Diclofenac Sodium

DICLOFENAC SODIUM- diclofenac sodium tablet, delayed release
Mylan Institutional Inc.

Cardiovascular Thrombotic Events

  • Nonsteroidal Anti-inflammatory Drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS).
  • Diclofenac sodium delayed-release tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS, WARNINGS).

Gastrointestinal Bleeding, Ulceration, And Perforation

  • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (see WARNINGS).

DESCRIPTION

Diclofenac sodium delayed-release tablets, USP are a benzene-acetic acid derivative. Diclofenac sodium delayed-release tablets are available as enteric-coated tablets of 50 mg (light brown) or 75 mg (light pink) for oral administration. Diclofenac sodium, USP is a faintly yellowish white to light beige crystalline powder and is sparingly soluble in water at 25°C. The chemical name is Sodium [ o -(2,6-dichloroanilino)phenyl]acetate. The molecular weight is 318.13. Its molecular formula is C 14 H 10 Cl 2 NNaO 2 and it has the following structural formula:

Diclofenac Structural Formula

The inactive ingredients in diclofenac sodium delayed-release tablets include: crospovidone, FD&C Yellow No. 6 Aluminum Lake, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, polyethylene glycol, povidone, simethicone, sodium hydroxide, talc and titanium dioxide. The 50 mg tablets also contain FD&C Blue No. 2 Aluminum Lake and yellow iron oxide. The 75 mg tablets also contain FD&C Red No. 40 Aluminum Lake.

The imprinting ink contains the following inactive ingredients: ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze.

CLINICAL PHARMACOLOGY

Mechanism of Action

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

The mechanism of action of diclofenac sodium delayed-release tablets, 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.

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 to 48 years)

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 mcg/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.

Elimination

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 CYP2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C9 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.

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