Cardiovascular Risk NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. See WARNINGS. Diclofenac sodium delayed-release tablets are contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft CABG surgery see 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. DESCRIPTION Diclofenac, as the sodium salt, is a benzene-acetic acid derivative.. The chemical name is 2-[2,6-dichlorophenylamino] benzeneacetic acid, monosodium salt. The molecular weight is Its molecular formula is C14H10Cl2NNaO2, and it has the following structural formula Each enteric-coated tablet for oral administration contains 50 mg or 75 mg of diclofenac sodium. In addition, each tablet contains the following inactive ingredients; black iron oxide, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, pharmaceutical glaze, polyethylene glycol, povidone, sodium starch glycolate, talc, titanium dioxide, triethyl citrate. 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 hours and a reduction in peak plasma levels of 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. 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 eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc., Diclofenac 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 nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms, and the appropriate action patients should take if the signs and symptoms appear. To minimize the potential risk for an adverse liver related event in patients treated with Diclofenac, the lowest effective dose should be used for the shortest duration possible. Caution should be exercised in prescribing Diclofenac with concomitant drugs that are known to be potentially hepatotoxic antibiotics, anti-epileptics. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to diclofenac . Diclofenac 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. Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions NSAIDs, including diclofenac, 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 should be avoided because it may cause premature closure of the ductus arteriosus. PRECAUTIONS General Diclofenac sodium delayed-release tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of diclofenac in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including diclofenac. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including diclofenac, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving diclofenac who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, diclofenac should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. Diclofenac, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up see WARNINGS, CARDIOVASCULAR EFFECTS. Diclofenac, like other NSAIDs, can cause GI discomfort and, rarely, more serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up see WARNINGS, Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation. Diclofenac, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. Patients should be informed of the warning signs and symptoms of hepatotoxicity nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms. If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. See WARNINGS; Hepatic Effects Patients should be informed of the signs of an anaphylactoid reaction difficulty breathing, swelling of the face or throat. If these occur, patients should be instructed to seek immediate emergency help see WARNINGS. In late pregnancy, as with other NSAIDs, diclofenac should be avoided because it may cause premature closure of the ductus arteriosus. Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. In patients on long-term treatment with NSAIDs, including diclofenac, the CBC and a chemistry profile including transaminase levels should be checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur eosinophilia, rash, etc. or if abnormal liver tests persist or worsen, diclofenac should be discontinued. Drug Interactions Aspirin When diclofenac are administered with aspirin, its protein binding is reduced. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Cyclosporine Diclofenac, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with diclofenac may increase cyclosporine’s nephrotoxicity. Caution should be used when diclofenacare administered concomitantly with cyclosporine. ACE-inhibitor Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Furosemide Clinical studies, as well as post-marketing observations, have shown that diclofenac can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure see WARNINGS, Renal Effects, as well as to assure diuretic efficacy. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. Pregnancy Teratogenic Effects Pregnancy Category C Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Nonteratogenic Effects Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system closure of ductus arteriosus, use during pregnancy particularly late pregnancy should be avoided. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of diclofenac on labor and delivery in pregnant women are unknown. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from diclofenac, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use As with any NSAIDs, caution should be exercised in treating the elderly 65 years and older. 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, liver failure, 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 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. 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. 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, 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 or or 75 mg For the relief of rheumatoid arthritis, the recommended dosage is 150-200 mg/day in divided doses 50 mg or or 75 mg For the relief of ankylosing spondylitis, the recommended dosage is 100-125 mg/day, administered as 25 mg 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. HOW SUPPLIED Repackaged by Aphena Pharma Solutions - Repackaging Information for available configurations. Diclofenac sodium delayed-release tablets 50 mg - white to off-white, biconvex, round-shaped, unscored imprinted "CTI 102" on one side, supplied in bottles of 180 NDC 42291-230-181000 NDC 42291-230-10 75 mg - white to off-white, biconvex, round shaped, unscored imprinted "CTI 103" on one side, supplied in bottles of 180 NDC 42291-231-181000 NDC 42291-231-10 Store at 20° to 25°C 68° to 77°F see USP Controlled Room Temperature. Protect from moisture. Dispense in a tight, light-resistant container. Manufactured by Carlsbad Technology, CA 92008 USA Distributed by AvKARE TN 38478 Revised February 2010CTI-11 Rev. CAK02-11Printed in USA MEDICATION GUIDE for Non-Steroidal Anti-Inflammatory Drugs NSAIDs See the end of this Medication Guide for a list of prescription NSAID medicines. What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs NSAIDs? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases • with longer use of NSAID medicines • in people who have heart disease NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft CABG.” NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding • can happen without warning symptoms • may cause death The chance of a person getting an ulcer or bleeding increases with • taking medicines called “corticosteroids” and “anticoagulants” • longer use • smoking • drinking alcohol • older age • having poor health NSAID medicines should only be used • exactly as prescribed • at the lowest dose possible for your treatment • for the shortest time needed What are Non-Steroidal Anti-Inflammatory Drugs NSAIDs? NSAID medicines are use to treat pain and redness, swelling, and heat inflammation from medical conditions such as • different types of arthritis • menstrual cramps and other types of short-term pain Who should not take a Non-Steroidal Anti-Inflammatory Drug NSAID? Do not take an NSAID medicine • if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine • for pain right before or after heart bypass surgery Tell your healthcare provider • about all of your medical conditions. • about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side a list of your medicines to show to your healthcare provider and pharmacist. • if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. • if you are breastfeeding. Talk to your doctor. What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs NSAIDs? Serious side effects include • heart attack• stroke• high blood pressure• heart failure from body swelling fluid retention• kidney problems including kidney failure• bleeding and ulcers in the stomach and intestine• low red blood cells anemia • life-threatening skin reactions• life-threatening allergic reactions• liver problems including liver failure• asthma attacks in people who have asthma Other side effects include • stomach pain• constipation• diarrhea• gas• heartburn• nausea• vomiting• dizziness Get emergency help right away if you have any of the following symptoms • shortness of breath or trouble breathing • chest pain • weakness in one part or side of your body • slurred speech • swelling of the face or throat Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms • nausea • more tired or weaker than usual • itching • your skin or eyes look yellow • stomach pain • flu-like symptoms • vomit blood • there is blood in your bowel movement or it is black and stickylike tar • unusual weight gain • skin rash or blisters with fever • swelling of the arms and legs, hands and feet These are not all the side effects with NSAID medicines. Talk to your health care provider or pharmacist for more information about NSAID medicines. Call your doctor for medical advice about the side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about Non-Steroidal Anti-Inflammatory Drugs NSAIDs • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some of these NSAID medicines are sold in lower doses without a prescription over-the-counter. Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. NSAID medicines that need a prescription Generic Name Tradename Celecoxib Celebrex Diclofenac Cataflam, Voltaren, Arthrotec combined with misoprostol DiflunisalDolobid EtodalacLodine, Lodine XL Fenoprofen Nalfon, Nalfon 200 FlurbiprofenAnsaid Ibuprofen Motrin, Tab-Profen, Vicoprofen* combined with hydrocodone, Combunox combined with oxycodone Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan KetoprofenOruvail KetorolacToradol Mefenamic AcidPonstel MeloxicamMobic NabumetoneRelafen Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac copackaged with lansoprazole OxaprozinDaypro PiroxicamFeldene SulindacClinoril Tolmetin Tolectin, Tolectin DS, Tolectin 600 *Vicoprofen contains the same dose of ibuprofen as over-thecounter OTC NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke. This Medication Guide has been approved by the Food and Drug Administration. Repackaging Information Please reference the How Supplied section listed above for a description of individual tablets or capsules. This drug product has been received by Aphena Pharma - TN in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below Count50mg 6043353-784-53 Store between 20°-25°C 68°-77°F. See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children. Repackaged by Cookeville, TN 38506 20120706AW PRINCIPAL DISPLAY PANEL - 50mg NDC 43353-784Diclofenac NA DR 50mg - Rx Only Aphena Pharma Solutions - Tennessee, Inc.