their effect on platelet function is quantitatively less, or of shorter duration, and is reversible.

Diclofenac potassium and other NSAIDs have no proven efficacy as anti-platelet agents and should NOT be used as a substitute for ASA or other anti-platelet agents for prophylaxis of cardiovascular thromboembolic diseases. Anti-platelet therapies (e.g. ASA) should NOT be discontinued. There is some evidence that use of NSAIDs with ASA can markedly attenuate the cardioprotective effects of ASA (see DRUG INTERACTIONS - Drug-Drug Interactions - Acetylsalicylic Acid (ASA) or other NSAIDs).

Concomitant administration of diclofenac potassium with low dose ASA increases the risk of GI ulceration and associated complications.

Blood dyscrasias: Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of NSAIDs are rare, but could occur with severe consequences.

Anemia is sometimes seen in patients receiving NSAIDs, including diclofenac potassium. 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 diclofenac potassium,

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 diclofenac potassium, borderline elevations of one or more liver enzyme tests (AST, ALT, alkaline phosphatase) may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction, while on therapy with diclofenac potassium. Severe hepatic reactions including jaundice and cases of fatal hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes, have been reported with diclofenac potassium.

Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop (e.g. jaundice), or if systemic manifestations occur (e.g. eosinophilia, associated with rash, etc.), this drug should be discontinued.

If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.

Caution is advised when using diclofenac potassium in patients with hepatic porphyria, since diclofenac potassium may trigger an attack.

Hypersensitivity Reactions

Anaphylactoid reactions: As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to diclofenac potassium. In post-marketing experience, rare cases of anaphylactic/ anaphylactoid reactions and angioedema have been reported in patients receiving diclofenac potassium. Diclofenac potassium should NOT be given to patients with the ASA-triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking ASA or other NSAIDs (see CONTRAINDICATIONS).

* *

ASA-intolerance: Diclofenac potassium should NOT be given to patients with complete or partial syndrome of ASA-intolerance (rhinosinusitis, urticaria/angioedema, nasal polyps, asthma) in whom asthma, anaphylaxis, urticaria/angioedema, rhinitis or other allergic manifestations are precipitated by ASA or other NSAIDs. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse reaction. (See CONTRAINDICATIONS).

Cross Sensitivity: Patients sensitive to 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

Diclofenac potassium, in common with other NSAIDs, may mask signs and symptoms of an underlying infectious disease.

Aseptic Meningitis: Rarely, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissue diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the health care provider must be vigilant to the development of this complication.

Neurologic

Some patients may experience drowsiness, dizziness, blurred vision, vertigo, tinnitus, hearing loss, insomnia or depression with the use of NSAIDs, such as diclofenac potassium. If patients experience such adverse reaction(s) they should exercise caution in carrying out activities that require alertness.

Ophthalmologic

Blurred and/or diminished vision has been reported with the use of NSAIDs. If such symptoms develop, Diclofenac potassium should be discontinued and an ophthalmologic examination performed. Ophthalmologic examination should be carried out at periodic intervals in any patient receiving diclofenac potassium for an extended period of time.

Sun exposure in patients using diclofenac potassium 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 and glomerular filtration rate (GFR). In these patients, administration of a NSAID may cause a reduction in prostaglandin synthesis leading to impaired renal function. Patients at greatest risk of this reaction are those with pre-existing renal insufficiency (GFR< 60 mL/min or 1 mL/s), dehydrated patients, patients on salt restricted diets, those with congestive heart failure, cirrhosis, liver dysfunction, taking angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, cyclosporin, diuretics, and those who are elderly. Serious or life-threatening renal failure has been reported in patients with normal or impaired renal function after short term therapy with NSAIDs. Even patients at risk who demonstrate the ability to tolerate a NSAID under stable conditions may decompensate during periods of added stress (e.g. dehydration due to gastroenteritis). Discontinuation of NSAIDs is usually followed by recovery to the pre-treatment state.

Caution should be used when initiating treatment with NSAIDs, such as diclofenac potassium, 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)

Advanced Renal Disease: (See CONTRAINDICATIONS)

Fluid and Electrolyte Balance: Use of NSAIDs, such as diclofenac potassium, can promote sodium retention in a dose-dependant 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 diclofenac potassium in patients with a history of congestive heart failure, compromised cardiac function, hypertension, increased age or other conditions predisposing to fluid retention (see WARNINGS AND PRECAUTIONS - Cardiovascular).

Use of NSAIDs, such as diclofenac potassium, can increase the risk of hyperkalemia, especially in patients with diabetes mellitus, renal failure, increased age, or those receiving concomitant therapy with adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists, cyclosporin, or some diuretics. Electrolytes should be monitored periodically (see CONTRAINDICATIONS).

Respiratory

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

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 diclofenac potassium, 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 diclofenac potassium should be considered.

Skin

In rare cases, serious skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis and erythema multiforme have been associated with the use of some NSAIDs. Because the rate of these reactions is low, they have usually been noted during post-marketing surveillance in patients taking other medications also associated with the potential development of these serious skin reactions. Thus, causality is NOT clear. These reactions are potentially life threatening but may be reversible if the causative agent is discontinued and appropriate treatment instituted. Patients should be advised that if they experience a skin rash they should discontinue their NSAID and contact their physician for assessment and advice, including which additional therapies to discontinue.

Use of diclofenac potassium 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: Diclofenac potassium is CONTRAINDICATED for use during the third trimester of pregnancy because of risk of premature closure of the ductus arteriosus and the potential to prolong parturition (see TOXICOLOGY).

Caution should be exercised in prescribing diclofenac potassium during the first and second trimesters of pregnancy (see TOXICOLOGY).

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or the embryofoetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy.

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 potassium 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 most 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, the dosage should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision.

Monitoring and Laboratory Tests

Cardiovascular (Hypertension): Blood pressure should be monitored regularly during therapy with diclofenac potassium.

Hematologic: Patients on long-term treatment with diclofenac potassium 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.

Hepatic: Hepatic function (e.g.serum transaminases, bilirubine) should be monitored regularly during therapy with diclofenac potassium.

Ophthalmologic: Patients on long-term treatment with diclofenac potassium 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, cyclosporin, diuretics, and the elderly should have their renal function monitored (e.g. urine output, serum creatinine, creatinine clearance and serum urea) during therapy with diclofenac potassium.

Electrolytes, including serum potassium, should be monitored periodically, especially in patients with diabetes mellitus, renal failure, increased age, or those receiving concomitant therapy with adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists, cyclosporin, or some diuretics.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Although not all adverse drug reactions have been reported with diclofenac potassium, the types of adverse drug reactions are expected to be similar to those of diclofenac potassium and

diclofenac sodium 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 and post-marketing experience with diclofenac potassium and diclofenac sodium.

Frequency estimate:

Very common: ≥10%

Common: ≥1% and < 10%

Uncommon: ≥0.01% and < 1%

Very Rare <0.01%, including isolated reports.

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

Table 2: Less Common Adverse Drug Reactions (<1%)

Post-Market Adverse Drug Reactions

Hepatic: hepatic necrosis, hepatic failure

DRUG INTERACTIONS

Drug-Drug Interactions

Table 3: Established Potential Drug-Drug Interactions

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 diclofenac potassium should refrain from driving or using machines.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Geriatrics: In the elderly, frail and debilitated, the dosage should be reduced to the lowest level providing control of symptoms, and adjusted when necessary (See WARNINGS AND PRECAUTIONS - Special Populations - Geriatrics)

Renal Insufficiency: Lower doses of NU-DICLO RAPIDE should be considered in patients with impaired renal function (see WARNINGS AND PRECAUTIONS - Renal).

Hepatic Impairment: Lower doses of NU-DICLO RAPIDE 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 and the lowest effective dose given for the shortest possible duration.

NU-DICLO RAPIDE (diclofenac potassium) 50 mg film coated tablets:

NU-DICLO RAPIDE is indicated for short-term (up to one week) treatment only.

NU-DICLO RAPIDE should be taken with food.

The recommended daily dose for NU-DICLO RAPIDE is one 50 mg tablet, every 6-8 hours as required for a total daily maximum amount of 150 mg. For primary dysmenorrhea, treatment may be initiated with a loading dose of 100 mg, followed by 50 mg every six to eight hours, when required. When a loading dose is necessary, the first day maximum total amount is 200 mg.

Patients should be maintained on the lowest effective dose.

Missed Dose

Patients who miss one or more doses of NU-DICLO RAPIDE (diclofenac potassium) should not increase the dose of NU-DICLO RAPIDE 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 Immediately.

Symptoms

There is no typical clinical picture resulting from diclofenac overdosage. Overdosage can cause symptoms such as vomiting, gastrointestinal haemorrhage, diarrhoea, dizziness, tinnitus or convulsions. In the event of significant poisoning, acute renal failure and liver damage are possible.

Therapeutic measures

Management of acute poisoning with NSAIDs, including diclofenac potassium, 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 diclofenac potassium, due to the high protein binding and extensive metabolism. Activated charcoal may be considered 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, the active substance of NU-DICLO RAPIDE (diclofenac potassium), is a non-steroidal anti-inflammatory (NSAID) drug with analgesic properties. Diclofenac inhibits prostaglandin synthesis by interfering with the action of prostaglandin synthetase. This inhibitory effect may partially explain its actions. It is considered to be a peripherally acting analgesic.

Diclofenac potassium tablets have a rapid onset of action, making them particularly suitable for the treatment of acute painful inflammatory conditions.

Pharmacodynamics

The effects of diclofenac potassium 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, diclofenac can be detected in the plasma within 10 minutes of oral administration of diclofenac potassium tablets. Absorption is virtually complete. The area under the plasma curve (AUC) is dose proportional. A 50 mg tablet produces a mean peak plasma concentration of 3.8 µmol/L, 20-60 min post dose. The amount of diclofenac absorbed from diclofenac potassium tablet is the same as that obtained from an equivalent diclofenac sodium enteric-coated tablet dose. Since diclofenac undergoes extensive first pass metabolism, only half of an orally administered dose is systemically available. The rate and extent of absorption of diclofenac are insignificantly affected (slightly delayed) when diclofenac potassium tablets are taken with food. When given in a regimen of 50 mg TID for 8 days, diclofenac potassium did not produce plasma accumulation of diclofenac.

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 T_max occurs 2 to 4 hours after plasma Tmax. Synovial fluid concentrations exceed plasma levels 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.

Metabolism: The potassium salt of diclofenac in diclofenac potassium tablet yields the same active organic anion produced by the sodium salt found in diclofenac sodium enteric coated tablets. Therefore, the fate of the systemically available anion is the same for both formulations.

Diclofenac undergoes single and multiple hydroxylation and 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 the bile in the feces. 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 to occur, caution is advised while administering diclofenac potassium to patients with impaired kidney function (ie GFR < 60 mL/min or 1 mL/sec) (see WARNINGS AND PRECAUTIONS _- Renal). Diclofenac potassium is 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 100 mg oral dose of diclofenac sodium, the kinetics and metabolism of diclofenac were similar to patients without liver disease.

Pediatrics: Diclofenac potassium is contraindicated in children and adolescents less than 16 years of age (see CONTRAINDICATIONS).

Geriatrics: No relevant age-dependant differences in the absorption, metabolism, or excretion of diclofenac have been observed.

STORAGE AND STABILITY

Protect from heat (store at 15 to 30°C) and humidity.

DOSAGE FORMS, COMPOSITION AND PACKAGING

NU-DICLO RAPIDE (diclofenac potassium) 50 mg Tablets: Each reddish-brown, round, biconvex, coated tablet, engraved “50” on one side and plain on the other side, contains 50 mg of diclofenac potassium. Available in bottles of 100 and 500 tablets.

NU-DICLO RAPIDE (diclofenac potassium) 50 mg tablets also contain: tribasic calcium phosphate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and red ferric oxide.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance:

Proper name: Diclofenac potassium

Chemical Name: 1) 2-((2,6-Dichlorophenyl)amino)-benzeneacetic acid monopotassium salt.

1. 2) (o-(2,6-Dichloroanilino)phenyl)acetic acid potassium salt.
2. 3) Potassium (o-((2,6-dichlorophenyl)amino)phenyl)acetate.

Structural Formula:

Molecular Formula: C₁₄H₁₀CI₂NO₂ • K

Molecular Weight: 334.25

Description: Diclofenac potassium is a white to off-white crystalline powder, free of foreign particulate matter. It has a pH between 7.0 and 8.5 in a 1 to 100 water solution. As determined by DSC thermal analysis, diclofenac potassium is thermally stable, and displays an endotherm and decomposes without melting at an onset temperature of 314°C. It is also freely soluble in methanol, soluble in ethanol and water, sparingly soluble in acetic acid, slightly soluble in acetone, and practically insoluble in chloroform, ether and aqueous acidic solutions.

NH

Cl Cl

CO₂K

CLINICAL TRIALS

A comparative bioavailability study was performed using healthy human volunteers. The rate and extent of absorption of diclofenac was measured and compared following oral administration of a 1 x 50 mg dose of NU-DICLO RAPIDE 50 mg film coated tablets or Voltaren Rapide® 50 mg sugar coated tablets, under fed conditions. The results from measured data are summarized as follows:

Randomized clinical trials with diclofenac potassium 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.

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.

Although the rate of absorption of diclofenac from sugar coated tablets containing the potassium salt is faster than that from the enteric coated tablet containing the sodium salt, the extent of absorption is comparable. The extent of absorption of diclofenac potassium whether given with a phosphate buffer or a fat-protein breakfast is equivalent. However, the rate of absorption in the presence of food is slightly reduced, resulting in lower maximum concentrations in plasma.

Several controlled, double blind clinical studies have compared the safety and efficacy of diclofenac potassium to that of ASA or naproxen for the relief of pain following dental surgery, episiotomy and dysmenorrhea.

The efficacy of diclofenac potassium and ASA were compared following impacted molar extraction. Dosages of 50 mg diclofenac potassium and 650 mg ASA were statistically significantly more effective than was placebo in relieving pain following this dental procedure. In one study (04) a 50 mg dose of diclofenac potassium was also statistically superior to ASA 650 mg for “total pain relief at 8 hours”, “sum of pain intensity difference at 8 hours” and time to remedication.

Table 4: Summary of clinical studies in moderate or severe pain following removal of one or more impacted third molar teeth

The safety and efficacy of diclofenac potassium for pain relief following episiotomy was

demonstrated in a trial using 50 mg diclofenac potassium and 650 mg of ASA.

Female patients with a history of regular menses accompanied by dysmenorrhea were enrolled into two double blind, randomized clinical studies in which they received a three day t.i.d. treatment with either diclofenac potassium 50 mg (100 mg loading dose) or naproxen 275 mg (loading dose of 550 mg). Both treatments were efficacious for the treatment of moderate to severe dysmenorrhea.

DETAILED PHARMACOLOGY

Diclofenac potassium contains the same active principle, diclofenac, as diclofenac sodium; therefore, the two salts have similar pharmacological profiles. Diclofenac is a phenyl-acetic acid derivative possessing anti-inflammatory, analgesic activities as shown in various pharmacological models.

Anti-inflammatory Activity in Rats

The anti-inflammatory potency of diclofenac was assessed by testing inhibition of paw edema (carrageenin solution and kaolin suspension) and reduction of adjuvant arthritis (Freund’s adjuvant).

*determined by graphic interpolation from 3 or more doses.

Analgesic Activity in Mice and Rats

The antinociceptive effect of diclofenac was assessed by established tests with results as tabulated.

Inhibition of Prostaglandin

A close correlation exists between certain febrile reactions and increased prostaglandin levels in the brain. Diclofenac (0.5 mg/mL reduces prostaglandin E₂ formation. The inhibition of prostaglandin synthesis in-vitro (IC₅₀ mM/L) is 1.6.

Platelet Adhesiveness

At 15 mg/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, a 10-day treatment with oral doses of 5 mg/kg diclofenac sodium and diclofenac potassium caused a cumulative blood loss of 360 µL and 410 µL, respectively, as measured by the administration of ⁵¹Cr-labelled erythrocytes.

TOXICOLOGY

Since the same active principle, diclofenac, is absorbed from the potassium and sodium salts, toxicological findings with diclofenac sodium are representative of systemic toxicities with diclofenac potassium:

Acute Toxicity

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

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 food 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.

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 erythrocyte sedimentation rate 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 total oral doses of 5 or 10 mg/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.

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 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.

REFERENCES

1. 1. Andrade D, Gutierrez-Mendez G, Garcia-Miranda R. Clinical response of ankle sprains to diclofenac potassium and naproxen sodium. Invest Med Int 1984;11(2):30-134.
2. 2. Bahamonde LA, Saavedra H. Comparison of the analgesic and anti-inflammatory effects of diclofenac potassium versus piroxicam versus placebo in ankle sprain patients. J Intl Med Res 1990;18:104-111.
3. 3. Bakshi R, Jacobs LD, Lehnert S, Picha B, Reuther J. A double-blind placebo-controlled trial comparing the analgesic efficacy of two formulations of diclofenac in postoperative dental pain. Curr Ther Res 1992;52(3):435-442.
4. 4. Moran M. An observer-blind comparison of diclofenac potassium, piroxicam and placebo in the treatment of ankle sprains. Curr Med Res Opin 1990;12:268-274.
5. 5.

   Villasenor FJM. Treatment of primary dysmenorrhoea with diclofenac potassium. Invest

   Med Int 1984;11(1):49-52.

6. 6.

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

   DD-33; August 21, 1985.

7. 7.

   Health Canada GUIDANCE DOCUMENT: Basic Product Monograph Information for

   Nonsteroidal; Anti-Inflammatory Drugs (NSAIDs). Effective date: November 23, 2006

8. 8.

   Product Monograph - ^PrVoltaren Rapide* (diclofenac potassium). Novartis

   Pharmaceutical Canada Inc., Date of Revision: September 8, 2009, Control Number: 125854.