Professional Information — Diclofenac Sodium

Indications and Usage

Carefully consider the potential benefits and risks of diclofenac sodium extended release tablets, USP 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, USP 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 are 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 (diclofenac sodium enteric-coated tablets; diclofenac sodium extended-release tablets, USP, diclofenac potassium immediate-release tablets) are not necessarily bioequivalent even if the milligram strength is the same.

Contraindications

Diclofenac sodium extended-release tablets, USP 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, USP 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

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, urticaria

Special Senses :conjunctivitis, hearing impairment.

To report SUSPECTED ADVERSE EVENTS, contact Lannett Company, Inc. at 1-844-834-0530 or FDA at 1-800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

Overdosage

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and coma have occurred, but were rare. (see WARNINGS; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Hypertension, Renal Toxicity and Hyperkalemia) .

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg in pediatric patients) and/or osmotic cathartic  in symptomatic patients seen within four hours of ingestion or in patients with a large overdose (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

Description

Diclofenac sodium extended-release tablets, USP is a benzeneacetic acid derivative. Diclofenac sodium extended-release tablets of 100 mg (pink) are available for oral administration. Diclofenac sodium is a white or slightly yellowish 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. Its molecular formula is C ₁₄H ₁₀Cl ₂NNaO _2,and it has the following structural formula:

The inactive ingredients in diclofenac sodium extended-release tablets include: carnauba wax, cetostearyl alcohol, colloidal silicon dioxide, compressible sugar, copovidone, gum acacia, hydroxypropyl methylcellulose, iron oxide red, magnesium stearate, polyethylene glycol, povidone, sugar, talc, titanium dioxide.

Meets USP Dissolution Test 2.

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 vivoeffects. 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). When diclofenac sodium extended-release tablet are taken with food, there is a delay of 1 to 2 hours in the T _maxand a two-fold increase in C _maxvalues. The extent of absorption of diclofenac, however, is not significantly affected by food intake.

Table 1. Pharmacokinetic Parameters for Diclofenac

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 (0.15-105 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.

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

Drug Interaction Studies

Voriconazole: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) .

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 / Storage and Handling

Diclofenac sodium extended-release tablets, USP

100 mg- Pink round convex film coated tablet debossed with DX 41 on one side.

Bottle of 7 NDC 68071-3556-7

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

Dispense in tight container (USP).

Manufactured by:

Dexcel ^®Ltd.

1 Dexcel Street

Or-Akiva 3060000, Israel

Distributed by:

Lannett Company, Inc.

Philadelphia, PA 19136

L6771B

Rev. 03/2021