Voltaren (Diclofenac Sodium)

VOLTAREN®

Novartis Pharmaceuticals

Diclofenac Sodium

Anti-inflammatory – Analgesic

Action And Clinical Pharmacology: Diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. The mode of action is not fully known but it does not act through the pituitary-adrenal axis. Diclofenac inhibits prostaglandin synthesis by interfering with the action of prostaglandin synthetase. This inhibitory effect may partially explain its actions.

From a clinical efficacy standpoint, diclofenac sodium 75 mg has activity similar to 3.6 g of ASA.

Diclofenac sodium is similar in activity to equivalent dosages of indomethacin (75 to 150 mg daily), and causes less CNS side effects at these doses.

Although diclofenac sodium does not alter the course of the underlying disease, it has been found to relieve pain, reduce fever, swelling and tenderness, and increase mobility in patients with rheumatic disorders of the types listed.

Pharmacokinetics: Absorption: In humans, orally-administered diclofenac sodium is rapidly and almost completely absorbed and distributed to blood, liver, and kidneys. The plasma concentrations show a linear relationship to the amount of drug administered. No accumulation occurs provided the recommended dosage intervals are observed.

Enteric coating may delay the onset of absorption from 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 g/mL (5 mol/L) is attained, on average, 2 hours after ingestion of one 50 mg enteric-coated tablet.

Following administration of slow-release (SR) diclofenac sodium, Cmax 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 100 mg, or 16 hours after diclofenac sodium slow release 75 mg (single dose). Trough levels are approximately 22 to 25 ng/mL (70 to 80 nmol/L) during treatment with diclofenac sodium slow release 100 mg once daily or diclofenac sodium slow release 75 mg twice daily. In pharmacokinetic studies no accumulation of diclofenac sodium was found following repeated once daily administration of diclofenac sodium slow release 100 mg tablets or repeated twice daily administration of diclofenac sodium slow release 75 mg tablets.

Suppositories have a more rapid onset, but slower rate of absorption than oral enteric-coated tablets. Cmax is approximately 2/3 of that produced by an equivalent 50 mg enteric-coated tablet oral dose. Tmax occurs within 1 hour. The unchanged diclofenac plasma AUC values for rectal administration are within the range of values produced by equivalent oral enteric-coated tablet doses. Since about half the active substance is metabolized during its first passage through the liver (“first pass” effect), the area under the concentration curve (AUC) following oral or rectal administration is about half as large as it is following a parenteral dose of equal size.

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 (oral 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.

Biotransformation: 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.

Elimination: Plasma clearance of diclofenac is 263±56 mL/minute. 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: Renal Impairment: A single dose pharmacokinetic study in patients with varying degrees of renal dysfunction (creatinine clearance rates ranging from 3 to 42 mL/minute), suggests that moderate renal impairment does not affect the elimination rate of unchanged diclofenac from plasma but that it may reduce the elimination rate of the metabolites of the drug. In one patient with a creatinine clearance of
Hepatic Impairment: The kinetics and metabolism of diclofenac, as revealed in a study of 10 patients with impaired hepatic function (chronic hepatitis and nondecompensated cirrhosis) receiving a single oral dose of 100 mg, were the same as in patients without liver disease.

Geriatrics: The ability of elderly subjects to absorb, metabolize and excrete diclofenac sodium does not appear to differ significantly from those of young subjects.

Indications And Clinical Uses: The symptomatic treatment of rheumatoid arthritis and osteoarthritis, including degenerative joint disease of the hip.

Contra-Indications: Patients with active, or recent history of, inflammatory diseases of the gastrointestinal tract such as peptic ulcer, gastritis, regional enteritis, or ulcerative colitis.

Known or suspected hypersensitivity to the drug. Since cross sensitivity has been demonstrated, diclofenac sodium should not be given to patients in whom ASA or other nonsteroidal anti-inflammatory agents (NSAIDs) have induced asthma, rhinitis, urticaria or other allergic manifestations. Fatal anaphylactoid reactions have occurred in such individuals.

Suppositories are contraindicated in patients with any inflammatory lesions of rectum or anus and in patients with recent history of rectal or anal bleeding.

Manufacturers’ Warnings In Clinical States: Peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal, in either the presence or absence of previous symptoms have been known to occur during therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) including diclofenac sodium.

Diclofenac should be given under close medical supervision to patients prone to gastrointestinal tract irritation particularly those with a history of peptic ulcer, melena, diverticulosis or other inflammatory disease of the gastrointestinal tract (such as ulcerative colitis or Crohn’s disease). In these cases the physician must weigh the benefits of treatment against the possible hazards (see Contraindications and Adverse Effects).

Patients should be instructed to contact their physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur at any time during treatment, without warning symptoms or signs. If peptic ulceration is suspected or confirmed, or if gastrointestinal bleeding occurs, diclofenac sodium should be discontinued, appropriate treatment instituted and the patient closely monitored.

Diclofenac sodium is not recommended for routine use with other NSAIDs because of the potential for additive side effects.

Pregnancy and Lactation: Diclofenac sodium readily crosses the placental barrier. The safety in pregnancy and lactation has not been established and its use is therefore not recommended. It should only be used during pregnancy for the most compelling reasons, and then only at the lowest effective dose. As with other prostaglandin inhibitors, this applies particularly to the last 3 months of pregnancy, because of the possibility of uterine inertia and/or premature closing of the ductus arteriosus.

The highest diclofenac level observed in the breast milk of 6 patients receiving oral diclofenac sodium doses of 3´50 mg day 1, followed by 2´50 mg day 2, was smaller than 5 ng/g. By extrapolation, an infant of 3 kg, consuming 500 g/day (with a maximum concentration of 5 ng/g) of breast milk, would receive less than 0.83 g/kg/day of diclofenac sodium. On the other hand, in 1 patient on long-term treatment with diclofenac sodium 150 mg daily, a level of 100 ng/mL (100 ng/g) was measured in breast milk; by extrapolation, an infant of 3 kg consuming 500 g/day of breast milk would receive less than 17 g/kg/day of diclofenac sodium.

Geriatrics: When administering diclofenac to the elderly, frail, and debilitated, special care is indicated. These patients appear to have a higher risk for development of adverse reactions. The dosage should be reduced to the lowest level that will provide control of symptoms adjusted when necessary and closely supervised.

Children: Diclofenac sodium is not recommended in children under 16 years of age. Safety and dosages for the pediatric age group have not been established.

Occupational Hazards: CNS: Headache, dizziness, lightheadedness, and mental confusion have been reported following therapy. Patients experiencing these symptoms should be made aware that these side effects may occur, and be cautioned against operating machinery or motor vehicles should they experience any of these.

Precautions: Diclofenac sodium should not be used concomitantly with diclofenac potassium since both exist in plasma as the same active organic ion.

Gastrointestinal: If, during therapy, peptic ulceration is suspected or confirmed, or if gastrointestinal bleeding or perforation occurs, diclofenac sodium should be withdrawn immediately. Appropriate treatment should be instituted and the patient should be closely monitored.

There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow continuation of diclofenac sodium therapy when and if these adverse reactions appear.

Hematology: Caution should be exercised in patients with a history of blood dyscrasias or coagulation disorders since drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to some degree (see Adverse Effects).

Patients on long-term diclofenac sodium treatment should have their hemopoietic system evaluated periodically. Bone marrow functional abnormalities, although rare, could have severe consequences. Periodic hematologic examinations (CBC and blood film examination) can detect anemias or blood dyscrasias secondary to possible gastrointestinal tract or bone marrow toxicity.

Fluid and Electrolyte Balance: As with many other nonsteroidal anti-inflammatory drugs (NSAIDs), fluid retention and edema have been reported; therefore the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Diclofenac sodium should be used with caution in patients with cardiac decompensation, hypertension, renal diseases and in those recovering from surgical operations under general anesthesia and other conditions predisposing to fluid retention.

There is a risk of hyperkalemia with NSAID treatment. Patients most at risk are: the elderly, those having conditions such as diabetes mellitus or renal failure, or those receiving concomitant therapy with B-adrenergic blockers, angiotensin converting enzyme inhibitors or some diuretics. Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients at risk.

Renal Function: As with other NSAIDs, long-term administration of diclofenac sodium to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.

In patients with prerenal conditions leading to reduction in renal blood flow or blood volume, renal prostaglandins have a supportive role in the maintenance of renal perfusion. Administration of NSAIDS may precipitate overt renal decompensation due to a dose-dependent reduction in prostaglandin formation. Patients at greatest risk are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Recovery to the pretreatment state usually follows discontinuation of NSAID therapy.

Diclofenac sodium and its metabolites are eliminated primarily (60%) by the kidneys; therefore, the drug should be used with great caution in patients with impaired renal function (see Pharmacology). In these cases lower doses of diclofenac should be considered. Urine output, serum urea, and serum creatinine should be carefully monitored.

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

Hepatic Function: As with other NSAIDs, borderline elevations of one or more liver tests may occur. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Patients manifesting abnormal liver function test results, or signs or symptoms that suggest liver dysfunction, should be evaluated for evidence of progression to a more severe hepatic reaction, while on therapy with diclofenac sodium. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with this drug as with other NSAIDs. If abnormal liver function test results persist or worsen, or if systemic manifestations or clinical signs consistent with liver disease develop, discontinue diclofenac sodium treatment. Liver function should be monitored during long-term treatment with this drug. Minimize hepatic injury risk by informing patients of hepatotoxicity symptoms. Patients will then be alerted that nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and “flu-like” symptoms, are signs of possible liver injury.

If this drug is to be used in the presence of impaired liver function, it must be done under strict observation. Caution is called for when using diclofenac sodium in patients with hepatic porphyria, since diclofenac sodium may trigger an attack.

Infection: The anti-inflammatory, antipyretic, and analgesic effects of diclofenac sodium may mask the usual signs of infection. Physicians should be alert to the development of infection in patients receiving the drug.

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

Hypersensitivity: As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can occur without prior exposure to drug. Careful questioning for patient history of asthma, nasal polyps, urticaria, and hypotension associated with NSAIDs is important before starting therapy.

Drug Interactions: ASA: Serum levels of diclofenac may be reduced when the two drugs are taken simultaneously. The bioavailability of ASA is reduced by the presence of diclofenac. Although these pharmacokinetic interactions do not appear to be clinically relevant, there is no proven advantage in using these two medications together.

Digoxin: Diclofenac may increase the plasma concentration of digoxin. Dosage adjustment may be required.

Lithium: Lithium plasma concentrations will increase when administered concomitantly with diclofenac (which affects lithium renal clearance). Dosage adjustment of lithium may be required.

Oral hypoglycemic drugs: 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.

Anticoagulants: Although clinical investigations would appear to indicate that diclofenac has no influence on the effect of anticoagulants, there have been isolated reports of an increased risk of hemorrhage with the combined use of diclofenac and acenocoumarol anticoagulant therapy. Special caution is therefore recommended and frequent laboratory tests should be performed to check that the desired response to the anticoagulant is being maintained. Although diclofenac, as with other NSAIDs, is an inhibitor of induced platelet aggregation in vitro and in vivo, it has little effect on spontaneous platelet aggregation at usual therapeutic dosages.

Diuretics: NSAIDs have been reported to decrease the activity of diuretics. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium, thus making it necessary to monitor levels.

Glucocorticoids: Concomitant administration may aggravate gastrointestinal side effects.

NSAIDs: Concurrent oral treatment with two or more NSAIDs may promote the occurrence of side effects (see Warnings).

Methotrexate: Caution should be exercised when NSAIDs are administered less than 24 hours before or after treatment with methotrexate. Elevated blood concentrations of methotrexate may occur, increasing toxicity.

Cyclosporine: Nephrotoxicity of cyclosporine may be increased because of the effect of NSAIDs on renal prostaglandins.

Quinolone antibacterials: There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.

Antihypertensive agents: Like other NSAIDs, diclofenac can reduce the antihypertensive effects of propranolol and other B-blockers, as well as other antihypertensive agents.

Clinical Laboratory Tests: 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.

Information to be Provided to the Patient. See Information for the Patient.

Adverse Reactions: Gastrointestinal, dermatological and CNS adverse reactions are most commonly seen. The most severe gastrointestinal adverse reactions observed were ulceration and bleeding while the most severe dermatological albeit rare reactions observed were erythema multiforme (Stevens-Johnson syndrome and Lyell’s syndrome). Fatalities have occurred on occasion, particularly in the elderly.

Adverse reactions reported in clinical trials and spontaneous reports are summarized below.

Frequency estimate: Frequent >10%, Occasional >1-10%, Rare >0.001-1%, isolated cases
Gastrointestinal: Occasional: epigastric, gastric, or abdominal pain, abdominal cramps, nausea, dyspepsia, anorexia, diarrhea, vomiting, flatulence. Rare: gastrointestinal bleeding (bloody diarrhea, melena, hematemesis) gastric and intestinal ulcerations with or without bleeding or perforation. Isolated: lower gut disorders (e.g., nonspecific hemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), diaphragm-like intestinal strictures, hyperacidity, stomatitis, glossitis, coated tongue, esophageal lesions, constipation, pancreatitis.

CNS: Occasional: dizziness, headache, vertigo. Rare: drowsiness, malaise, impaired concentration, tiredness. Isolated: sensory disturbances including paresthesia, memory disturbance, disorientation, insomnia, irritability, convulsions, depression, anxiety, nightmares, tremor, psychotic reactions, aseptic meningitis.

Special Senses: Isolated: vision disturbances (blurred vision, diplopia), impaired hearing, tinnitus, taste alteration disorders.

Cardiovascular: Rare: palpitation, angina, arrhythmias. Isolated: exacerbation of cardiac failure, hypertension.

Dermatologic: Occasional: rash, pruritus. Rare: urticaria. Isolated: bullous eruption, erythema, eczema, erythema multiforme, Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), erythroderma (exfoliative dermatitis), loss of hair, photosensitivity reactions, purpura including allergic purpura.

Renal System: Rare: edema (facial, general, peripheral). Isolated: acute renal failure, nephrotic syndrome, urinary abnormalities (e.g., hematuria and proteinuria), interstitial nephritis, papillary necrosis.

Hematologic: Isolated: thrombocytopenia, leukopenia, agranulocytosis, hemolytic anemia, aplastic anemia, anemia secondary to gastrointestinal bleeding.

Hepatic: Occasional: elevations (³3 times the upper normal limit) of serum aminotransferase enzymes (AST, ALT). Rare: liver function disorders including hepatitis with or without jaundice. Isolated: fulminant hepatitis.

Hypersensitivity: Rare: hypersensitivity reactions such as asthma in patients sensitive to ASA e.g., bronchospasm; anaphylactic/anaphylactoid systemic reactions including hypotension. Isolated: vasculitis, pneumonitis.

Other: Administration of the suppositories may occasionally give rise to local irritation, rarely local bleeding and exacerbation of hemorrhoids.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no specific antidote. In cases of overdosage, absorption should be prevented as soon as possible by the induction of vomiting, gastric lavage or treatment with activated charcoal. Supportive and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal irritation and respiratory depression. Measures to accelerate elimination (forced diuresis, hemoperfusion, dialysis) may be considered, but may be of limited use because of the high protein-binding and extensive metabolism.

Dosage And Administration: Voltaren Tablets: In rheumatoid arthritic patients, treatment should be initiated with 75 to 150 mg/day in 3 divided doses, depending on the severity of the condition. For maintenance, the dose should be reduced to the minimum amount that will provide continuous control of symptoms, usually 75 to 100 mg daily in 3 divided doses.

In osteoarthritic patients, the starting and maintenance dose is usually 75 mg/day in 3 divided doses. The dose should be adjusted individually to the minimum dose that will provide control of symptoms.

The maximum recommended daily dose is 150 mg.

Diclofenac sodium should be taken with food and the tablets should be swallowed whole.

Voltaren SR Tablets: Treatment should be initiated and individual titration carried out using Voltaren enteric coated tablets.

Patients with rheumatoid arthritis or osteoarthritis on a maintenance dose of 75 mg per day may be changed to a once daily dose of Voltaren SR 75 mg administered morning or evening.

Patients on a maintenance dose of 100 mg/day may be changed to a once-daily dose of Voltaren SR 100 mg tablets, administered morning or evening.

Patients on a maintenance dose of 150 mg per day may be changed to a twice daily dose of one Voltaren SR 75 mg tablet administered morning and evening.

The maximum daily dose of Voltaren should not exceed 150 mg.

Voltaren SR tablets should be swallowed whole with liquid preferably at mealtime.

Voltaren Suppositories: 50 or 100 mg, may be given as substitute for the last of the 3 oral daily doses, to a total daily dose not greater than 150 mg.

Availability And Storage: Voltaren Tablets: 25 mg: Each yellow, round, slightly biconvex, enteric-coated tablet, printed VOLTAREN on one side and 25 on the other, contains: diclofenac sodium 25 mg. Nonmedicinal ingredients: black ink, castor oil derivatives, cellulose compound, colloidal silicon dioxide, cornstarch, iron oxides, lactose, magnesium stearate, polymethacrylate, povidone, polyethylene glycol, sodium starch glycolate, talc and titanium dioxide. Energy: 1.1 kJ (0.26 kcal). Sodium:
50 mg: Each light brown, round, slightly biconvex, enteric-coated tablet, printed VOLTAREN on one side and 50 on the other, contains: diclofenac sodium 50 mg. Nonmedicinal ingredients: black ink, castor oil derivatives, cellulose compound, colloidal silicon dioxide, cornstarch, iron oxides, lactose, magnesium stearate, polymethacrylate, povidone, polyethylene glycol, sodium starch glycolate, talc and titanium dioxide. Energy: 1.6 kJ (0.39 kcal). Sodium:
Voltaren SR Tablets: 75 mg: Each light pink, triangular, biconvex, film-coated, slow-release tablet, printed VOLTAREN on one side and Ñ on the other, contains: diclofenac sodium 75 mg. Nonmedicinal ingredients: black ink, carnauba wax, cellulose compounds, cetyl alcohol, colloidal silicon dioxide, iron oxides, magnesium stearate, povidone, sugar, talc and titanium dioxide. Energy: 1.56 kJ (0.37 kcal). Sodium:
100 mg: Each pink, round, biconvex, film-coated, slow-release tablet, printed VOLTAREN SR on one side and 100 on the other, contains: diclofenac sodium 100 mg. Nonmedicinal ingredients: black ink, carnauba wax, cellulose compounds, cetyl alcohol, colloidal silicon dioxide, iron oxides, magnesium stearate, povidone, sugar, talc and titanium dioxide. Energy: 2.04 kJ (0.49 kcal). Sodium:
Voltaren Suppositories: 50 mg: Each yellowish-white, torpedo-shaped suppository, with smooth surface, contains: diclofenac sodium 50 mg. Nonmedicinal ingredients: semi-synthetic glycerides. Sodium:
100 mg: Each yellowish-white, torpedo-shaped suppository, with smooth surface, contains: diclofenac sodium 100 mg. Nonmedicinal ingredients: semi-synthetic glycerides. Sodium:
Protect the tablets from heat (store below 30°C) and humidity. Protect suppositories from heat (store below 30°C). (Shown in Product Recognition Section)

VOLTAREN® Novartis Pharmaceuticals Diclofenac Sodium Anti-inflammatory – Analgesic

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