DICLOFENAC SODIUM- diclofenac sodium_solution

Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of diclofenac sodium, 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 in vivo Absorption: After administration of diclofenac sodium topical solution (40 mg/knee every 12 h; total daily diclofenac exposure: 80 mg/knee) for 7. 5 days, the mean (SD) AUC 0-12 max 0-12 max The pharmacokinetics and effect of diclofenac sodium were not evaluated under the conditions of heat application, occlusive dressings overlay, or exercise following product application. Therefore, concurrent use of diclofenac sodium under these conditions is not recommended. Distribution: Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. 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: 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. 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. Specific Populations: Pediatric: Race: Drug Interaction Studies Aspirin: Table 3 see Drug Interactions (7).

Diclofenac sodium topical solution is indicated for the treatment of the pain of osteoarthritis of the knee(s). Diclofenac sodium topical solution is a nonsteroidal anti-inflammatory drug indicated for the treatment of the pain of osteoarthritis of the knee(s).

DOSAGE AND ADMINISTRATION
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. The recommended dose is 2 pump actuations on each painful knee, 2 times a day. ( 2 Apply diclofenac sodium topical solution to clean, dry skin. 1 Dispense 40 mg (2 pump actuations) directly onto the knee or first into the hand and then onto the knee. Spread evenly around front, back and sides of the knee. 1 Wash hands completely after administering the product. 2 Wait until the area is completely dry before covering with clothing or applying sunscreen, insect repellent, cosmetics, topical medications, or other substances. 2 Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s). 2 Do not get diclofenac sodium topical solution in your eyes, nose, or mouth ( 2. 2 Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions (5. 2) For relief of the pain of osteoarthritis (OA) of the knee(s), the recommended dose is 40 mg of diclofenac sodium (2 pump actuations) on each painful knee, 2 times a day. Apply diclofenac sodium topical solution to clean, dry skin. The pump must be primed before first use. Instruct patients to fully depress the pump mechanism (actuation) 4 times while holding the bottle in an upright position. This portion should be discarded to ensure proper priming of the pump. No further priming of the bottle should be required. After the priming procedure, diclofenac sodium topical solution is properly dispensed by completely depressing the pump 2 times to achieve the prescribed dosage for one knee. Deliver the product directly into the palm of the hand and then apply evenly around front, back, and sides of the knee. Application of diclofenac sodium topical solution in an amount exceeding or less than the recommended dose has not been studied and is therefore not recommended. Avoid showering/bathing for at least 30 minutes after the application of diclofenac sodium topical solution to the treated knee. Wash and dry hands after use. Do not apply diclofenac sodium topical solution to open wounds. Avoid contact of diclofenac sodium topical solution with eyes and mucous membranes. Do not apply external heat and/or occlusive dressings to treated knees. Avoid wearing clothing over the diclofenac sodium topical solution-treated knee(s) until the treated knee is dry. Protect the treated knee(s) from natural and artificial sunlight. Wait until the treated area is dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same knee you have just treated with diclofenac sodium topical solution. Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s). Do not use combination therapy with diclofenac sodium and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
Instructions for Use
Diclofenac Sodium (dye kloe'' fen ak soe'' dee um) Topical Solution USP, 2% w/w Read the Medication Guide that comes with diclofenac sodium topical solution first. Be sure that you read, understand and follow these Instructions for Use before you use diclofenac sodium topical solution for the first time. Important: For use on the skin only (topical). Do not get diclofenac sodium topical solution in your eyes, nose or mouth. Before you use diclofenac sodium topical solution: Apply diclofenac sodium topical solution exactly as your health care provider tells you. Talk with your health care provider or pharmacist if you are not sure. Only use diclofenac sodium topical solution to treat pain from osteoarthritis in your knee or knees. Apply diclofenac sodium topical solution on clean, dry skin that does not have any cuts, infections or rashes. Use diclofenac sodium topical solution two times a day on your knee or knees as prescribed. If you get diclofenac sodium topical solution in your eyes, rinse your eyes right away with water or saline. Call your health care provider if your eyes are irritated for more than one hour. Diclofenac sodium topical solution comes in a pump bottle. If you are using a diclofenac sodium topical solution pump bottle follow the steps below: Before you use diclofenac sodium topical solution pump bottle for the first time, you will need to prime the pump. Figure A Figure B Figure A. Steps for using diclofenac sodium topical solution pump bottle: Step 1: Wash your hands with soap and water before applying diclofenac sodium topical solution. Step 2: Remove the bottle cap and press the pump head down firmly and fully to dispense diclofenac sodium topical solution into the palm of your hand. Release the pump head and then press the pump head down firmly and fully a second time. When you use your diclofenac sodium topical solution pump bottle, you can hold the bottle at an angle. Put 2 pumps of diclofenac sodium topical solution on your hand (see Figure C Figure C. Step 3: Apply diclofenac sodium topical solution evenly around the front, back, and sides of your knee. Diclofenac sodium topical solution should be applied without massaging the knee (see Figures D E Figure D. Step 4: Repeat Steps 2 and 3 for your other knee if your health care provider has prescribed diclofenac sodium topical solution for both knees. Step 5: Wash your hands with soap and water right away after applying diclofenac sodium topical solution. Step 6: Replace the cap on the bottle and store in an upright position. After you use diclofenac sodium topical solution: Do not: cover your knee with clothing until your knee is completely dry. put sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medicines on your knee until it is completely dry. take a shower or a bath for at least 30 minutes after you put diclofenac sodium topical solution on your knee(s). use heating pads or cover the treated area with bandages where you have applied diclofenac sodium topical solution. exercise following application of diclofenac sodium topical solution. use sunlamp and tanning beds. Protect your treated knee from sunlight. Wear clothes that cover your skin if you have to be in the sunlight. How should I store diclofenac sodium topical solution? Store diclofenac sodium topical solution at room temperature between 68°F to 77°F (20°C to 25°C). Keep diclofenac sodium topical solution and all medicines out of the reach of children. This Instructions for Use has been approved by the U. Food and Drug Administration. Manufactured by: Taro Pharmaceuticals Inc. , Brampton, Ontario, Canada L6T 1C1 Sun Pharmaceuticals U. , Figure A Figure B Figure C Figure D Figure E.

The following adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [ see Warnings and Precautions (5. 1) GI Bleeding, Ulceration and Perforation [ see Warnings and Precautions (5. 2) Hepatotoxicity [ see Warnings and Precautions (5. 3) Hypertension [ see Warnings and Precautions (5. 4) Heart Failure and Edema [ see Warnings and Precautions (5. 5) Renal Toxicity and Hyperkalemia [ see Warnings and Precautions (5. 6) Anaphylactic Reactions [ see Warnings and Precautions (5. 7) Serious Skin Reactions [ see Warnings and Precautions (5. 9) Hematologic Toxicity [ see Warnings and Precautions (5. 12) The most common adverse reactions with diclofenac sodium topical solution are application site reactions. 1 To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceuticals Industries, Inc. , at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. Diclofenac Sodium Topical Solution The data described below reflect exposure to diclofenac sodium topical solution of 130 patients treated for 4 weeks (mean duration of 28 days) in one Phase 2 controlled trial. This population's mean age was approximately 60 years, 85% of patients were Caucasian, 65% were females, and all patients had primary osteoarthritis. The most common adverse events with diclofenac sodium topical solution were application site skin reactions. These events were the most common reason for withdrawing from the study. Application Site Reactions: In this controlled trial, application site reactions were characterized by one or more of the following: dryness (22%), exfoliation (7%), erythema (4%), pruritus (2%), pain (2%), induration (2%), rash (2%), and scabbing (<1%). Other Common Adverse Reactions: Table 1 lists all adverse reactions occurring in >1% of patients receiving diclofenac sodium topical solution, where the rate in the diclofenac sodium topical solution group exceeded vehicle, from a controlled study conducted in patients with osteoarthritis. Table 1: Incidence of Adverse Reactions Occurring in >1% of Subjects with Osteoarthritis Using Diclofenac Sodium Topical Solution and More Often than in Subjects with OA Using Vehicle Control (Pooled) Adverse Reaction Diclofenac Sodium Topical Solution Vehicle Control Urinary tract infection 4 (3%) 1 (<1%) Application site induration 2 (2%) 1 (<1%) Contusion 2 (2%) 1 (<1%) Sinus congestion 2 (2%) 1 (<1%) Nausea 2 (2%) 0 Diclofenac Sodium Topical Solution 1. 5% The safety of diclofenac sodium topical solution 2% is based in part, on prior experience with diclofenac sodium topical solution 1. The data described below reflect exposure to diclofenac sodium topical solution 1. 5% of 911 patients treated between 4 and 12 weeks (mean duration of 49 days) in seven Phase 3 controlled trials, as well as exposure of 793 patients treated in an open-label study, including 463 patients treated for at least 6 months, and 144 patients treated for at least 12 months. The population mean age was approximately 60 years, 89% of patients were Caucasian, 64% were females, and all patients had primary osteoarthritis. The most common adverse events with diclofenac sodium topical solution 1. 5% were application site skin reactions. These events were the most common reason for withdrawing from the studies. Application Site Reactions: In controlled trials, application site reactions were characterized by one or more of the following: dryness, erythema, induration, vesicles, paresthesia, pruritus, vasodilation, acne, and urticaria. The most frequent of these reactions were dry skin (32%), contact dermatitis characterized by skin erythema and induration (9%), contact dermatitis with vesicles (2%) and pruritus (4%). In one controlled trial, a higher rate of contact dermatitis with vesicles (4%) was observed after treatment of 152 subjects with the combination of diclofenac sodium topical solution 1. 5% and oral diclofenac. In the open-label uncontrolled long-term safety study, contact dermatitis occurred in 13% and contact dermatitis with vesicles in 10% of patients, generally within the first 6 months of exposure, leading to a withdrawal rate for an application site event of 14%. Other Common Adverse Reactions: In controlled trials, subjects treated with diclofenac sodium topical solution 1. 5% experienced some adverse events associated with the NSAID class more frequently than subjects using placebo (constipation, diarrhea, dyspepsia, nausea, flatulence, abdominal pain, edema; see Table 2 Table 2 lists all adverse reactions occurring in >=1% of patients receiving diclofenac sodium topical solution 1. 5%, where the rate in the diclofenac sodium topical solution 1. 5% group exceeded placebo, from seven controlled studies conducted in patients with osteoarthritis. Since these trials were of different durations, these percentages do not capture cumulative rates of occurrence. Table 2: Adverse Reactions Occurring in >=1% of Patients Treated with Diclofenac Sodium Topical Solution 1. 5% in Placebo and Oral Diclofenac-Controlled Trials Treatment Group: Diclofenac Sodium Topical Solution 1. 5% Topical Placebo Adverse Reaction N (%) N (%) Dry Skin (Application Site) 292 (32) 17 (5) Contact Dermatitis (Application Site) 83 (9) 6 (2) Dyspepsia 72 (8) 13 (4) Abdominal Pain 54 (6) 10 (3) Flatulence 35 (4) 1 (<1) Pruritus (Application Site) 34 (4) 7 (2) Diarrhea 33 (4) 7 (2) Nausea 33 (4) 3 (1) Pharyngitis 40 (4) 13 (4) Constipation 29 (3) 1 (<1) Edema 26 (3) 0 Rash (Non-Application Site) 25 (3) 5 (2) Infection 25 (3) 8 (2) Ecchymosis 19 (2) 1 (<1) Dry Skin (Non-Application Site) 19 (2) 1 (<1) Contact Dermatitis, vesicles (Application Site) 18 (2) 0 Paresthesia (Non-Application Site) 14 (2) 3 (<1) Accidental Injury 22 (2) 7 (2) Pruritus (Non-Application Site) 15 (2) 2 (<1) Sinusitis 10 (1) 2 (<1) Halitosis 11 (1) 1 (<1) Application Site Reaction (not otherwise specified) 11 (1) 3 (<1) In postmarketing surveillance, the following adverse reactions have been reported during post-approval use of diclofenac sodium topical solution 1. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Cardiovascular: Gastrointestinal: Metabolic and Nutritional: Musculoskeletal: Nervous: Respiratory: Skin and Appendages: At the Application Site: Other Skin and Appendages Adverse Reactions: Special Senses: Vascular:.

Diclofenac sodium is contraindicated in the following patients: Known hypersensitivity (e. , anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [ see Warnings and Precautions (5. 9) 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 and Precautions (5. 8) In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions (5. 1) Known hypersensitivity to diclofenac or any components of the drug product. ( 4 History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. ( 4 In the setting of coronary artery bypass graft (CABG) surgery.

Infertility: 8. 3 Risk Summary Use of NSAIDs, including diclofenac sodium, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of diclofenac sodium topical solution use between about 20 and 30 weeks of gestation, and avoid diclofenac sodium topical solution use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations Data Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including diclofenac sodium, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, no evidence of malformations were observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses up to approximately 0. 3 times, respectively, the maximum recommended human dose (MRHD) of 162 mg diclofenac sodium via diclofenac sodium topical solution, despite the presence of maternal and fetal toxicity at these doses (see Data The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of the Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including diclofenac sodium, can cause premature closure of the fetal ductus arteriosus (see Data Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If diclofenac sodium topical solution treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac sodium topical solution and follow up according to clinical practice (see Data Labor or Delivery There are no studies on the effects of diclofenac sodium during labor or delivery. In animal studies, NSAIDs, including diclofenac inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with 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. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce malformations despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 0. 6 times the maximum recommended human dose [MRHD] of diclofenac sodium topical solution, 162 mg diclofenac sodium/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0. 3-times, respectively, the MRHD based on BSA comparison). Published reproductive and developmental studies of dimethyl sulfoxide (DMSO, the solvent used in diclofenac sodium topical solution) are equivocal as to potential teratogenicity. In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0. 24 times the MRHD, respectively, based on BSA comparison) 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 and rats. In published studies, diclofenac administration to pregnant rats prolonged gestation and produced liver toxicity and neuronal loss in offspring (1 mg/kg, IP; 0. 06 times the MRHD based on BSA comparison), impaired nephrogenesis in the kidney (3. 6 mg/kg, IP; 0. 2 times the MRHD based on BSA comparison), and caused adverse effects on the developing testes (6. 1 mg/kg, oral; 0. 4 times the MRHD based on BSA comparison). Risk Summary Based on available data, diclofenac may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for diclofenac sodium topical solution and any potential adverse effects on the breastfed infant from the diclofenac sodium topical solution or from the underlying maternal condition. Data One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0. 03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period). Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including diclofenac sodium, 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 sodium topical solution, in women who have difficulties conceiving or who are undergoing investigation of infertility. Males Published studies in adult male rodents report that diclofenac, at clinically relevant doses, can produce adverse effects on male reproductive tissues. The impact of these findings on male fertility is not clear [ See Nonclinical Toxicology (13. 1) Safety and effectiveness in pediatric patients have not been established. 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 and Precautions (5. 14) Of the 911 patients treated with diclofenac sodium 1. 5% in seven controlled, Phase 3 clinical trials, 444 subjects were 65 years of age and over. There was no age-related difference in the incidence of adverse events. Of the 793 patients treated with diclofenac sodium topical solution 1. 5% in one open-labeled safety trial, 334 subjects were 65 years of age and over including 107 subjects 75 and over. There was no difference in the incidence of adverse events with long-term exposure to diclofenac sodium topical solution 1. 5% for this elderly population.

See Table 3 Table 3: 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 increased the 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 sodium with anticoagulants (e. , warfarin), antiplatelet agents (e. , aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5. 12) 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 and Precautions (5. 2) Intervention: Concomitant use of diclofenac sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5. 12) 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 sodium and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium 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 and Precautions (5. 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. , 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 sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5. 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 sodium 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 sodium 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. , neutropenia, thrombocytopenia, renal dysfunction) Intervention: During concomitant use of diclofenac sodium and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of diclofenac sodium and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of diclofenac sodium 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. , diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5. Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of diclofenac sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of diclofenac sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Drugs that Interfere with Hemostasis (e. , warfarin, aspirin, SSRIs/SNRIs) 7 ACE Inhibitors, Angiotensin Receptor Blockers (ARB) or Beta-Blockers 7 ACE Inhibitors and ARBs 7 Diuretics 7 Digoxin: 7.

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 and Precautions (5.1 5.2 5.4 5.6) Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Emesis is not recommended due to a possibility of aspiration and subsequent respiratory irritation by DMSO contained in diclofenac sodium. Consider 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 overdosage (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).
NONCLINICAL TOXICOLOGY
Carcinogenesis Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent for 2 years resulted in no significant increases in tumor incidence at doses up to 2 mg/kg/day approximately 0. 7 times, respectively, the maximum recommended human topical dose of diclofenac sodium topical solution (based on apparent bioavailability and body surface area comparison). In a dermal carcinogenicity study conducted in albino mice, daily topical applications of diclofenac sodium for two years at concentrations up to 0. 035% diclofenac sodium (a 57-fold lower diclofenac sodium concentration than present in diclofenac sodium topical solution) did not increase neoplasm incidence. In a photococarcinogenicity study conducted in hairless mice, topical application of diclofenac sodium at doses up to 0. 035% diclofenac sodium (a 57-fold lower diclofenac sodium concentration than present in diclofenac sodium topical solution) resulted in an earlier median time of onset of tumors. Mutagenesis Diclofenac was not mutagenic or clastogenic in a battery of genotoxicity tests that included the bacterial reverse mutation assay, in vitro in vitro in vivo Impairment of Fertility Fertility studies have not been conducted with diclofenac sodium topical solution. Diclofenac sodium administered to male and female rats at doses up to 4 mg/kg/day (approximately 3. 4 times the MRHD of diclofenac sodium topical solution based on apparent bioavailability and body surface area comparison) did not affect fertility. Studies conducted in rats found no effect of dermally applied DMSO on fertility, reproductive performance, or offspring performance. However, published studies report that treatment of adult male rats with diclofenac by the oral route at 10 mg/kg (0. 6 times the MRHD) for 14 days and at 0. 25 mg/kg (0. 01 times the MRHD) for 30 days produced adverse effects on male reproductive hormones and testes. Ocular Effects No adverse effects were observed using indirect ophthalmoscopy after multiple-daily dermal application to rats for 26 weeks and minipigs for 52 weeks of DMSO at twice the concentration found in diclofenac sodium topical solution. Published studies of dermal or oral administration of DMSO to rabbits, dogs and pigs described refractive changes of lens curvature and cortical fibers indicative of myopic changes and/or incidences of lens opacity or discoloration when evaluated using slit-lamp biomicroscopy examination, although no ocular abnormalities were observed in rhesus monkeys during daily oral or dermal treatment with DMSO for 9 to 18 months.
CLINICAL STUDIES
Diclofenac Sodium Topical Solution The use of diclofenac sodium topical solution for the treatment of pain of osteoarthritis of the knee was evaluated in a single double-blind controlled trial conducted in the US, involving patients treated with diclofenac sodium topical solution at a dose of 2 pumps twice a day for 4 weeks. Diclofenac sodium topical solution was compared to topical vehicle, applied directly to the study knee. In this trial, patients treated with diclofenac sodium topical solution experienced a greater reduction in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale compared to patients treated with vehicle. Numerical results of the WOMAC pain subscale are summarized in Table 4. Table 4: Change in Treatment Outcomes after 4 Weeks of Treatment with Diclofenac Sodium Topical Solution Efficacy Variable Treatment Diclofenac Sodium Topical Solution Vehicle Control WOMAC Pain Subscale WOMAC pain subscale is based on the sum of pain scores for five items using a 5-point Likert scale. Baseline 12.4 12.6 Mean Change from Baseline -4.5 -3.6

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