Diclofenac Sodium Delayed Release

DICLOFENAC SODIUM DELAYED RELEASE- diclofenac sodium tablet, delayed release
Blenheim Pharmacal, Inc.

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 C₁₄ H₁₀ Cl₂ NaO₂ , and it has the following structural formula

Each enteric-coated tablet for oral administration contains 50 mg or 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 first-pass 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
Tmax (hr) [N = 56]	2.3	69
Oral Clearance(CL/F; mL/min) [N = 56]	582	23
Renal Clearance(% unchanged drug inurine) [N = 7]	<1	—
Apparent Volume ofDistribution (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 (0.15-105 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. 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. However, diclofenac metabolites undergo further glucuronidation and sulfation followed by biliary excretion.

One diclofenac metabolite 4′-hydroxy- diclofenac has very weak pharmacologic activity.

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.

Special Populations

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

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

Hepatic Insufficiency: Hepatic metabolism accounts for almost 100% of diclofenac elimination, so patients with hepatic disease may require reduced doses of diclofenac compared to patients with normal hepatic function.

Renal Insufficiency: Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. No differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60-90, 30-60, and <30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects.

INDICATIONS AND USAGE

Carefully consider the potential bene ts and risks of diclofenac sodium delayed-release tablets and other treatment options before deciding to use diclofenac. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Diclofenac is indicated:

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For relief of the signs and symptoms of osteoarthritis

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For relief of the signs and symptoms of rheumatoid arthritis

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For acute or long-term use in the relief of signs and symptoms of ankylosing spondylitis