Diclofenac 100 mg, Eperisone 150 mg Hard-gelatin capsules

Diclofenac has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of Diclofenac Potassium Capsules, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

The pharmacokinetics of Diclofenac Potassium Capsules was assessed in 24 healthy, normal adult volunteers who received 25 mg Diclofenac Potassium Capsules under fasting conditions. The mean pharmacokinetic parameters for Diclofenac Potassium Capsules are shown in Table 4.

The pharmacokinetics of Diclofenac Potassium Capsules was also assessed in pediatric patients 12 to 17 years of age [see Specific Populations: Pediatric] and was also found to be similar to adults.

Absorption — Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. After repeated oral administration, no accumulation of diclofenac in plasma occurred.

The extent of diclofenac absorption is not significantly affected when Diclofenac Potassium Capsules is taken with food. However, the rate of absorption is reduced by food, as indicated by a two-fold increase of T maxand a 47% decrease in C max.

Distribution — The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg.

Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 μg/mL) achieved with recommended doses.

Diclofenac has been shown to cross the placental barrier in humans.

Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac.

Metabolism — Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4'-hydroxy diclofenac is primarily mediated by CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy- diclofenac.

In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy-and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects.

Excretion — Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine, and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 1 hour.

Specific Populations — Pediatric: The pharmacokinetics of Diclofenac Potassium Capsules was assessed in 24 pediatric patients 12 years to 17 years of age with mild to moderate acute pain who received 25mg Diclofenac Potassium Capsules every six hours as needed for pain for up to four days. The mean pharmacokinetic parameters of Diclofenac Potassium Capsules on Day 1 in pediatric patients 12 years to 17 years of age are shown in Table 5. Peak plasma levels were noted in one hour, with an elimination half-life of less than 2 hours. The pharmacokinetics of Diclofenac Potassium Capsules in pediatric patients 12 years to 17 years of age was similar to that in adults.

Race:Pharmacokinetic differences due to race have not been studied.

Hepatic Impairment:Hepatic metabolism accounts for almost 100% of diclofenac elimination. Therefore, in patients with hepatic impairment, start with the lowest dose and if efficacy is not achieved, consider use of an alternate product [ see Warnings and Precautions (5.3)].

The reference describes suppression of spinal reflexes and reduced muscle-spindle sensitivity through gamma-motor-neuron pathways. The supporting experiments include animal studies and human muscle-spindle observations, rather than a single fully established molecular mechanism.

Eight healthy adult men received a study dose of 150 mg once daily for 14 days. Reported peak times were 1.6–1.9 hours and elimination half-lives 1.6–1.8 hours, with similar profiles on days 1, 8 and 14. The label explicitly notes that this single 150 mg study dose is unapproved; it is study context, not a dosing recommendation. Sustained-release kinetics require separate evidence.