Diclofenac Potassium

DICLOFENAC POTASSIUM- diclofenac potassium tablet, film coated
Golden State Medical Supply, Inc.

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

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 potassium 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 potassium tablets, USP are a benzeneacetic acid derivative. Diclofenac potassium tablets, USP are available as tablets of 50 mg (light brown) for oral administration. The chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monopotassium salt. The molecular weight is 334.25. Its molecular formula is C 14 H 10 C l2 NKO 2 , and it has the following structural formula:

Diclofenac Potassium Structural Formula

Each diclofenac potassium tablet, USP intended for oral administration, contains 50 mg diclofenac potassium for oral administration. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, hydroxyethyl cellulose, iron oxide red, magnesium stearate, methanol, polyethylene glycol, povidone, sodium bicarbonate, titanium dioxide and yellow iron oxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

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

The mechanism of action of diclofenac potassium 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). In some fasting volunteers, measurable plasma levels are observed within 10 minutes of dosing with diclofenac potassium tablets. Peak plasma levels are achieved approximately 1 hour in fasting normal volunteers, with a range of .33 to 2 hours. Food has no significant effect on the extent of diclofenac absorption. However, there is usually a delay in the onset of absorption and a reduction in peak plasma levels of approximately 30%.

Table 1. Pharmacokinetic Parameters for Diclofenac

PK Parameter

Normal Healthy Adults
(20-52 years)

Mean

Coefficient of Variation (%)

Absolute Bioavailability (%)

[N = 7]

55

40

T max (hr)

[N = 65]

1.0

76

Oral Clearance (CL/F; mL/min)

[N = 61]

622

21

Renal Clearance (% unchanged drug in urine)

[N = 7]

< 1

Apparent Volume of Distribution (V/F; L/kg)

[N = 61]

1.3

33

Terminal Half-life (hr)

[N = 48]

1.9

29

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 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 CYP2C8 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 2 hours.

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