Voltaren Rapide (Diclofenac Potassium)

VOLTAREN RAPIDE®

Novartis Pharmaceuticals

Diclofenac Potassium

Anti-inflammatory – Analgesic

Action And Clinical Pharmacology: Diclofenac potassium, the active substance of Voltaren Rapide is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic 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.

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 mol/L, 20 to 60 minutes post dose. The amount of diclofenac absorbed from diclofenac potassium is the same as that obtained from an equivalent diclofenac 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 t.i.d. 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 (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: The potassium salt of diclofenac yields the same active organic anion produced by the sodium salt found in diclofenac 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.

Elimination: 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: Renal Impairment: A single study using the sodium salt in patients with varying degrees of renal dysfunction (creatinine clearance rates ranging from 3 to 42 mL/min), suggested that moderate renal impairment may not affect the elimination rate of unchanged diclofenac. It may reduce the elimination rate of metabolites. At a creatinine clearance of
Hepatic Impairment: The kinetics and metabolism of diclofenac in 10 patients with impaired hepatic function (chronic hepatitis and nondecompensated cirrhosis) receiving a single 100 mg oral dose of diclofenac sodium were similar to patients without liver disease.

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

Indications And Clinical Uses: For the short-term 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, postoperative pain following dental extraction, episiotomy or dysmenorrhea.

Contra-Indications: Should not be used in patients with active, or recent history of, inflammatory diseases of the gastrointestinal tract such as: peptic ulcer, gastritis, regional enteritis, ulcerative colitis.

Diclofenac potassium is contraindicated in patients with known or suspected hypersensitivity to diclofenac. Since cross-sensitivity has been demonstrated, diclofenac potassium should not be given to patients in whom ASA or other NSAIDs have induced asthma, rhinitis, urticaria or other allergic manifestations. Fatal anaphylactoid reactions have occurred in such individuals.

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 NSAIDs including diclofenac.

Diclofenac potassium 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 potassium should be discontinued, appropriate treatment instituted and the patient closely monitored.

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

Pregnancy: Diclofenac readily crosses the placental barrier and 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. Diclofenac potassium is not recommended for use in obstetrical analgesia, including preoperative medication, because of the known effects of NSAIDs on uterine contraction and fetal circulation.

Lactation: The administration of diclofenac potassium is not recommended during lactation, since its safety has not been established in this condition. The maximum diclofenac levels measured in the breast milk of 6 patients receiving oral doses of diclofenac sodium of 3´50 mg on day 1, followed by 2´50 mg on day 2, were smaller than 5 ng/g. In another patient on long-term treatment with diclofenac 150 mg daily, a level of 100 ng/g was measured. Extrapolating these 2 concentration estimates, a 3-kg infant, consuming 500 g/day of breast milk, would receive at most 0.83 to 17 g/kg/day of diclofenac.

Elderly, Frail and Debilitated: When administering diclofenac potassium 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 providing control of symptoms, adjusted when necessary and closely supervised.

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

CNS: Headache, dizziness, lightheadedness and mental confusion have been reported following therapy with diclofenac. Patients 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 potassium should not be used concomitantly with diclofenac sodium since both exist in plasma as the same active organic anion.

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

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

Hematology: Caution should be exercised in patients with a history of blood dyscrasias or coagulation disorders since drugs inhibiting prostaglandin biosynthesis interfere with platelet function to some degree (see Adverse Effects). When patients are on long-term treatment with diclofenac, a periodic evaluation of their hemopoietic system is advised. 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. However, diclofenac potassium is indicated for short-term treatment only.

Fluid and Electrolyte Balance: As with many other 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 potassium 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 beta-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. Diclofenac potassium is indicated for short-term therapy only.

Renal Function: As with other NSAIDs, long-term administration of diclofenac 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 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 potassium should be considered. Urine output, serum urea and serum creatinine should be carefully monitored.

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 potassium. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with diclofenac as with other NSAIDs. The incidence of transaminase elevations during long-term treatment is similar to that for diclofenac sodium. If abnormal liver function test results persist or worsen, or if systemic manifestations or clinical signs consistent with liver disease develop, discontinue diclofenac potassium treatment. Minimize hepatic injury risk by informing patients of hepatotoxicity symptoms. Patients will then be alerted that nausea, fatigue, lethargy, pruritus, jaundice, right upper guadrant 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 potassium in patients with hepatic porphyria, since diclofenac potassium may trigger an attack.

Infection: The anti-inflammatory, antipyretic and analgesic effects of diclofenac potassium 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 potassium and with other NSAIDs. If such symptoms develop, this drug should be discontinued and an ophthalmologic examination performed.

Hypersensitivity Reactions: As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can occur without prior exposure to the 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 2 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 2 medications together.

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

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 2 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.

Cyclosporin: Nephrotoxicity of this compound 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.

Adverse Reactions: 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 sodium since both formulations exist in the plasma as the same active organic anion.

Gastrointestinal, dermatological and CNS adverse reactions are the most commonly seen with diclofenac. The most severe gastrointestinal adverse reactions are ulceration and bleeding, while the most severe dermatological, albeit rare, reaction observed with diclofenac is 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 with diclofenac dosage forms 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: 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 for diclofenac potassium. In an overdose, 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 value because of the high protein-binding and extensive metabolism.

Dosage And Administration: Diclofenac potassium is indicated for short-term treatment only, i.e., for a maximum of a few weeks only.

Diclofenac potassium should be taken with food.

The recommended daily dose for diclofenac potassium is 50 mg every 6 to 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 6 to 8 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.

Diclofenac potassium is not recommended for use in patients under 16 years of age.

Lower doses of diclofenac potassium should be considered in patients with impaired renal function (see Precautions).

In the elderly, frail and debilitated, the dosage should be reduced to the lowest level providing control of symptoms, and adjusted when necessary (see Precautions).

Availability And Storage: Each reddish-brown, round, biconvex, sugar-coated tablet, VOLTAREN printed in white on one side and RAPIDE 50 on the other, contains: diclofenac potassium 50 mg. Nonmedicinal ingredients: carnauba wax, cellulose, colloidal silicon dioxide, cornstarch, ferric oxide, magnesium stearate, polyethylene glycol, povidone, sodium carboxymethyl starch, sucrose, talc, titanium dioxide, tribasic calcium phosphate and white ink. Bottles of 100 or 500. Protect from heat (store below 30°C) and humidity.

VOLTAREN RAPIDE® Novartis Pharmaceuticals Diclofenac Potassium Anti-inflammatory – Analgesic

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