APO-DICLO (diclofenac sodium) and APO-DICLO SR (diclofenac sodium) are indicated for the following:

• the symptomatic treatment of rheumatoid arthritis and osteoarthritis,  including degenerative  joint disease of the hip.

 

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 Gl adverse events, other management strategies that do NOT include the  use of NSAIDs  should be  considered first. (See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS)

Use of APO-DICLO or APO-DICLO 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)

 

APO-DICLO and APO-DICLO SR, as NSAIDs, do NOT treat clinical disease or prevent its progression.

APO-DICLO and APO-DICLO SR, as NSAIDs, only relieve symptoms and decrease inflammation for as long as the patients 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.

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. (See WARNINGS AND PRECAUTIONS _special Populations Geriatrics)

 

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

 

Hepatic Impairment: Lower doses of APO-DICLO or APO-DICLO SR should be considered in patients with impaired hepatic function. (see WARNINGS AND PRECAUTIONS _ Hepatic/Biliary/Pancreatic)

 

Recommended Dose and Dose Adjustment

APO-DICLO and APO-DICLO SR are to be used for maintenance therapy only.

As a general recommendation, the dose should be individually adjusted and the lowest effective dose given for the shortest possible duration.

 

APO-DICLO Tablets 25 mg and 50 mg (enteric-coated)

Rheumatoid arthritis and osteoarthritis patients may use APO-DICLO (diclofenac sodium) enteric-coated tablets if:

• They were previously initiated at the lowest dose of 75 mg (enteric-coated) per day in 3 divided doses and required up-titration because they did not respond to that dose.
• The maximum recommended daily dose is 100 mg.
• For patients experiencing an inflammatory flare, who do not achieve control of symptoms with 100 mg of diclofenac, the dosage may be increased to a maximum of 150 mg per day in divided doses (50 mg TID), for the shortest possible duration and under close monitoring (See WARNINGS and PRECAUTIONS- Cardiovascular).
• In elderly patients, and patients with renal insufficiency, hepatic impairment or with a cardiovascular risk, the maximum daily dose should not exceed 100 mg of diclofenac (see Dosing Considerations).
• APO-DICLO should be taken with food and the tablets should be swallowed whole.

 

APO-DICLO 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 APO-DICLO 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 APO-DICLO SR 100 mg, administered morning or evening.
• The maximum recommended daily dose is 100 mg.
• For patients experiencing an inflammatory flare, who do not achieve control of symptoms with 100 mg of diclofenac, the dosage may be increased to a maximum of 150 mg per day in divided doses (75 mg administered morning and evening), for the shortest possible duration and under close monitoring (See WARNINGS and PRECAUTIONS- Cardiovascular).
• In elderly patients, and patients with renal insufficiency, hepatic impairment or with a cardiovascular risk, the maximum daily dose should not exceed 100 mg of diclofenac (see Dosing Considerations).
• APO-DICLO SR tablets should be swallowed whole with liquid, preferably at mealtime.

 

Missed Dose

Patients who miss one or more doses of APO-DICLO (diclofenac sodium) 25 and 50 mg tablets or APO-DICLO SR 75 and 100 mg tablets should not increase the dose of APO-DICLO (diclofenac sodium) or APO-DICLO SR to compensate for the missed dose or doses, but should continue with their therapy as soon as possible.

Diclofenac is contraindicated in following conditions: a. Ischemic heart disease b. Peripheral arterial disease c. Cerebrovascular disease d. Congestive heart failure (New York Heart Association [NYHA] classification II- IV) • the peri-operative setting of coronary artery bypass graft surgery (CABG). Although APO- DICLO and APO-DICLO SR 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 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 APO-DICLO or APO-DICLO 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 be kept in mind (see WARNINGS AND PRECAUTIONS _Hypersensitivity Reactions - Anaphylactoid Reactions). • active gastric I duodenal I peptic ulcer, active Gl bleeding or perforation, regional ulcer, gastritis or ulcerative colitis • 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

Diclofenac treatment should only be initiated after careful consideration for patients with significant risk factors for cardiovascular events (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking) . As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically .

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 sodium (enteric coated tablets and slow release tablets) are 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 sodium should not be used concomitantly with diclofenac potassium (such as Apo-Diclo Rapide) since both exist in plasma as the same active organic ion.

 

Carcinogenesis and Mutagenesis

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.

 

Cardiovascular

Diclofenac sodium (enteric coated tablets and slow release tablets) are 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 sodium (enteric coated tablets and slow release tablets) 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 I Hyperlipidemia
• Diabetes Mellitus
• Congestive Heart Failure (NYHA I)
• Coronary Artery Disease (Atherosclerosis)
• Peripheral Arterial Disease
• Smoking
• Creatinine Clearance< 60 mL/min or 1 mUsec

Use of NSAIDs, such as diclofenac sodium (enteric coated tablets and slow release tablets), 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 sodium (enteric coated tablets and slow release tablets) should hypertension either develop or worsen with its use.

 

Use of NSAIDs, such as diclofenac sodium (enteric coated tablets and slow release tablets), 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 sodium (enteric coated tablets and slow release tablets) are NOT a substitute for corticosteroids. They do 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 Gl 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 sodium (enteric coated or slow release tablets). Minor upper Gl problems, such as dyspepsia, commonly occur at any time. Health care providers should remain alert for ulceration and bleeding in patients treated with diclofenac sodium (enteric coated tablets or slow release tablets), even in the absence of previous Gl tract symptoms. Most spontaneous reports of fatal Gl 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 Gl 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 Gl toxicity and instructed to discontinue using diclofenac sodium (enteric coated tablets or slow release tablets) 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 Gl adverse event on NSAID therapy have no symptoms. Upper Gl 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 Gl event at some time during the course of therapy. Even a short-term therapy has its risks.

 

Caution should be taken if prescribing diclofenac sodium (enteric coated tablets or slow release tablets) to patients with a prior history of peptic I duodenal ulcer disease or gastrointestinal bleeding as these individuals have a greater than 10-fold higher risk for developing a Gl bleed when taking a NSAID than patients with neither of these risk factors. Other risk factors for Gl ulceration and bleeding include the following: He/icobacter 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 sodium slow release tablet or the enteric- coated formulation of diclofenac sodium. Concurrent administration of histamine H2-receptor antagonists and/or antacids with the enteric-coated version of diclofenac sodium might results 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 diclofenac sodium (enteric coated tablets or slow release tablets) 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 sodium (enteric coated tablets or slow release tablets) 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 sodium (enteric coated tablets or slow release tablets) 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 sodium (enteric coated tablets and slow release tablets) 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 sodium (enteric coated tablets or slow release tablets) with low dose ASA increases the risk of Gl 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 slow release tablets). This may be due to fluid retention, Gl blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including diclofenac sodium (enteric coated tablets and slow release tablets), 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 sodium (enteric coated tablets and slow release tablets), 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 sodium (enteric coated tablets or slow release tablets). 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 sodium (enteric coated tablets and slow release tablets).

 

Although such reactions are rare, if abnormal liver function 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 sodium (enteric coated tablets or slow release tablets) in patients with hepatic porphyria, since diclofenac sodium (enteric coated tablets or slow release tablets) 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 sodium (enteric coated tablets or slow release tablets). In post-marketing experience, rare cases of anaphylactic/ anaphylactoid reactions and angioedema have been reported in patients receiving diclofenac sodium (enteric coated tablets or slow release tablets). Diclofenac sodium (enteric coated tablets or slow release tablets) 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 CONTRAINDICATION).

 

ASA-intolerance

Diclofenac sodium (enteric coated tablets or slow release tablets) 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 sodium (enteric coated tablets and slow release tablets), 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 v1s1on, vertigo, insomnia, depression, tinnitus or hearing loss with the use of NSAIDs, such as diclofenac sodium (enteric coated tablets and slow release tablets). 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 sodium (enteric coated tablets or slow release tablets) should be discontinued and an ophthalmologic examination performed. Ophthalmologic examination should be carried out at periodic intervals in any patient receiving diclofenac sodium (enteric

 

coated tablets or slow release tablets) for an extended period of time.

Sun exposure in patients using diclofenac sodium (enteric coated tablets or slow release tablets) 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 PHARMACOLOGICAL PROPERTIES)

 

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-11 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 sodium (enteric coated tablets or slow release tablets), 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 sodium (enteric coated tablets or slow release tablets), 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 sodium (enteric coated tablets or slow release tablets) 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 sodium (enteric coated tablets or slow release tablets), 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-11 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 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 I 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.

 

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 sodium (enteric coated tablets or slow release tablets) 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 sodium (enteric coated tablets or slow release tablets) are 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 sodium (enteric coated tablets and slow release tablets) 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 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 Gl events are in this population. Older patients are also at risk of lower esophageal injury including ulceration and bleeding.

 

For such patients, consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision.

 

Monitoring and Laboratory Tests

Cardiovascular (Hypertension): Blood pressure should be monitored regularly during therapy with diclofenac sodium (enteric coated tablets or slow release tablets).

 

Hematologic: Patients on long-term treatment with diclofenac sodium (enteric coated tablets or slow release tablets) 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 sodium (enteric coated tablets or slow release tablets).

 

Ophthalmologic: Patients on long-term treatment with diclofenac sodium (enteric coated tablets or slow release tablets) 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-11 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 sodium (enteric coated tablets or slow release tablets).

 

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-11 receptor antagonists, cyclosporin, or some diuretics.

Drug-Drug Interactions

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	The use of diclofenac sodium (enteric coated tablets or slow release tablets) in addition to any other NSAID, including over the counter ones (such as ASA and ibuprofen) for analgesic and/or anti- inflammatory effects is NOT recommended because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions.   The exception is the use of low dose ASA for cardiovascular protection when another NSAID is being used for its analgesic/anti- inflammatory effect, keeping in mind that combination NSAID therapy is associated with additive adverse reactions.   Some NSAIDs (e.g. ibuprofen) may interfere with the anti-platelet effects of low dose ASA, possible by competing with ASA for access to the active site of cyclooxygenase-1.   Diclofenac sodium should not be used concomitantly with diclofenac potassium (such as Apo-Diclo Rapide) since both exist in plasma as the same active organic ion.   Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the 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-11 antagonists, or diuretics with NSAIDs might have an increased risk for acute renal failure and hyperkalemia. Blood pressure and renal function (including electrolytes) should be monitored more closely in this situation, as occasionally there can be a substantial increase in blood pressure.(see WARNINGS AND PRECAUTIONS -Renal)   Therefore the combination should be administered with caution and patients, especially the elderly (see WARNINGS AND PRECAUTIONS -Monitoring and Laboratorl 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 diclofenac sodium (enteric coated tablets and slow release tablets) (see WARNINGS AND PRECAUTIONS _Hematologic _ Anti-platelet Effects).
Cyclosporin or Tacrolimus	Nephrotoxicity of cyclosporin and 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 cyclosporin or tacrolimus.
Digoxin	Diclofenac may increase the plasma concentration of 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 be associated with increased serum potassium, thus making it necessary to monitor levels. (see WARNINGS AND PRECAUTIONS Monitoring and Laboratorl Tests _Renal)
Glucocorticoids	Some studies have shown that concomitant use of NSAIDS and oral glucocorticoids increases the risk of Gl 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 or starting a NSAID, as increased lithium concentrations can occur in patients taking lithium. Dosage adjustment of lithium may be required.
Methotrexate	Caution should be exercised when NSAIDs, including diclofenac sodium (enteric coated tablets and slow release tablets), are administered less than 24 hours before or after treatment with methotrexate. Elevated blood concentrations of methotrexate may occur, increasing toxicity.

Oral Hypoglycemics	Pharmacodynamic studies have shown no potentiation of 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. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.
Probenecid	May decrease the excretion and 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 of NSAIOS, including diclofenac sodium (enteric coated tablets and slow release tablets), and SSRis may increase the risk of gastrointestinal ulceration and bleeding. (see WARNINGS AND PRECAUTIONS- Gastrointestinal (GI))

 

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.

The use of diclofenac sodium (enteric coated tablets or slow release tablets), 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 sodium (enteric coated tablets or slow release tablets) should be considered. (see TOXICOLOGY).

Patients experiencing visual disturbances, dizziness, vertigo, somnolence or other central nervous system disturbances while taking diclofenac sodium (enteric coated tablets or slow release tablets) should refrain from driving or using machines.

 Adverse Drug Reaction Overview

Although not all adverse drug reactions have been reported with diclofenac sodium (enteric coated tablets or slow release tablets), 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 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%)

Gastrointestinal disorders	Very common	nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence, anorexia
Nervous System	Common	dizziness, headache, vertigo
Hepatic	Common	elevations (≥ 3 times the upper normal limit) of serum aminotransferase enzymes (SGOT or AST, SGPT or ALT).
Skin and subcutaneous disorders	Common	rash, pruritus

 

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

Gastrointestinal disorders	Uncommon	gastritis, gastrointestinal hemorrhage, hemorrhagic diarrhea, melena, hematemesis gastric and 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), diaphragm-like intestinal strictures, hyperacidity, stomatitis, glossitis, coated tongue, esophageal lesions, constipation, pancreatitis
Nervous System	Uncommon	drowsiness, malaise, impaired concentration, tiredness

Nervous System	Very rare	sensory disturbances including paresthesia, memory disturbance, convulsions, anxiety, tremor, aseptic meningitis, cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage)
Special senses	Very rare	vision disturbances (blurred vision, diplopia), impaired hearing, tinnitus, taste alteration disorders
Cardiac disorders	Uncommon	palpitation, angina, arrhythmias
	Very rare	exacerbation of cardiac failure, hypertension, myocardial infarction
Skin and subcutaneous disorders	Uncommon	urticaria
	Very rare	bullous eruption, erythema, eczema, erythema multiforme, Stevens-Johnson Syndrome, Lyell Syndrome (toxic epidermal necrolysis), erythroderma (exfoliative dermatitis), loss of hair, photosensitivity reactions, purpura, allergic purpura
Renal and urinary disorders	Uncommon	edema (facial, general, peripheral)
	Very rare	acute renal failure, nephrotic syndrome, urinary abnormalities (e.g., hematuria and proteinuria), interstitial 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, jaundice
	Very rare	fulminant hepatitis
Immune system disorders	Uncommon	hypersensitivity anaphylactic I anaphylactoid systemic reactions (including hypotension and shock)
	Very rare	angioneurotic edema, (including face edema)
Psychiatric disorders	Very rare	disorientation, depression, insomnia, nightmare, irritability, psychotic disorder
Respiratory disorders	Uncommon	asthma
	Very rare	pneumonitis

Post-Market Adverse Drug Reactions

Hepatic: hepatic necrosis, hepatic failure

 

To report any side effect(s)

 

Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC) Fax: +966-11-205-7662 Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. Toll-free: 8002490000 E-mail: npc.drug@sfda.gov.sa Website: www.sfda.gov.sa/npc

 

Other GCC States:

Please contact the relevant competent authority.

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 sodium (enteric coated tablets and slow release tablets), 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 sodium (enteric coated tablets and slow release tablets), 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.

The effects of diclofenac sodium (enteric coated tablets or slow release tablets) 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.

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 25 and 50 mg tablets. Absorption occurs more rapidly when the drug is administered on an empty stomach <Tmax 2.5 hours), than with meals (Tmax 6 hours). The bioavailability remains the same under both conditions. The mean peak plasma concentration of 1.5 ug/mL (5 umol/L) is attained, on average, 2 hours after ingestion of one 50 mg enteric-coated tablet.

 

Following    administration       of slow-release      (SR) diclofenac      sodium,    C max,   is reached      at 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 slow-release (SR) 100 mg tablets, or 16 hours after diclofenac sodium slow-release (SR) 75 mg tablets (single dose). Trough levels are approximately 22-25 ng/ml(70-80 nmol/L) during treatment with diclofenac sodium slow-release (SR) 100 mg tablets once daily or diclofenac sodium slow-release (SR) 75 mg tablets twice daily. In pharmacokinetic studies no accumulation of diclofenac sodium was found following repeated once daily administration of diclofenac sodium slow-release (SR) 100 mg tablets or repeated twice daily administration of diclofenac sodium slow-release (SR) 75 mg 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 Tmax 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: 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 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 to occur, caution is advised while administering diclofenac sodium (enteric coated tablets or slow release tablets) to patients with impaired kidney function (i.e. GFR < 60 ml/min or 1 ml/sec) (see WARNINGS AND PRECAUTIONS. Renal . Diclofenac sodium (enteric coated tablets and slow release tablets) 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: Diclofenac sodium (enteric coated tablets and slow release tablets) 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 diclofenac sodium (enteric coated tablets or slow release tablets) does not appear to differ significantly from those of younger subjects.

Acute Toxicity

Species	Route	LD50 (mg/kg)	95% Confidence Limits (mg/kg)
Mouse	P.O.	389	197-  595
	I.V.	133	126- 140
Rat	P.O.	173	133-213
	I.V.	106	80-132
Guinea-pig	P.O. I.V.	1110 127	950-1270 123- 132
Rabbit	P.O.	194	151-259

The symptoms included bradycardia and convulsions.

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

 

Long-Term Toxicity Studies

Species	Period	Daily Dose mg/kg/day  P.O.
		No signs  of intoxication	Reversible signs of toxicity, mainly  Gl Tract	Minimum lethal dose
Rat	3 months 6 months 98 weeks	2 1 0.25	- 2 -	6 4 1
Dog	3 months	-	0.5	2
Rhesus  Monkey	6 months	-	5-15	75
Baboon	12months	-	5	10

 

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.

 

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. UIceration 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.

 

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.

Name of the excipients(s) for E.C. 25 & 50 mg	Name of the excipients(s) for  S.R. 100 mg
dextrates	dextrates
methylcellulose	microcrystalline cellulose
stearic acid	hydroxyethyl cellulose
magnesium stearate	magnesium stearate
colloidal silicon dioxide	hydroxypropyl methylcellulose
hydroxypropyl methylcellulose	polyethylene glycol
polyethylene glycol	titanium dioxide
titanium dioxide	red ferric oxide
yellow ferric oxide
FD & C yellow #6
25 mg only (D&C yellow #10)
polyvinylacetate phthalate
triethyl citrate
methanol

This medicinal product must not be mixed with other medicinal products.

36 months for 25 & 50 mg and 24 months for 100 mg.

Store below 25°C & protect from high humidity.

Primary packaging: Blister

Film PVC/PVdc Clear 10 MIL 250/60 205 mm

Foil Silver Plain 205 mm 20µm

 

Secondary packaging: Carton

No special requirements.