Get your patient on Inflammacin (Diclofenac Sodium, Capsaicin)

Carefully consider the potential benefits 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:

• For relief of the signs and symptoms of osteoarthritis
• For relief of the signs and symptoms of rheumatoid arthritis
• For acute or long-term use in the relief of signs and symptoms of ankylosing spondylitis.

Carefully consider the potential benefits 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 ].

After observing the response to initial therapy with diclofenac, the dose and frequency should be adjusted to suit an individual patient's needs.

For the relief of osteoarthritis, the recommended dosage is 100 to 150 mg/day in divided doses (50 mg b.i.d. or t.i.d., or 75 mg b.i.d.).

For the relief of rheumatoid arthritis, the recommended dosage is 150 to 200 mg/day in divided doses (50 mg t.i.d. or q.i.d., or 75 mg b.i.d.).

For the relief of ankylosing spondylitis, the recommended dosage is 100 to 125 mg/day, administered as 25 mg q.i.d., with an extra 25-mg dose at bedtime if necessary.

Different formulations of diclofenac (diclofenac sodium delayed-release tablets; diclofenac sodium extended-release tablets; diclofenac potassium immediate-release tablets) are not necessarily bioequivalent even if the milligram strength is the same.

Diclofenac sodium delayed-release tablets is contraindicated in patients with known hypersensitivity to diclofenac.

Diclofenac should not be given to patients who have experienced asthma, urticaria, or other 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].

In the setting of coronary artery bypass graft (CABG) surgery [see WARNINGS ]

In patients taking diclofenac sodium delayed-release tablets, or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1%-10% of patients are:

• Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and vomiting.
• Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes and tinnitus.

Additional adverse experiences reported occasionally include:

Body as a Whole : fever, infection, sepsis

C ardiovascular System : congestive heart failure, hypertension, tachycardia, syncope

Digestive System : dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice

Hemic and Lymphatic System : ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia

Metabolic and Nutritional : weight changes

Nervous System : anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo

Respiratory System : asthma, dyspnea

Skin and Appendages : alopecia, photosensitivity, sweating increased

Special Senses : blurred vision

Urogenital System : cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure

Other adverse reactions, which occur rarely are:

Body as a Whole : anaphylactic reactions, appetite changes, death

Cardiovascular System : arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis

Digestive System : colitis, eructation, fulminant hepatitis with and without jaundice, liver failure, liver necrosis, pancreatitis

Hemic and Lymphatic System : agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia

Metabolic and Nutritional : hyperglycemia

Nervous System : convulsions, coma, hallucinations, meningitis

Respiratory System : respiratory depression, pneumonia

Skin and Appendages : angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria

Special Senses : conjunctivitis, hearing impairment

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.

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%.

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.

Race: Pharmacokinetics 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 (insulin clearance 60 to 90, 30 to 60, and <30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects.

Diclofenac Sodium Delayed-Release Tablets

75 mg -- white to off-white, biconvex, round shaped, unscored (imprinted CTI 103 on one side), supplied in bottles of 60.

Store at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature). Protect from moisture.

Dispense in a tight, light-resistant container as defined in the USP.