Diclofenac Sodium Delayed Release Delayed Release

DICLOFENAC SODIUM DELAYED RELEASE DELAYED RELEASE- diclofenac sodium tablet, delayed release
Cambridge Therapeutics Technologies, LLC

Delayed-Release Tablets USP
Rx only Prescribing information

DESCRIPTION

Diclofenac, as the sodium salt, is a benzene-acetic acid derivative. The chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C ₁₄ H ₁₀ Cl ₂ NNaO ₂ , and it has the following structural formula:

Each enteric-coated tablet for oral administration contains 75 mg of diclofenac sodium. In addition, each tablet contains the following inactive ingredients; black iron oxide, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, pharmaceutical glaze, polyethylene glycol, povidone, sodium starch glycolate, talc, titanium dioxide, triethyl citrate.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Diclofenac sodium delayed-release tablets is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of diclofenac, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Pharmacokinetics

Absorption

Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to firstpass metabolism, only about 50% of the absorbed dose is systemically available (see Table 1). Food has no significant effect on the extent of diclofenac absorption. However, there is usually a delay in the onset of absorption of 1 to 4.5 hours and a reduction in peak plasma levels of <20%.

Table 1. Pharmacokinetic Parameters for Diclofenac

PK Parameter	Normal Healthy Adults (20-48 yrs.)
	Mean	Coefficient of mean Variation (%)
Absolute Bioavailability (%) [N =7]	55	40
T max (hr) [N = 56]	2.3	69
Oral Clearance (CL/F; mL/min) [N = 56]	582	23
Renal Clearance (% unchanged drug in urine) [N = 7]	<1	—
Apparent Volume of Distribution (V/F; L/kg) [N = 56]	1.4	58
Terminal Half-life (hr) [N = 56]	2.3	48

Distribution

The apparent volume of distribution (V/F) of diclofenac sodium is 1.4 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 to 105 μg/mL) achieved with recommended doses.

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-hydroxyand 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 2 hours.

Drug Interactions

When co-administered with voriconazole (inhibitor of CYP2C9, 2C19 and 3A4 enzyme), the Cmax and AUC of diclofenac increased by 114% and 78%, respectively [see Precautions, Drug Interactions].

Special Populations

Pediatric: The pharmacokinetics of diclofenac has not been investigated in pediatric patients.