Diclofenac Potassium

DICLOFENAC POTASSIUM- diclofenac potassium tablet, film coated
Apotex Corp

Structure50 mg 100 tab bottel

BOXED WARNING

Cardiovascular Risk

• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (See WARNINGS).

• Diclofenac potassium immediate-release tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk

• NSAIDs cause an increased risk of serious gastrointestinal adverse events including inflammation, 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 are at greater risk for serious gastrointestinal events (See WARNINGS).

DESCRIPTION

Diclofenac potassium tablets, USP are a benzeneacetic acid derivative. Diclofenac potassium tablets, USP are available as immediate-release 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 C14 H10 Cl2 NKO2 , and it has the following structural formula:

Structure

Each diclofenac potassium immediate-release tablet, USP are 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 and titanium dioxide.

CLINICAL PHARMACOLOGY

Pharmacodynamics Diclofenac 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). In some fasting volunteers, measurable plasma levels are observed within 10 minutes of dosing with diclofenac potassium immediate-release 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 to 52 yrs.)
Mean Coefficient of Variation (%)
Absolute Bioavailability (%)[N = 7] 55 40
Tmax (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 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.

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 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.

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 potassium immediate-release tablets 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 benefits and risks of diclofenac potassium immediate-release tablets and other treatment options before deciding to use diclofenac potassium immediate-release tablets, USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Diclofenac potassium immediate-release tablets, USP are indicated:

  • For treatment of primary dysmenorrhea

  • For relief of mild to moderate pain
  • For relief of the signs and symptoms of osteoarthritis
  • For relief of the signs and symptoms of rheumatoid arthritis

CONTRAINDICATIONS

Diclofenac potassium immediate-release tablets are contraindicated in patients with known hypersensitivity to diclofenac. Diclofenac potassium immediate-release tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactic Reactions, and PRECAUTIONS, Preexisting Asthma).

Diclofenac potassium immediate-release tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

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