DICLOFENAC SODIUM- diclofenac sodium_liquid

CLINICAL PHARMACOLOGY
Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of diclofenac sodium topical solution, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2) Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. After topical administration to healthy human volunteers of single and multiple maximum doses of diclofenac sodium topical solution, 40 drops (approximately 1. 2 mL) to each knee (80 drops total dose), the following diclofenac pharmacokinetic parameters were obtained: (see Table 2). Table 2 Single-Dose (80 drops) and Multiple Dose (80 drops four times daily for 7 days) Diclofenac sodium topical solution Pharmacokinetic Parameters Pharmacokinetic Parameters Diclofenac sodium Normal Adults [N=18] (Age: 18 to 55 years) Normal Adults [N=19] (Age: 18 to 55 years) Single Dose Multiple Dose AUC0-t 177. h/mL AUC0-inf 196. h/mL Plasma Cmax 8. 3 ng/mL Plasma Tmax (h) 11. 5 Plasma t1/2 (h) 36. 004 CL/F (L/h) 244. 71 - Diclofenac systemic exposure from diclofenac sodium topical solution application (4 times daily for 1 week) was approximately 1/3 of the diclofenac systemic exposure from the Solaraze # 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. 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. 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. Pediatric: Race: Aspirin [see Drug Interactions ( 7.
Absorption
Diclofenac systemic exposure from diclofenac sodium topical solution application (4 times daily for 1 week) was approximately 1/3 of the diclofenac systemic exposure from the Solaraze #
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 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.
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.
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

Diclofenac sodium topical solution, 1. 5% w/w is a nonsteroidal anti-inflammatory drug indicated for the treatment of signs and symptoms of osteoarthritis of the knee(s). ( 1 Diclofenac sodium topical solution is indicated for the treatment of signs and symptoms of osteoarthritis of the knee(s) ( 1.

Instructions for Use
Diclofenac Sodium Topical Solution USP, 1.5% 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 D i cl o f e na c so d i u m topical solution: Apply diclofenac sodium topical solution exactly as your healthcare provider tells you. Talk with your healthcare 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 4 times each day on your knee or knees as prescribed. Your total dose for each knee is 40 drops of diclofenac sodium topical solution, each time you use it. If you get diclofenac sodium topical solution in your eyes, rinse your eyes right away with water or saline. Call your healthcare provider if your eyes are irritated for more than one hour. Steps for using Diclofenac sodium topical solution: Step 1. Wash your hands with soap and water before applying diclofenac sodium topical solution. Step 2. Put 10 drops of diclofenac sodium topical solution either or Figure A Figure A. Step 3. Spread diclofenac sodium topical solution evenly on the front, back and sides of your knee (see Figures B C total Figure B Figure C Step 4. If your healthcare provider has prescribed diclofenac sodium topical solution for both knees, repeat steps 2 and 3 for the other knee. After you use Diclofenac sodium topical solution: Wash your hands with soap and water right away after applying diclofenac sodium topical solution. Do not: touch the treated knee or allow another person to touch the knee treated with diclofenac sodium topical solution until your knee is completely dry. 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. use heating pads or cover the treated area with bandages where you have applied diclofenac sodium topical solution. use sunlamps and tanning beds. Protect your treated knee from sunlight. Wear clothes that cover your skin if you have to be in sunlight. How should I store Diclofenac sodium topical solution Store diclofenac sodium topical solution 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. # are trademarks of respective owners. Medication Guide available at www.vionausa.com/medguides or call 1-888-304-5011. This Instructions for Use has been approved by the U.S. Food and Drug Administration.">DOSAGE AND ADMINISTRATION
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. The recommended dose is 40 drops on each painful knee, 4 times a day. ( 2 Apply diclofenac sodium topical solution to clean, dry skin. 1 Dispense diclofenac sodium topical solution 10 drops at a time either directly onto the knee or first into the hand and then onto the knee. Spread diclofenac sodium topical solution evenly around front, back and sides of the knee. Repeat this procedure until 40 drops have been applied and the knee is completely covered with solution. 1 Wash hands completely after administering the product. Wait until the area is completely dry before covering with clothing or applying sunscreen, insect repellent, cosmetics, topical medications, or other substances. 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 Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warning and Precautions ( 5. 2 For the relief of the signs and symptoms of osteoarthritis of the knee(s), the recommended dose is 40 drops per knee, 4 times a day. Apply diclofenac sodium topical solution to clean, dry skin. To avoid spillage, dispense diclofenac sodium topical solution 10 drops at a time either directly onto the knee or first into the hand and then onto the knee. To treat the other knee, if symptomatic, repeat the procedure. 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 or 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 topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
Instructions for Use
Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: Increased risk of a heart attack or stroke that can lead to death with increasing doses of NSAIDs with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG). " Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: anytime during use without warning symptoms that may cause death The risk of getting an ulcer or bleeding increases with: past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs taking medicines called "corticosteroids", "anticoagulants", "SSRIs", or "SNRIs" increasing doses of NSAIDs older age longer use of NSAIDs poor health o smoking advanced liver disease drinking alcohol bleeding problems NSAIDs should only be used: exactly as prescribed at the lowest dose possible for your treatment for the shortest time needed What are NSAIDs? NSAIDs are used 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 NSAIDs? Do not take NSAIDs: if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: have liver or kidney problems have high blood pressure have asthma are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See "What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?" new or worse high blood pressure heart failure liver problems including liver failure kidney problems including kidney failure low red blood cells (anemia) life-threatening skin reactions life-threatening allergic reactions Other side effects of NSAIDs include: Get emergency help right away if you get any of the following symptoms: shortness of breath or trouble breathing slurred speech chest pain swelling of the face or throat weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: nausea vomit blood more tired or weaker than usual there is blood in your bowel movement or it is black and sticky like tar diarrhea itching unusual weight gain your skin or eyes look yellow skin rash or blisters with fever indigestion or stomach pain swelling of the arms, legs, hands and feet flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to Viona Pharmaceuticals Inc. at 1-888-304-5011 or FDA at 1-800-FDA-1088. Other information about NSAIDs: Aspirin is an NSAID 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 NSAIDs 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. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Please address medical inquiries to, drugsafety@vionausa. : 1-888-304-5011. Medication Guide available at www. com/medguides or call 1-888-304-5011. This Medication Guide has been approved by the U. Food and Drug Administration. Manufactured by: Zydus Lifesciences Ltd. Changodar, Ahmedabad, India Distributed by: Viona Pharmaceuticals Inc. Cranford, NJ 07016 Rev: 07/24 Diclofenac Sodium Topical Solution USP, 1. 5% 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 D i cl o f e na c so d i u m topical solution: Apply diclofenac sodium topical solution exactly as your healthcare provider tells you. Talk with your healthcare 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 4 times each day on your knee or knees as prescribed. Your total dose for each knee is 40 drops of diclofenac sodium topical solution, each time you use it. If you get diclofenac sodium topical solution in your eyes, rinse your eyes right away with water or saline. Call your healthcare provider if your eyes are irritated for more than one hour. Steps for using Diclofenac sodium topical solution: Step 1. Wash your hands with soap and water before applying diclofenac sodium topical solution. Put 10 drops of diclofenac sodium topical solution either or Figure A Figure A. Spread diclofenac sodium topical solution evenly on the front, back and sides of your knee (see Figures B C total Figure B Figure C Step 4. If your healthcare provider has prescribed diclofenac sodium topical solution for both knees, repeat steps 2 and 3 for the other knee. After you use Diclofenac sodium topical solution: Wash your hands with soap and water right away after applying diclofenac sodium topical solution. Do not: touch the treated knee or allow another person to touch the knee treated with diclofenac sodium topical solution until your knee is completely dry. 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. use heating pads or cover the treated area with bandages where you have applied diclofenac sodium topical solution. use sunlamps and tanning beds. Protect your treated knee from sunlight. Wear clothes that cover your skin if you have to be in sunlight. How should I store Diclofenac sodium topical solution Store diclofenac sodium topical solution 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. # are trademarks of respective owners. This Instructions for Use has been approved by the U. Diclofenac sodium topical solution Diclofenac sodium topical solution Diclofenac sodium topical solution.
Instructions for Use
Diclofenac Sodium Topical Solution USP, 1.5% 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 D i cl o f e na c so d i u m topical solution: Apply diclofenac sodium topical solution exactly as your healthcare provider tells you. Talk with your healthcare 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 4 times each day on your knee or knees as prescribed. Your total dose for each knee is 40 drops of diclofenac sodium topical solution, each time you use it. If you get diclofenac sodium topical solution in your eyes, rinse your eyes right away with water or saline. Call your healthcare provider if your eyes are irritated for more than one hour. Steps for using Diclofenac sodium topical solution: Step 1. Wash your hands with soap and water before applying diclofenac sodium topical solution. Step 2. Put 10 drops of diclofenac sodium topical solution either or Figure A Figure A. Step 3. Spread diclofenac sodium topical solution evenly on the front, back and sides of your knee (see Figures B C total Figure B Figure C Step 4. If your healthcare provider has prescribed diclofenac sodium topical solution for both knees, repeat steps 2 and 3 for the other knee. After you use Diclofenac sodium topical solution: Wash your hands with soap and water right away after applying diclofenac sodium topical solution. Do not: touch the treated knee or allow another person to touch the knee treated with diclofenac sodium topical solution until your knee is completely dry. 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. use heating pads or cover the treated area with bandages where you have applied diclofenac sodium topical solution. use sunlamps and tanning beds. Protect your treated knee from sunlight. Wear clothes that cover your skin if you have to be in sunlight. How should I store Diclofenac sodium topical solution Store diclofenac sodium topical solution 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. # are trademarks of respective owners. Medication Guide available at www.vionausa.com/medguides or call 1-888-304-5011. This Instructions for Use has been approved by the U.S. Food and Drug Administration.

ADVERSE REACTIONS
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 Most common adverse reactions with diclofenac sodium topical solution are application site reactions. 1 To report SUSPECTED ADVERSE REACTIONS, contact Viona Pharmaceuticals Inc. at 1-888-304-5011 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. The data described below reflect exposure to diclofenac sodium topical solution 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 Caucasians, 64% were females, and all patients had primary osteoarthritis. The most common adverse events with diclofenac sodium were application site skin reactions. These events were the most common reason for withdrawing from the studies. Application Site Reactions In controlled trials, the most common treatment-related adverse events in patients receiving diclofenac sodium were application site skin reactions. 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 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%. Adverse Events Common to the NSAID Class In controlled trials, subjects treated with diclofenac sodium topical solution 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 1). The combination of diclofenac sodium and oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%), and hemoglobin (13% vs. 9%), but no difference in elevation of liver transaminases. Table 1 lists all adverse reactions occurring in >= 1% of patients receiving diclofenac sodium, where the rate in the diclofenac sodium topical solution 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 1 Adverse Reactions occurring in >= 1% of patients treated with diclofenac sodium topical solution in placebo and oral diclofenac-controlled trials dagger Treatment Group: Diclofenac sodium topical solution N=911 Topical Placebo N=332 Adverse Reactiondagger 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 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 11 (1) 3 (<1) In non-U. postmarketing surveillance, the following adverse reactions have been reported during post-approval use of diclofenac sodium topical solution. 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: Digestive: Metabolic and Nutritional: Musculoskeletal: Nervous: Respiratory: Skin and Appendages: At the Application Site: Other Skin and Appendages Adverse Reactions: Special Senses:.
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.

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 ( 4 Diclofenac sodium topical solution 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.

USE IN SPECIFIC POPULATIONS
Infertility: 8. 3 Risk Summary Use of NSAIDs, including diclofenac sodium topical solution, 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 topical solution, 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 teratogenicity was observed in mice, rats, or rabbits given diclofenac daily during the period of organogenesis at doses up to approximately 0. 3 times, respectively, the maximum recommended human dose (MRHD) of diclofenac sodium topical solution, despite the presence of maternal and fetal toxicity at these doses [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac sodium, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. 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 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including diclofenac sodium topical solution, 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 topical solution 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 teratogenicity 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, 154 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0. 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 rats, maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. 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 CATAFLAM and any potential adverse effects on the breastfed infant from the CATAFLAM 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 topical solution, 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 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. Safety and effectiveness in pediatric patients have not been established. Elderly patients, compared to younger patients, are a 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 topical solution 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 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 for this elderly population.
Specific Populations
Pediatric: Race:

RECENT MAJOR CHANGES
Warnings and Precautions (5.9) 07/2024
DRUG INTERACTIONS
Drugs that Interfere with Hemostasis (e. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly using diclofenac sodium topical solution with drugs that interfere with hemostasis. Concomitant use of diclofenac sodium topical solution and analgesic doses of aspirin is not generally recommended ( 7 ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with diclofenac sodium topical solution may diminish the antihypertensive effect of these drugs. Monitor blood pressure ( 7 ACE Inhibitors and ARBs: Concomitant use with diclofenac sodium topical solution in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function ( 7 Diuretics: NSAIDS can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects ( 7 Digoxin: Concomitant use with diclofenac sodium topical solution can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels ( 7 See Table 2 for clinically significant drug interactions with diclofenac. Table 2 Clinically Significant Drug Interactions with Diclofenac Drugs That Interfere with Hemostasis Clinical Impact Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Intervention Monitor patients with concomitant use of diclofenac sodium topical solution 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 NSAID alone [see Warnings and Precautions ( 5. 2 Intervention Concomitant use of diclofenac sodium topical solution 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). Intervention During concomitant use of diclofenac sodium topical solution and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. [see Warnings and Precautions( 5. 6 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 topical solution with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( 5. 6 Digoxin Clinical Impact The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life digoxin. Intervention During concomitant use of diclofenac sodium topical solution 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 topical solution and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e. , neutropenia, thrombocytopenia, renal dysfunction). Intervention During concomitant use of diclofenac sodium topical solution and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact Concomitant use of diclofenac sodium topical solution and cyclosporine may increase cyclosporine''s nephrotoxicity. Intervention During concomitant use of diclofenac sodium topical solution and cyclosporine, monitor patients for signs or 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. 2 Intervention The concomitant use of diclofenac with other NSAIDs or salicyclates is not recommended. Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations. Pemetrexed Clinical Impact Concomitant use of diclofenac sodium topical solution 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 topical solution and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Drug Interaction Studies
Aspirin [see Drug Interactions ( 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 topical solution. 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 overdose treatment, contact a poison control center (1-800-2221222).
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 corresponding to approximately 0. 7-fold (mouse and rat, respectively) of the maximum recommended human topical dose (MRHD) 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 43-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 43-fold lower diclofenac sodium concentration than present in diclofenac sodium topical solution) resulted in an earlier median time of onset of tumors. 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 Fertility studies have not been conducted with diclofenac sodium topical solution. Diclofenac sodium topical solution administered to male and female rats at doses up to 4 mg/kg/day (1. 4-fold of the MRHD of diclofenac sodium topical solution based on apparent bioavailability and body surface area comparison) did not affect fertility. Studies have not been conducted to determine the safety of DMSO on fertility. 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
The use of diclofenac sodium topical solution for the treatment of the signs and symptoms of osteoarthritis of the knee was evaluated in two double-blind controlled trials conducted in the US and Canada, involving patients treated with diclofenac sodium topical solution at a dose of 40 drops four times a day for 12 weeks. Diclofenac sodium topical solution was compared to topical placebo (2.3% DMSO with other excipients) and/or topical vehicle solution (45.5% w/w DMSO with other excipients), applied directly to the study knee. In both trials, diclofenac sodium topical solution treatment resulted in statistically significant clinical improvement compared to placebo and/or vehicle, in all three primary efficacy variableshorizontal barpain, physical function (Western Ontario and McMaster Universities LK3.1 OA Index (WOMAC) pain and physical function dimensions) and Patient Overall Health Assessment (POHA)/Patient Global Assessment (PGA). Numerical results are summarized in Tables 3 and 4. Table 3 Change in treatment outcomes after 12 weeks of treatment in one study of efficacy of diclofenac sodium topical solution Efficacy Variable Study I Mean baseline score and mean change in efficacy variables after 12 weeks of treatment Mean Baseline score Diclofenac sodium topical solution N=154 Topical placebo 1 N=155 Topical vehicle 2 N=161 WOMAC pain score 13 -6.0 -4.7 -4.7 WOMAC physical 42 -15.7 -12.3 -12.1 POHA 2.3 -1.0 -0.4 -0.6 1 2 Table 4 Change in treatment outcomes after 12 weeks of treatment in one study of efficacy of diclofenac sodium topical solution Efficacy Variable Study II Mean baseline score and mean change in efficacy variables after 12 weeks of treatment Mean Baseline score Diclofenac sodium topical solution N=164 Topical vehicle1 N=162 WOMAC pain score 13 -5.9 -4.4 WOMAC physical function 42 -15.3 -10.3 PGA (0en dash4) 3.1 -1.3 -1.0 1

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