nimize the potential risk for an adverse cv event in nsaid-treated patients, use the lowest effective dose for the shortest duration possible. physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous cv symptoms. patients should be informed about the symptoms of serious cv events and the steps to take if they occur. there is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious cv thrombotic events associated with nsaid use. the concurrent use of aspirin and an nsaid, such as diclofenac sodium, increases the risk of serious gastrointestinal (gi) events [see warnings]. status post coronary artery bypass graft (cabg) surgery two large, controlled clinical trials of a cox-2 selective nsaid for the treatment of pain in the first 10–14 days following cabg surgery found an increased incidence of myocardial infarction and stroke. nsaids are contraindicated in the setting of cabg [see contraindications]. post-mi patients observational studies conducted in the danish national registry have demonstrated that patients treated with nsaids in the post-mi period were at increased risk of reinfarction, cv-related death, and all-cause mortality beginning in the first week of treatment. in this same cohort, the incidence of death in the first year post mi was 20 per 100 person years in nsaid-treated patients compared to 12 per 100 person years in non-nsaid exposed patients. although the absolute rate of death declined somewhat after the first year post-mi, the increased relative risk of death in nsaid users persisted over at least the next four years of follow-up. avoid the use of diclofenac sodium delayed-release tablets in patients with a recent mi unless the benefits are expected to outweigh the risk of recurrent cv thrombotic events. if diclofenac sodium delayed-release tablets is used in patients with a recent mi, monitor patients for signs of cardiac ischemia. hypertension nsaids, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of cv events. patients taking thiazides or loop diuretics may have impaired response to these therapies when taking nsaids. nsaids, including diclofenac sodium delayed-release tablets, should be used with caution in patients with hypertension. blood pressure (bp) should be monitored closely during the initiation of nsaid treatment and throughout the course of therapy. heart failure and edema the coxib and traditional nsaid trialists’ collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in cox-2 selective-treated patients and nonselective nsaid-treated patients compared to placebo-treated patients. in a danish national registry study of patients with heart failure, nsaid use increased the risk of mi, hospitalization for heart failure, and death. additionally, fluid retention and edema have been observed in some patients treated with nsaids. use of diclofenac sodium may blunt the cv effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ace inhibitors, or angiotensin receptor blockers (arbs)] [see drug interactions ]. avoid the use of diclofenac sodium delayed-release tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. if diclofenac sodium delayed-release tablets is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. gastrointestinal (gi) effects – risk of gi ulceration, bleeding, and perforation nsaids, including diclofenac sodium delayed-release tablets, can cause serious gastrointestinal (gi) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. these serious adverse events can occur at any time, with or without warning symptoms, in patients treated with nsaids. only one in five patients, who develop a serious upper gi adverse event on nsaid therapy, is symptomatic. upper gi ulcers, gross bleeding, or perforation caused by nsaids occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. these trends continue with longer duration of use, increasing the likelihood of developing a serious gi event at some time during the course of therapy. however, even short-term therapy is not without risk. nsaids should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use nsaids have a greater than 10-fold increased risk for developing a gi bleed compared to patients with neither of these risk factors. other factors that increase the risk for gi bleeding in patients treated with nsaids include concomitant use of oral corticosteroids or anticoagulants, longer duration of nsaid therapy, smoking, use of alcohol, older age, and poor general health status. most spontaneous reports of fatal gi events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. to minimize the potential risk for an adverse gi event in patients treated with an nsaid, the lowest effective dose should be used for the shortest possible duration. patients and physicians should remain alert for signs and symptoms of gi ulceration and bleeding during nsaid therapy and promptly initiate additional evaluation and treatment if a serious gi adverse event is suspected. this should include discontinuation of the nsaid until a serious gi adverse event is ruled out. for high risk patients, alternate therapies that do not involve nsaids should be considered. renal effects caution should be used when initiating treatment with diclofenac sodium delayed-release tablets in patients with considerable dehydration. long-term administration of nsaids has resulted in renal papillary necrosis and other renal injury. renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. in these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ace inhibitors, and the elderly. discontinuation of nsaid therapy is usually followed by recovery to the pretreatment state. advanced renal disease no information is available from controlled clinical studies regarding the use of diclofenac sodium delayed-release tablets in patients with advanced renal disease. therefore, treatment with diclofenac sodium delayed-release tablets are not recommended in these patients with advanced renal disease. if diclofenac sodium delayed-release tablets therapy must be initiated, close monitoring of the patient’s renal function is advisable. hepatic effects elevations of one or more liver tests may occur during therapy with diclofenac delayed-release tablets. these laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. borderline elevations (i.e., less than 3 times the uln [uln = the upper limit of the normal range]) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. of the markers of hepatic function, alt (sgpt) is recommended for the monitoring of liver injury. in clinical trials, meaningful elevations (i.e., more than 3 times the uln) of ast (got) (alt was not measured in all studies) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment. in a large, open-label, controlled trial of 3,700 patients treated for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. meaningful elevations of alt and/or ast occurred in about 4% of patients and included marked elevations (i.e., more than 8 times the uln) in about 1% of the 3,700 patients. in that open-label study, a higher incidence of borderline (less than 3 times the uln), moderate (3-8 times the uln), and marked (>8 times the uln) elevations of alt or ast was observed in patients receiving diclofenac when compared to other nsaids. elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. almost all meaningful elevations in transaminases were detected before patients became symptomatic. abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. in postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the firth 2 months of therapy, but can occur at any time during treatment with diclofenac. postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. some of these reported cases resulted in fatalities or liver transplantation. physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. the optimum times for making the first and subsequent transaminase measurements are not known. based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. however, severe hepatic reaction can occur at any time during treatment with diclofenac. if abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium delayed-release tablets should be discontinued immediately. to minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms), and the appropriate action patients should take if these signs and symptoms appear. to minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium delayed-release tablets, the lowest effective dose should be used for the shortest duration possible. caution should be exercised in prescribing diclofenac sodium delayed-release tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics). anaphylactic reactions as with other nsaids, anaphylactic reactions may occur both in patients with the aspirin traid and in patients without known sensitivity to nsaids or known prior exposure to diclofenac sodium delayed-release tablets. diclofenac sodium delayed-release tablets should not be given to patients with the aspirin triad. this symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other nsaids (see contraindications and precautions, preexisting asthma.) anaphylaxis-type reactions have been reported with nsaid products, including with diclofenac products, such as diclofenac sodium delayed-release tablet. emergency help should be sought in cases where an anaphylactic reaction occurs. skin reactions nsaids, including diclofenac sodium delayed-release tablets, can cause serious skin adverse events such as exfoliative dermatitis, stevens-johnson syndrome (sjs), and toxic epidermal necrolysis (ten), which can be fatal. these serious events may occur without warning. patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. pregnancy in late pregnancy, as with other nsaids, diclofenac sodium delayed-release tablets should be avoided because it may cause premature closure of the ductus arteriosus.

ulations 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.

ombocytopenia 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.

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.

..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. manufactured by: unique pharmaceutical laboratories. (a div. of j. b. chemicals & pharmaceuticals ltd.) mumbai 400 030, india. manufactured for: rising® rising pharmaceuticals, inc. allendale, nj 07401 1-800-521-5340 118063 july 2015