diclofenac sodium 20 MG/ML Topical Solution [Pennsaid]

INDICATIONS AND USAGE Diclofenac sodium is a non-steroidal anti-inflammatory drug indicated for the relief of the pain of osteoarthritis of joints amenable to topical treatment, such as the knees and those of the hands. ( 1 ) Diclofenac sodium topical gel was not evaluated for use on joints of the spine, hip, or shoulder. ( 14.1 ) Diclofenac sodium topical gel is indicated for the relief of the pain of osteoarthritis of joints amenable to topical treatment, such as the knees and those of the hands. Diclofenac sodium topical gel has not been evaluated for use on the spine, hip, or shoulder. INSTRUCTIONS FOR USE Diclofenac Sodium Topical Gel, 1% Important: Use the dosing card that is inside the diclofenac sodium topical gel carton to correctly measure each dose. The dosing card is re-usable. Do not throw the dosing card away. Before you use diclofenac sodium topical gel for the first time, your healthcare provider or pharmacist should show you how to correctly measure your dose using the dosing card. Read this Instructions for Use before you start using diclofenac sodium topical gel and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Your healthcare provider has prescribed diclofenac sodium topical gel to help relieve arthritis pain in some of your joints. Diclofenac sodium topical gel may be used to treat arthritis pain in the arms (hands, wrists, and elbows) and in the legs (feet, ankles, and knees). It is not known if diclofenac sodium topical gel is safe and effective if used on your spine, hips, or shoulders. Use diclofenac sodium topical gel exactly how your healthcare provider prescribes it for you. Do not apply diclofenac sodium topical gel anywhere other than where your healthcare provider tells you to. Do not use more than a total of 32 grams of diclofenac sodium topical gel each day. If you add up the amount of diclofenac sodium topical gel as directed by your healthcare provider, it should not be more than 32 grams in one day. The dose for your hands, wrists, or elbows is 2 grams of diclofenac sodium topical gel each time you apply it. Apply diclofenac sodium topical gel 4 times a day (a total of 8 grams each day). Do not apply more than 8 grams each day to any one of your affected hands, wrists, or elbows. Some examples of diclofenac sodium topical gel application include: If you use 2 grams of diclofenac sodium topical gel on one hand, 4 times a day, your total dose for one day is 8 grams. If you use 4 grams of diclofenac sodium topical gel on one knee, 4 times a day, your total dose for one day is 16 grams. Your total dose for one day, treating one hand and one knee, is 8 grams plus 16 grams, which equals 24 grams of diclofenac sodium topical gel. Before you use a new tube of diclofenac sodium topical gel for the first time, open the foil seal that covers the tube opening by using the spiked top of the cap. Remember to remove the dosing card from the carton to measure your dose (see Figure A). Apply diclofenac sodium topical gel to clean, dry skin that does not have any cuts, open wounds, infections, or rashes. Do not use heating pads or apply bandages to where you have applied diclofenac sodium topical gel. Avoid exposing skin where you apply diclofenac sodium topical gel to sunlight and artificial light, such as tanning booths. Do not use sunscreens, cosmetics, lotions, moisturizers, insect repellants, or other topical medicines on the same skin areas where you have applied diclofenac sodium topical gel. Do not get diclofenac sodium topical gel in your eyes, nose, or mouth. Diclofenac sodium topical gel is only to be used on your skin (topical use). If you get diclofenac sodium topical gel in your eyes, rinse your eyes right away with water or saline. Talk with your healthcare provider if eye irritation lasts for more than one hour. What if I miss a dose? If you miss a dose of diclofenac sodium topical gel, continue with your next scheduled dose using the prescribed amount of diclofenac sodium topical gel. Do not double the dose. Applying 2 grams (2 g) of diclofenac sodium topical gel to hands, wrists, or elbows: Step 1. Remove the dosing card that is attached inside the diclofenac sodium topical gel carton. Use the dosing card to correctly measure each dose of diclofenac sodium topical gel. To measure the correct amount of diclofenac sodium topical gel, place the dosing card on a flat surface so that you can read the print. If the print is backwards, flip dosing card over (see Figure A). If you lose or misplace your dosing card, you can ask your pharmacist for a new one or call 1-866-604-3268. Ask your healthcare provider or pharmacist to show you how to correctly measure your dose of diclofenac sodium topical gel while you are waiting to receive your new dosing card. Step 2. Squeeze diclofenac sodium topical gel onto the dosing card evenly, up to the 2 g line (a 2.25 inch length of gel). Make sure that the gel covers the 2 g area of the dosing card (see Figure B). Put the cap back on the tube of diclofenac sodium topical gel. Ask your healthcare provider or pharmacist if you are not sure how to correctly measure your dose of diclofenac sodium topical gel. Step 3. Apply the gel to your hand, wrist, or elbow. You can use the dosing card to apply the gel (see Figure C). Then, use your hands to gently rub the gel into the skin (see Figure D). Do not share your dosing card with another person. Make sure to cover the entire affected hand, wrist, or elbow with the gel. Remember that the hand includes the palm of your hand, the top of your hand, and your fingers. Step 4. After using the dosing card, hold end with fingertips, rinse and dry. Store the dosing card until next use. Do not shower or bathe for at least 1 hour after applying diclofenac sodium topical gel. Do not wash your treated hands for at least 1 hour after applying the diclofenac sodium topical gel. Step 5. After applying diclofenac sodium topical gel, wait 10 minutes before covering the treated skin with gloves or clothing. Applying 4 grams (4 g) of diclofenac sodium topical gel to feet, ankles, or knees: Step 1. Refer to Step 1 above. Step 2. Squeeze diclofenac sodium topical gel onto the dosing card evenly up to the 4 g line (a 4.5 inch length of gel), making sure the gel covers the 4 g area of the dosing card (see Figure E). Put the cap back on the tube of diclofenac sodium topical gel. Ask your healthcare provider or pharmacist if you are not sure how to correctly measure your dose of diclofenac sodium topical gel. Step 3. Apply diclofenac sodium topical gel to your foot, ankle, or knee. You can use the dosing card to apply the gel (see Figure F). Then, use your hands to gently rub the gel into the skin (see Figure G). Do not share your dosing card with another person. Make sure to cover your entire foot, ankle, or knee area with the gel. For example, cover the skin above, below, inside and outside the knee cap. Remember that the foot includes the sole of your foot, the top of your foot, and your toes. Refer to Steps 4 and 5 above. Wash your hands after applying diclofenac sodium topical gel to your foot, ankle, or knee. What are the ingredients in diclofenac sodium topical gel? Active ingredient: diclofenac sodium, USP Inactive ingredients: carbomer homopolymer Type C, cocoyl caprylocaprate, fragrance, isopropyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water, and strong ammonia solution. How should I store diclofenac sodium topical gel? ● Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). ● Do not freeze diclofenac sodium topical gel. ● Store the dosing card with your diclofenac sodium topical gel. Keep diclofenac sodium topical gel, the dosing card, and all medicines out of the reach of children. This Medication Guide and Instructions for Use have bee

DOSAGE AND ADMINISTRATION Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions (5) ]. • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals (2.1) • Lower extremities: Apply the gel (4 g) to the affected area 4 times daily. Do not apply more than 16 g daily to any one affected joint of the lower extremities. (2.2) • Upper extremities: Apply the gel (2 g) to the affected area 4 times daily. Do not apply more than 8 g daily to any one affected joint of the upper extremities. (2.3) • Total dose should not exceed 32 g per day, over all affected joints. (2.3) Diclofenac sodium topical gel should be measured onto the enclosed dosing card to the appropriate 2 g or 4 g designation. (2) 2.1 Dosing Card [See the patient Instructions for Use] The dosing card can be found attached to the inside of the carton. The proper amount of diclofenac sodium topical gel should be measured using the dosing card supplied in the drug product carton. The dosing card is made of clear polypropylene. The dosing card should be used for each application of drug product. The gel should be applied within the rectangular area of the dosing card up to the 2 gram or 4 gram line (2 g for each elbow, wrist, or hand, and 4 g for each knee, ankle, or foot). The 2 g line is 2.25 inches long. The 4 g line is 4.5 inches long. The dosing card containing diclofenac sodium topical gel can be used to apply the gel. The hands should then be used to gently rub the gel into the skin. After using the dosing card, hold with fingertips, rinse, and dry. If treatment site is the hands, patients should wait at least one (1) hour to wash their hands. 2.2 Lower extremities, including the feet, ankles, or knees Apply the gel (4 g) to the affected foot, ankle, or knee 4 times daily. Diclofenac sodium topical gel should be gently massaged into the skin ensuring application to the entire affected foot, or knee or ankle. The entire foot includes the sole, top of the foot and the toes. Do not apply more than 16 g daily to any single joint of the lower extremities. 2.3 Upper extremities including the hands, wrists, or elbows Apply the gel (2 g) to the affected hand, wrist, or elbow 4 times daily. Diclofenac sodium topical gel should be gently massaged into the skin ensuring application to the entire affected hand, wrist, or elbow. The entire hand includes the palm, back of the hands, and the fingers. Do not apply more than 8 g daily to any single joint of the upper extremities. Total dose should not exceed 32 g per day, over all affected joints. 2.4 Special Precautions • Avoid showering/bathing for at least 1 hour after the application. Inform patient to wash his/her hands after use, unless the hands are the treated joint. If diclofenac sodium topical gel is applied to the hand(s) for treatment; inform patient not to wash the treated hand(s) for at least 1 hour after the application. • Do not apply diclofenac sodium topical gel to open wounds. • Avoid contact of diclofenac sodium topical gel with eyes and mucous membranes. • Do not apply external heat and/or occlusive dressings to treated joints. • Avoid exposure of the treated joint(s) to natural or artificial sunlight. • Avoid concomitant use of diclofenac sodium topical gel on the treated skin site with other topical products, including sunscreens, cosmetics, lotions, moisturizers, insect repellants, or other topical medications • Concomitant use of diclofenac sodium topical gel with oral non-steroidal anti-inflammatory drugs (NSAIDs) has not been evaluated, and may increase adverse NSAIDs effects. Do not use combination therapy with diclofenac sodium topical gel and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations. • Avoid wearing of clothing or gloves for at least 10 minutes after applying diclofenac sodium topical gel

WARNINGS AND PRECAUTIONS Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop ( 5.3 ) Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs.Monitor blood pressure ( 5.4 , 7 ) Heart Failure and Edema : Avoid use of diclofenac sodium topical solution in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.5 ) Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of diclofenac sodium topical solution in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function ( 5.6 ) Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs ( 5.7 ) Exacerbation of Asthma Related to Aspirin Sensitivity : Diclofenac sodium topical solution is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8 ) Serious Skin Reactions : Discontinue diclofenac sodium topical solution at first appearance of skin rash or other signs of hypersensitivity. ( 5.9 , 5.15 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically ( 5.10 ) Fetal Toxicity : Limit use of NSAIDs, including diclofenac sodium topical solution, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus ( 5.11 , 8.1 ). Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.12 , 7 ) Exposure to light : Avoid exposure of treated knee(s) to natural or artificial sunlight. ( 5.15 ) Eye Contact : Avoid contact of diclofenac sodium topical solution with eyes and mucosa. ( 5.16 ) Oral Nonsteroidal Anti-inflammatory Drugs : Avoid concurrent use with oral NSAIDs.( 5.17 ) 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2) ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4) ]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of diclofenac sodium topical solution in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium topical solution is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue diclofenac sodium topical solution until a serious GI adverse event is ruled out. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [ see Drug Interactions ( 7 ) ]. 5.3 Hepatotoxicity In clinical trials of oral diclofenac containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies). In a large, open-label, controlled trial of 3,700 patients treat

CONTRAINDICATIONS Diclofenac sodium topical gel is contraindicated in the following patients: • With known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [ see Warnings and Precautions ( 5.1 , 5.3 , 5.10 ) and Description ( 11 ) ] • With the 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 ( 5.1 , 5.2 ) ] • Application on damaged skin resulting from any etiology, including exudative dermatitis, eczema, infected lesions, burns or wounds [ see Warnings and Precautions ( 5.3 ) ] • In the setting of coronary bypass graft (CABG) surgery [ see Warnings and Precautions ( 5.4 ) ] • Known hypersensitivity to diclofenac or any components of the drug product. ( 4 , 11 ) • History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. ( 4 ) • Use on damaged skin. ( 4 ) • In the setting of coronary artery bypass graft (CABG) surgery. ( 4 )

CLINICAL PHARMACOLOGY Mechanism of Action Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of diclofenac potassium tablets, 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. Pharmacokinetics Absorption Diclofenac is 100% absorbed after oral administration compared to intravenous (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). In some fasting volunteers, measurable plasma levels are observed within 10 minutes of dosing with diclofenac potassium tablets. Peak plasma levels are achieved approximately 1 hour in fasting normal volunteers, with a range of 0.33 to 2 hours. Food has no significant effect on the extent of diclofenac absorption. However, there is usually a delay in the onset of absorption and a reduction in peak plasma levels of approximately 30%. Table 1. Pharmacokinetic Parameters for Diclofenac PK Parameter Normal Healthy Adults (20 to 52 years) Mean Coefficient of Variation (%) Absolute Bioavailability (%) [N = 7] 55 40 T max (hr) [N = 65] 1.0 76 Oral Clearance (CL/F; mL/min) [N = 61] 622 21 Renal Clearance (% unchanged drug in urine) [N = 7] <1 - Apparent Volume of Distribution (V/F; L/kg) [N = 61] 1.3 33 Terminal Half-life (hr) [N = 48] 1.9 29 Distribution The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg. Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15 to 105 mcg/mL) achieved with recommended doses. Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac. Elimination Metabolism 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. In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy- and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. Excretion Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours. Special Populations Pediatric : The pharmacokinetics of diclofenac potassium tablets have not been investigated in pediatric patients. Race : Pharmacokinetic differences due to race have not been identified. Hepatic Impairment : Hepatic metabolism accounts for almost 100% of diclofenac potassium tablets elimination, so patients with hepatic disease may require reduced doses of diclofenac potassium tablets compared to patients with normal hepatic function. Renal Impairment : Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. No differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60 to 90, 30 to 60, and less than 30 mL/min; N=6 in each group), area under the curve (AUC) values and elimination rate were comparable to those in healthy subjects. Drug Interactions Studies Voriconazole : When co-administered with voriconazole (inhibitor of CYP2C9, 2C19 and 3A4 enzyme), the C max and AUC of diclofenac increased by 114% and 78%, respectively (see PRECAUTIONS ; Drug Interactions ). Aspirin : When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin (see PRECAUTIONS ; Drug Interactions ).