VOLTAREN

ADVERSE REACTIONS ADVERSE REACTIONS 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 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 REACTIONS, contact Rising Pharmaceuticals, Inc. at 1-866-562-4597 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CONTRAINDICATIONS Diclofenac Sodium Delayed-Release Tablets are contraindicated in patients with known hypersensitivity to Diclofenac. Diclofenac Sodium Delayed-Release Tablets 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, Anaphylactoid Reactions, and PRECAUTIONS, Preexisting Asthma). Diclofenac Sodium Delayed-Release Tablets, USP are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Warnings].

DESCRIPTION DESCRIPTION Diclofenac Sodium Delayed-Release Tablets, USP are a benzene-acetic acid derivative. Diclofenac Sodium Delayed-Release Tablets are available as delayed-release (delayed-release) tablets of 25 mg, 50 mg and 75mg for oral administration. The chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C14H10Cl2NNaO2, and it has the following structural formula [structural formula] The inactive ingredients in Diclofenac Sodium Delayed-Release Tablets include: lactose (monohydrate), microcrystalline cellulose, croscarmellose sodium, povidone, talc, magnesium stearate, methacrylic acid copolymer, polyethylene glycol, opadry brown (Titanium dioxide, hypromellose, polyethylene glycol, iron oxide red, iron oxide yellow) and purified water.

DOSAGE AND ADMINISTRATION DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of Diclofenac Sodium Delayed-Release Tablets and other treatment options before deciding to use Diclofenac Sodium Delayed-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 Delayed-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 100-150 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 150-200 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 100-125 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 enteric-coated tablets; Diclofenac sodium extended-release tablets, Diclofenac potassium immediate-Release tablets) are not necessarily bioequivalent even if the milligram strength is the same.

INDICATIONS AND USAGE INDICATIONS AND USAGE Carefully consider the potential benefits and risks of Diclofenac Sodium Delayed-Release Tablets and other treatment options before deciding to use Diclofenac Sodium Delayed-Release Tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Diclofenac Sodium Delayed-Release Tablets, USP, are indicated: For relief of signs and symptoms of osteoarthritis For relief of signs and symptoms of rheumatoid arthritis For acute or long-term use in the relief of signs and symptoms of ankylosing spondylitis

OVERDOSAGE OVERDOSAGE Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

CLINICAL PHARMACOLOGY CLINICAL PHARMACOLOGY Pharmacodynamics Diclofenac Sodium Delayed-Release Tablets, are a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Diclofenac Sodium Delayed-Release Tablets, 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). 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%. Table 1. Pharmacokinetic Parameters for Diclofenac Normal Healthy Adults (20-48 yrs.) PK Parameter Mean Coefficient of Mean Variation (%) Absolute Bioavailability (%) [N = 7] 55 40 Tmax (hr) [N = 56] 2.3 69 Oral Clearance (CL/F; mL/min) [N = 56] 582 23 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 (0.15-105 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-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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets elimination, so patients with hepatic disease may require reduced doses of Diclofenac Sodium Delayed-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.

20230331

3

VOLTAREN DICLOFENAC SODIUM D/R MAGNESIUM STEARATE METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A TITANIUM DIOXIDE HYPROMELLOSES WATER DICLOFENAC SODIUM DICLOFENAC LACTOSE MONOHYDRATE CELLULOSE, MICROCRYSTALLINE CROSCARMELLOSE SODIUM TALC FERRIC OXIDE RED FERRIC OXIDE YELLOW Light Brown round P;75

ANDA077863

VOLTAREN

DICLOFENAC SODIUM D/R

61919-060

HUMAN PRESCRIPTION DRUG

ORAL

diclofenac

HOW SUPPLIED HOW SUPPLIED Diclofenac Sodium Delayed-Release Tablets, USP, for oral administration, are available as: 25 mg: round, Light brown, enteric-coated tablets P 25 imprinted on one side in black ink and plain on the reverse side are supplied as: Bottles of 100.......................................NDC 16571-203-10 50 mg: round, Light brown, enteric-coated tablets P 50 imprinted on one side in black ink and plain on the reverse side are supplied as: Bottles of 60.........................................NDC 16571-202-06 Bottles of 100.......................................NDC 16571-202-10 Bottles of 1000.....................................NDC 16571-202-11 75 mg: round, Light brown, enteric-coated tablets P 75 imprinted on one side in black ink and plain on the reverse side are supplied as: Bottles of 60.........................................NDC 16571-201-06 Bottles of 100.......................................NDC 16571-201-10 Bottles of 500.......................................NDC 16571-201-50 Bottles of 1000.....................................NDC 16571-201-11 Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). Protect from moisture. Dispense in a tight, light-resistant container.

BOXED WARNING 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 and Precautions]. Diclofenac sodium delayed-release tablets is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications and 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).