DICLOFENAC SODIUM_DELAYED RELEASE- diclofenac sodium_tablet, delayed release

CLINICAL PHARMACOLOGY
Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of diclofenac, 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. 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 Table 1. Pharmacokinetic Parameters for Diclofenac PK Parameter Normal Healthy Adults (20-48 years) Mean Coefficient of Mean Variation (%) Absolute 55 40 T max 2. 3 69 Oral Clearance (CL/F; 582 23 Renal Clearance <1 em dash Apparent Volume of 1. 4 58 Terminal Half-life (hr) 2. 3 48 The apparent volume of distribution (V/F) of diclofenac sodium is 1. 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. 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-hydroxydiclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. 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. Pediatric: Race: Hepatic Impairment: Renal Impairment: Voriconazole: max see PRECAUTIONS; Drug Interactions Aspirin: Table 2 see PRECAUTIONS; Drug Interactions.
Mechanism of Action
Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of diclofenac, 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
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 Table 1. Pharmacokinetic Parameters for Diclofenac PK Parameter Normal Healthy Adults (20-48 years) Mean Coefficient of Mean Variation (%) Absolute 55 40 T max 2. 3 69 Oral Clearance (CL/F; 582 23 Renal Clearance <1 em dash Apparent Volume of 1. 4 58 Terminal Half-life (hr) 2. 3 48 The apparent volume of distribution (V/F) of diclofenac sodium is 1. 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. 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-hydroxydiclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. 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.
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 Table 1. Pharmacokinetic Parameters for Diclofenac PK Parameter Normal Healthy Adults (20-48 years) Mean Coefficient of Mean Variation (%) Absolute 55 40 T max 2.3 69 Oral Clearance (CL/F; 582 23 Renal Clearance <1 em dash Apparent Volume of 1.4 58 Terminal Half-life (hr) 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 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
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-hydroxydiclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. 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.
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-hydroxydiclofenac 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.
Masking of Inflammation and Fever
The pharmacological activity of diclofenac in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
Mutagenesis
Diclofenac sodium did not show mutagenic activity in in vitro in vitro in vivo

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; Gastrointestinal Bleeding, Ulceration, and Perforation 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; Gastrointestinal Bleeding, Ulceration, and Perforation 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 100-150 mg/day in divided doses (50 mg twice a day or three times a day, or 75 mg twice a day). For the relief of rheumatoid arthritis, the recommended dosage is 150-200 mg/day in divided doses (50 mg three times a day. or four times a day, or 75 mg twice a day.). For the relief of ankylosing spondylitis, the recommended dosage is 100-125 mg/day, administered as 25 mg four times a day, with an extra 25-mg dose at bedtime if necessary.

Gastrointestinal Bleeding,Ulceration, and Perforation
NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events Patients with a prior history of peptic ulcer disease and/or GI bleeding who use Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue diclofenac sodium delayed-release tablets until a In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding (see PRECAUTIONS; Drug Interactions.
Hepatotoxicity
In clinical trials of diclofenac- containing products,meaningful elevations (i.e.,more In a European retrospective population-based, case-controlled study, 10 cases of
Renal Toxicity and Hyperkalemia
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal Renal toxicity has also been seen in patients in whom renal prostaglandins have a Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac. PRECAUTIONS; Drug Interactions Increases in serum potassium concentration, including hyperkalemia, have been reported.
Hyperkalmia
Increases in serum potassium concentration, including hyperkalemia, have been reported
Anaphylactic Reactions
Diclofenac has been associated with anaphylactic reactions in patients with and without CONTRAINDICATIONS WARNINGS;Exacerbation of Asthma Related to Aspirin Sensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported
Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood PRECAUTIONS; Drug Interactions
Gastrointestinal Bleeding,Ulceration, and Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding (see WARNING; Gastrointestinal Bleeding, Ulceration, and Perforation
Hepatotoxicity
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop diclofenac and seek immediate medical therapy (see WARNINGS; Hepatotoxicity
Anaphylactic Reactions
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur (see WARNINGS; Anaphylactic Reactions
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 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. Additional adverse experiences reported occasionally include: Body as a Whole: fever, infection, sepsis Cardiovascular System Digestive System: Hemic and Lymphatic System Metabolic and Nutritional Nervous System Respiratory System Skin and Appendages Special Senses Urogenital System Other adverse reactions, which occur rarely are: Body as a Whole: Cardiovascular System Digestive System Hemic and Lymphatic System Metabolic and Nutritional: Nervous System Respiratory System Skin and appendages Special Senses

CONTRAINDICATIONS
Diclofenac sodium delayed-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 other 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 Reaction Exacerbation of Asthma Related to Aspirin Sensitivity In the setting of coronary artery bypass graft (CABG) surgery ( see Warnings; Cardiovascular Thrombotic Events
Hypertension
NSAIDs, including diclofenac, can lead to new onset of hypertension or worsening of PRECAUTIONS; Drug Interactions
Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may CONTRAINDICATIONS

Special Populations
Pediatric: Race: Hepatic Impairment: Renal Impairment: Voriconazole: max see PRECAUTIONS; Drug Interactions Aspirin: Table 2 see PRECAUTIONS; Drug Interactions.
Female Fertility
Advise females of reproductive potential who desire pregnancy that NSAIDs, including diclofenac, may be associated with a reversible delay in ovulation (see PRECAUTIONS; Carcinogenesis, Mutagenesis, Impairment of Fertility
Pregnancy Section
Use of NSAIDs, including diclofenac, can cause premature closure of the fetal ductus arteriosusand fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of Diclofenac Sodium use between about 20 and 30 weeks of gestation, and avoid Diclofenac Sodium use at about 30 weeks of gestation and later in pregnancy. Premature Closure of Fetal Ductus Arteriosus Oligohydramnios/Neonatal Renal Impairment Data WARNINGS; Fetal Toxicity Fetal/Neonatal Adverse Reactions WARNINGS; Fetal Toxicity Oligohydramnios/Neonatal Renal Impairment WARNINGS; Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus: Oligohydramnios/Neonatal Renal Impairment: Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce teratogenicity despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 0. 5 times the maximum recommended human dose [MRHD] of diclofenac, 200 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0. 5 and 1 times, respectively, the MRHD based on BSA comparison). In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0. 2 times the MRHD based on BSA) from Gestation Day 15 through Lactation Day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice, rats, and humans.
Risk Summary
Use of NSAIDs, including diclofenac, can cause premature closure of the fetal ductus arteriosusand fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of Diclofenac Sodium use between about 20 and 30 weeks of gestation, and avoid Diclofenac Sodium use at about 30 weeks of gestation and later in pregnancy. Premature Closure of Fetal Ductus Arteriosus Oligohydramnios/Neonatal Renal Impairment Data WARNINGS; Fetal Toxicity
Clinical Considerations
Fetal/Neonatal Adverse Reactions WARNINGS; Fetal Toxicity Oligohydramnios/Neonatal Renal Impairment WARNINGS; Fetal Toxicity
Nursing Mothers
Risk Summary Data
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects (see WARNINGS; Cardiovascular Thrombotic Events Gastrointestinal Bleeding, Ulceration, and Perforation Hepatotoxicity Renal Toxicity and Hyperkalemia PRECAUTIONS; Laboratory Monitoring Diclofenac is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (See CLINICAL PHARMACOLOGY ADVERSE REACTIONS

Drug Interactions Studies
Voriconazole: max see PRECAUTIONS; Drug Interactions Aspirin: Table 2 see PRECAUTIONS; Drug Interactions.
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation Drug Interactions
Use of NSAIDS and Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with diclofenac until they talk to their healthcare provider (see PRECAUTIONS; Drug Interactions
Drug Interactions
See Table 2 Table 2: Clinically Significant Drug Interactions with Diclofenac Drugs That Interfere with Hemostasis Clinical Impact: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of diclofenac with anticoagulants (e.g., warfarin), antiplatelet agents see PRECAUTIONS Hematological Toxicity Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation Intervention: Concomitant use of diclofenac and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding ( see PRECAUTIONS: Hematological Toxicity ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible Intervention: During concomitant use of diclofenac and ACE-inhibitors, ARBs, or betablockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function ( see WARNINGS; Renal Toxicity and Hyperkalemia When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of diclofenac with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects ( see WARNINGS; Renal Toxicity and Hyperkalemia Digoxin Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of diclofenac and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of diclofenac and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of diclofenac and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of diclofenac and cyclosporine may increase cyclosporine''s nephrotoxicity. Intervention: During concomitant use of diclofenac and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy ( see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of diclofenac and pemetrexed may increase the risk of pemetrexedassociated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of diclofenac and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. CYP2C9 Inhibitors or Inducers: Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac. Intervention: A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers ( see CLINICAL PHARMACOLOGY; Pharmacokinetics

WARNINGS
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three To minimize the potential risk for an adverse CV event in NSAID-treated patients, There is no consistent evidence that concurrent use of aspirin mitigates the WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment CONTRAINDICATIONS Observational studies conducted in the Danish National Registry have NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events Patients with a prior history of peptic ulcer disease and/or GI bleeding who use Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue diclofenac sodium delayed-release tablets until a In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding (see PRECAUTIONS; Drug Interactions In clinical trials of diclofenac- containing products,meaningful elevations (i. ,more In a European retrospective population-based, case-controlled study, 10 cases of NSAIDs, including diclofenac, can lead to new onset of hypertension or worsening of PRECAUTIONS; Drug Interactions The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized PRECAUTIONS; Drug Interactions in patients with severe heart failure, monitor patients for signs of worsening heart failure. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal Renal toxicity has also been seen in patients in whom renal prostaglandins have a Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac. PRECAUTIONS; Drug Interactions Increases in serum potassium concentration, including hyperkalemia, have been reported Diclofenac has been associated with anaphylactic reactions in patients with and without CONTRAINDICATIONS WARNINGS;Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may CONTRAINDICATIONS NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative CONTRAINDICATIONS Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported Avoid use of NSAIDs, including Diclofenac Sodium, in pregnant women at about 30 weeks Use of NSAIDs, including Diclofenac Sodium, at about 20 weeks gestation or later in PRECAUTIONS; Pregnancy Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood PRECAUTIONS; Drug Interactions.
Carcinogenesis,Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (approximately 0. 1 times maximum recommended human dose (MRHD) of diclofenac, 200 mg/day, based on body surface area (BSA) comparison ) have revealed no significant increases in tumor incidence. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0. 3 mg/kg/day (approximately 0. 007 times the MRHD based on BSA comparison) in males and 1 mg/kg/day (approximately 0. 02 times the MRHD based on BSA comparison) in females did not reveal any oncogenic potential. Diclofenac sodium did not show mutagenic activity in in vitro in vitro in vivo Diclofenac sodium administered to male and female rats at 4 mg/kg/day (approximately 0. 2 times the MRHD based on BSA comparison) did not affect fertility. Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including diclofenac, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including diclofenac, in women who have difficulties conceiving or who are undergoing investigation of infertility.
Carcinogenesis
Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (approximately 0.1 times maximum recommended human dose (MRHD) of diclofenac, 200 mg/day, based on body surface area (BSA) comparison ) have revealed no significant increases in tumor incidence. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (approximately 0.007 times the MRHD based on BSA comparison) in males and 1 mg/kg/day (approximately 0.02 times the MRHD based on BSA comparison) in females did not reveal any oncogenic potential.
Data: Human Data
Premature Closure of Fetal Ductus Arteriosus: Oligohydramnios/Neonatal Renal Impairment:
Data: Animal Data
Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce teratogenicity despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 0.5 times the maximum recommended human dose [MRHD] of diclofenac, 200 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0.5 and 1 times, respectively, the MRHD based on BSA comparison). In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0.1 and 0.2 times the MRHD based on BSA) from Gestation Day 15 through Lactation Day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice, rats, and humans.
ADVERSE REACTIONS SECTION
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 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 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. Additional adverse experiences reported occasionally include: Body as a Whole: fever, infection, sepsis Cardiovascular System Digestive System: Hemic and Lymphatic System Metabolic and Nutritional Nervous System Respiratory System Skin and Appendages Special Senses Urogenital System Other adverse reactions, which occur rarely are: Body as a Whole: Cardiovascular System Digestive System Hemic and Lymphatic System Metabolic and Nutritional: Nervous System Respiratory System Skin and appendages Special Senses.
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 of body weight 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).

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