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.
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 µg/mL (5 µmol/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 ? 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 [0.05 to 0.7 mL/s]), 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 <10 mL/minute, the theoretical steady-state plasma levels of metabolites (normally devoid of pharmacological activity) were about 4 times higher than those in normal subjects, with metabolites cleared through the bile. Although no accumulation of pharmacologically active substance seems to occur, caution is advised while administering diclofenac sodium to patients with impaired kidney function.
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.
