Diclofenac Sodium - Diclofenac Sodium tablet, Film Coated prescribing information
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 sodium extended-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 ).
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of diclofenac sodium extended-release tablets and other treatment options before deciding to use diclofenac sodium extended-release tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ; Gastrointestinal Bleeding, Ulceration, and Perforation ).
Diclofenac sodium extended-release tablets are indicated:
- for relief of the signs and symptoms of osteoarthritis
- for relief of the signs and symptoms of rheumatoid arthritis
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of diclofenac sodium extended-release tablets and other treatment options before deciding to use diclofenac sodium extended-release tablets. 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 sodium extended release tablets, the dose and frequency should be adjusted to suit an individual patient’s needs.
For the relief of osteoarthritis, the recommended dosage is 100-mg daily.
For the relief of rheumatoid arthritis, the recommended dosage is 100-mg daily. In the rare patient where diclofenac sodium extended release tablets 100 mg/day is unsatisfactory, the dose may be increased to 100 mg twice a day, if the benefits outweigh the clinical risks of increased side effects.
Different formulations of diclofenac [VOLTAREN ® (diclofenac sodium enteric-coated tablets); diclofenac sodium extended-release tablets; CATAFLAM ® (diclofenac potassium immediate-release tablets)] are not necessarily bioequivalent even if the milligram strength is the same.
CONTRAINDICATIONS
Diclofenac sodium extended-release tablets are contraindicated in the following patients:
- Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product (see WARNINGS ; Anaphylactic Reactions , Serious Skin Reactions ).
- History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see WARNINGS ; Anaphylactic Reactions , PRECAUTIONS ; Exacerbation of Asthma Related to Aspirin Sensitivity).
- In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ; Cardiovascular Thrombotic Events ).
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Cardiovascular Thrombotic Events (see WARNINGS )
- GI Bleeding, Ulceration and Perforation (see WARNINGS )
- Hepatotoxicity (see WARNINGS )
- Hypertension (see WARNINGS )
- Heart Failure and Edema (see WARNINGS )
- Renal Toxicity and Hyperkalemia (see WARNINGS )
- Anaphylactic Reactions (see WARNINGS )
- Serious Skin Reactions (see WARNINGS )
- Hematologic Toxicity (see WARNINGS )
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In patients taking diclofenac sodium extended-release tablets or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1% to 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
Cardiovascular 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, fixed drug eruption (FDE), urticaria
Special Senses: conjunctivitis, hearing impairment
To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interaction Studies
Voriconazole : When coadministered with voriconazole (inhibitor of CYP2C9, 2C19, and 3A4 enzyme), the C max and AUC of diclofenac increased by 114% and 78%, respectively (see PRECAUTIONS ; Drug Interactions ).
Aspirin : When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin (see PRECAUTIONS ; Drug Interactions ).
DESCRIPTION
Diclofenac sodium extended-release tablets, USP is a benzeneacetic acid derivative. Diclofenac sodium extended-release tablets are available as extended-release tablets of 100 mg (pink) for oral administration. Diclofenac sodium is a white to off-white, hygroscopic, crystalline powder and is sparingly soluble in water at 25°C. The chemical name is 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt. The molecular weight is 318.14 g/mol. Its molecular formula is C 14 H 10 Cl 2 NNaO 2 , and it has the following structural formula
The inactive ingredients in diclofenac sodium extended-release tablets include: anhydrous lactose, hydroxyethyl cellulose, povidone, colloidal silicon dioxide, talc, magnesium stearate, hypromellose, titanium dioxide, macrogol, iron oxide red, polysorbate 80.
Diclofenac sodium extended-release tablets, USP meet USP Dissolution Test 5.
CLINICAL PHARMACOLOGY
Mechanism of Action
Diclofenac sodium extended-release tablets have analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of diclofenac sodium extended-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 intravenous (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). When diclofenac sodium extended-release tablets are taken with food, there is a delay of 1 to 2 hours in the T max and a 2-fold increase in C max values. The extent of absorption of diclofenac, however, is not significantly affected by food intake.
PK Parameter | Normal Healthy Adults (18 to 48 years) | |
Mean | Coefficient of Variation (%) | |
Absolute bioavailability (%) [N = 7] | 55 | 40 |
T max (hr) [N = 12] | 5.3 | 28 |
Oral clearance (CL/F; mL/min) [N = 12] | 895 | 56 |
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. Acyl glucuronidation 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.
Special Populations
Pediatric : The pharmacokinetics of diclofenac sodium extended-release tablets has not been investigated in pediatric patients.
Race : Pharmacokinetic differences due to race have not been identified.
Hepatic Impairment : Hepatic metabolism accounts for almost 100% of diclofenac sodium extended-release tablets elimination, so patients with hepatic disease may require reduced doses of diclofenac sodium extended-release tablets compared to patients with normal hepatic function.
Renal Impairment : 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 to 90, 30 to 60, and less than 30 mL/min; N = 6 in each group), area under the curve (AUC) values and elimination rate were comparable to those in healthy subjects.
Drug Interaction Studies
Voriconazole : When coadministered with voriconazole (inhibitor of CYP2C9, 2C19, and 3A4 enzyme), the C max and AUC of diclofenac increased by 114% and 78%, respectively (see PRECAUTIONS ; Drug Interactions ).
Aspirin : When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin (see PRECAUTIONS ; Drug Interactions ).
HOW SUPPLIED
Diclofenac sodium extended-release tablets, USP
100 mg – Pink, round, convex film coated tablets debossed with ING on one side and 278 on the other side.
Bottles of 100: NDC 68001-612-00
Preserve in well-closed containers. Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Protect from light and moisture.
Manufactured by:
Ingenus Pharmaceuticals NJ, LLC
Fairfield, NJ 07004
For BluePoint Laboratories
555202
Revised: 03/2024
Dispense with Medication Guide available at: www.ingenus.com/medguide/bp/diclofenac-sodium-er-tablets.pdf
Mechanism of Action
Diclofenac sodium extended-release tablets have analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of diclofenac sodium extended-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
