DICLOFENAC SODIUM- diclofenac sodium_tablet, delayed release

Mechanism of Action Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. Pharmacokinetics Absorption Table 1. Pharmacokinetic Parameters for Diclofenac PK Parameter Normal Healthy Adults (20 to 48 years) Mean Coefficient of Absolute Bioavailability (%) [N = 7] 55 40 T max 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 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 Excretion Special Populations Pediatric: Race: Hepatic Impairment: Renal Impairment: Drug Interactions Studies Voriconazole: PRECAUTIONS ; Drug Interactions Aspirin: PRECAUTIONS ; Drug Interactions

Carefully consider the potential benefits and risks of diclofenac sodium delayed-release tablets and other treatment options before deciding to use diclofenac sodium. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation Diclofenac sodium delayed-release tablets are indicated: for relief of the signs and symptoms of osteoarthritis

Carefully consider the potential benefits and risks of diclofenac sodium delayed release tablets and other treatment options before deciding to use diclofenac sodium. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNING; Gastrointestinal Bleeding, Ulceration, and Perforation After observing the response to initial therapy with diclofenac sodium, the dose and frequency should be adjusted to suit an individual patient’s needs. For the relief of osteoarthritis, the recommended dosage is 100 to 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 to 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 to 125 mg/day, administered as 25 mg four times a day, with an extra 25-mg dose at bedtime if necessary. Different formulations of diclofenac [diclofenac sodium delayed-release tablets; diclofenac sodium extended-release tablets); diclofenac potassium immediate-release tablets] are not necessarily bioequivalent even if the milligram strength is the same.

Cardiovascular Thrombotic Events (see WARNINGS GI Bleeding, Ulceration and Perforation (see WARNING 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 delayed-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: 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:

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

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).">WARNINGS
Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize 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, increases the risk of serious gastrointestinal (GI) events (see WARNING; Gastrointestinal Bleeding, Ulceration, and Perforation Status Post Coronary Artery Bypass Graft (CABG) Surgery CONTRAINDICATIONS Post-MI Patients Avoid the use of diclofenac sodium in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Gastrointestinal Bleeding, Ulceration, and Perforation Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy, concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients 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 bleeding, consider alternate therapies other than NSAIDs. 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 serious GI adverse event is ruled out. 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 than 3 times the upper limit of normal [ULN]) of aspartate aminotransferase (AST) (also known as SGOT) were observed in about 2% of approximately 5700 patients at some time during diclofenac treatment (alanine aminotransferase [ALT] was not measured in all studies). In a large, open-label, controlled trial of 3700 patients treated with oral diclofenac sodium for 2 to 6 months, patients were monitored first at 8 weeks and 1200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 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 first 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. In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug- induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days. Physicians should measure transaminases at baseline and 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 reactions 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. 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). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue diclofenac sodium delayed-release tablets immediately, and perform a clinical evaluation of the patient. To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium delayed-release tablets, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing diclofenac sodium delayed-release tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti- epileptics). Hypertension NSAIDs, including diclofenac sodium, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs (see PRECAUTIONS; Drug Interactions Monitor blood pressure (BP) 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 2-fold increase in hospitalization 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 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 PRECAUTIONS; 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 are used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Renal Toxicity and Hyperkalemia Renal Toxicity 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 an NSAID 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, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of diclofenac sodium in patients with advanced renal disease. The renal effects of diclofenac sodium may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium delayed-release tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium (see PRECAUTIONS; Drug Interactions Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Anaphylactic Reactions CONTRAINDICATIONS WARNINGS; Exacerbation of Asthma Related to Aspirin Sensitivity Exacerbation of Asthma Related to Aspirin Sensitivity CONTRAINDICATIONS Serious Skin Reactions CONTRAINDICATIONS Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including diclofenac sodium, at about 20-weeks’ gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30-weeks’ gestation, limit diclofenac sodium use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium treatment extends beyond 48 hours. Discontinue diclofenac sodium delayed-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with diclofenac sodium delayed-release tablets, has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including diclofenac sodium, may increase the risk of bleeding events. Co-morbid conditions, such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding (see PRECAUTIONS; Drug Interactions
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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DICLOFENAC SODIUM- diclofenac sodium_tablet, delayed release Product manual source documgent