Diclofenac Sodium

6 ADVERSE REACTIONS Most common adverse reactions (incidence >2% of patients treated with diclofenac sodium topical gel and greater than placebo) are application site reactions, including dermatitis. (6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-398-5876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. During clinical development, 913 patients were exposed to diclofenac sodium topical gel in randomized, double-blind, multicenter, vehicle-controlled, parallel-group studies in osteoarthritis of the superficial joints of the extremities. Of these, 513 patients received diclofenac sodium topical gel for osteoarthritis of the knee and 400 were treated for osteoarthritis of the hand. Additionally, 583 patients were exposed to diclofenac sodium topical gel in an uncontrolled, open-label, long-term safety trial in osteoarthritis of the knee. Of these, 355 patients were treated for osteoarthritis of 1 knee and 228 were treated for osteoarthritis of both knees. Duration of exposure ranged from 8 to 12 weeks for the placebo-controlled studies, and up to 12 months for the open-label safety trial. Short-Term Placebo-Controlled Trials: Adverse reactions observed in at least 1% of patients treated with diclofenac sodium topical gel: Non-serious adverse reactions that were reported during the short-term placebo-controlled studies comparing diclofenac sodium topical gel and placebo (vehicle gel) over study periods of 8 to 12 weeks (16 g per day), were application site reactions. These were the only adverse reactions that occurred in >1% of treated patients with a greater frequency in the diclofenac sodium topical gel group (7%) than the placebo group (2%). Table 1 lists the types of application site reactions reported. Application site dermatitis was the most frequent type of application site reaction and was reported by 4% of patients treated with diclofenac sodium topical gel, compared to 1% of placebo patients. Table 1: Non-serious Application Site Adverse Reactions (≥1% Diclofenac Sodium Topical Gel Patients) – Short-term Controlled Trials Adverse Reaction † Diclofenac Sodium Topical Gel N=913 Placebo (vehicle) N=876 N (%) N (%) Any application site reaction 62 (7) 19 (2) Application site dermatitis 32 (4) 6 (<1) Application site pruritus 7 (<1) 1 (<1) Application site erythema 6 (<1) 3 (<1) Application site paresthesia 5 (<1) 3 (<1) Application site dryness 4 (<1) 3 (<1) Application site vesicles 3 (<1) 0 Application site irritation 2 (<1) 0 Application site papules 1 (<1) 0 † Preferred Term according to MedDRA 9.1. In the placebo-controlled trials, the discontinuation rate due to adverse reactions was 5% for patients treated with diclofenac sodium topical gel, and 3% for patients in the placebo group. Application site reactions, including application site dermatitis, were the most frequent reason for treatment discontinuation. Long-Term Open-Label Safety Trial: In the open-label, long-term safety study, distribution of adverse reactions was similar to that in the placebo-controlled studies. In this study, where patients were treated for up to 1 year with diclofenac sodium topical gel up to 32 g per day, application site dermatitis was observed in 11% of patients. Adverse reactions that led to the discontinuation of the study drug were experienced in 12% of patients. The most common adverse reaction that led to discontinuation of the study was application site dermatitis, which was experienced by 6% of patients.

4 CONTRAINDICATIONS The use of diclofenac sodium topical gel is contraindicated in patients with a known hypersensitivity to diclofenac. Diclofenac sodium topical gel should not be administered in patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.1)]. Diclofenac sodium topical gel is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] . • Known hypersensitivity to diclofenac, aspirin, or other NSAIDs. ( 4 , 5.2 ) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. ( 4 ) • Use during the peri-operative period in the setting of coronary artery bypass graft (CABG) surgery. ( 4 )

11 DESCRIPTION Diclofenac sodium topical gel is a non-steroidal anti-inflammatory drug (NSAID) for topical use only. It contains the active ingredient, diclofenac sodium, in an opaque, white gel base. Diclofenac sodium is a white to slightly yellow crystalline powder. Diclofenac sodium is a benzeneacetic acid derivative. The chemical name is 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C 14 H 10 Cl 2 NNaO 2 . It has the following structural formula: Diclofenac sodium topical gel also contains carbomer homopolymer Type C, cocoyl caprylocaprate, fragrance, isopropyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water, and strong ammonia solution. Formula

2 DOSAGE AND ADMINISTRATION 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 ) • 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 ) 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 rectangle 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 knees, ankles, and feet Apply the gel (4 g) to the affected foot or knee or ankle, 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 elbows, wrists, and hands Apply the gel (2 g) to the affected hand or elbow or wrist, 4 times daily. Diclofenac sodium topical gel should be gently massaged into the skin ensuring application to the entire affected hand or elbow or wrist. 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 • Showering/bathing should be avoided for at least 1 hour after the application. Patient should 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; patient should not wash the treated hand(s) for at least 1 hour after the application. • Diclofenac sodium topical gel should not be applied to open wounds. • Contact of diclofenac sodium topical gel with eyes and mucous membranes should be avoided. • External heat and/or occlusive dressings should not be applied to treated joints. • Exposure of the treated joint(s) to sunlight should be avoided. • 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 [see Drug Interactions (7.9)] . • 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. • Wearing of clothing or gloves should be avoided for at least 10 minutes after applying diclofenac sodium topical gel.

1 INDICATIONS AND USAGE 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. Diclofenac sodium topical gel 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)

10 OVERDOSAGE There has been no experience of overdose with diclofenac sodium topical gel. No events of accidental ingestion have been reported with diclofenac sodium topical gel. Effects similar to those observed after an overdose of diclofenac tablets can be expected if substantial amounts of diclofenac sodium topical gel are ingested. Symptoms following acute oral NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur after an overdose. In the event of oral ingestion resulting in significant systemic side effects, it is recommended that the stomach be emptied by vomiting or lavage. Forced diuresis may theoretically be beneficial because the drug is excreted in the urine. The effect of dialysis or hemoperfusion in the elimination of diclofenac (99% protein-bound) remains unproven. In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption of diclofenac. Supportive and symptomatic treatment should be given for complications such as renal failure, convulsions, gastrointestinal irritation, and respiratory depression. For additional information about overdose treatment, call a Poison Control Center (1-800-222-1222).

7 DRUG INTERACTIONS • Concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects including increased GI bleeding. ( 7.1 ) • Concomitant use of anticoagulants and diclofenac have a risk of serious GI bleeding higher than users of either drug alone. ( 7.2 ) 7.1 Aspirin When diclofenac is administered with aspirin, the binding of diclofenac to protein is reduced, although the clearance of free diclofenac is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects. 7.2 Anticoagulants The effects of anticoagulants such as warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. 7.3 ACE-Inhibitors NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. 7.4 Diuretics Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. The response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure [see Warnings and Precautions (5.6)] , as well as to assure diuretic efficacy. 7.5 Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs, including diclofenac, and lithium are administered concurrently, patients should be observed carefully for signs of lithium toxicity. 7.6 Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs, including diclofenac, are administered concomitantly with methotrexate. 7.7 Cyclosporine Diclofenac, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with diclofenac may increase cyclosporine’s nephrotoxicity. Caution should be used when diclofenac is administered concomitantly with cyclosporine. 7.8 Oral Non-steroidal Anti-inflammatory Drugs Specific interaction studies of diclofenac sodium topical gel and oral NSAIDs were not performed. Also, the clinical trials of diclofenac sodium topical gel prohibited concomitant use of oral NSAIDs. There is systemic exposure to diclofenac following normal use of diclofenac sodium topical gel, up to 6% of the systemic levels of a single oral dose of diclofenac sodium [see Clinical Pharmacology (12.3)] . Therefore, concomitant administration of diclofenac sodium topical gel with oral NSAIDs or aspirin may result in increased adverse NSAID effects. 7.9 Topical Treatments Concomitant use of diclofenac sodium topical gel with other topical products, including topical medications, sunscreens, lotions, moisturizers, and cosmetics, on the same skin site has not been tested and should be avoided because of the potential to alter local tolerability and absorption.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of diclofenac is similar to that of other non-steroidal anti-inflammatory drugs. Diclofenac inhibits the enzyme, cyclooxygenase (COX), an early component of the arachidonic acid cascade, resulting in the reduced formation of prostaglandins, thromboxanes and prostacylin. It is not completely understood how reduced synthesis of these compounds results in therapeutic efficacy. 12.2 Pharmacodynamics Diclofenac, the active component of diclofenac sodium topical gel has anti-inflammatory, anti-nociception, and anti-pyretic effects. 12.3 Pharmacokinetics The pharmacokinetics of diclofenac sodium topical gel were assessed in healthy volunteers following repeated applications during 7 days of diclofenac sodium topical gel to 1 knee (4 x 4 g per day) or to 2 knees and 2 hands (4 x 12 g per day) versus the recommended oral dose of diclofenac sodium for the treatment of osteoarthritis (3 x 50 mg per day). A summary of the pharmacokinetic parameters is presented in Table 2. Table 2. Pharmacokinetic Parameters and Comparison of Diclofenac Sodium Topical Gel to Oral Diclofenac Sodium Tablets After Repeated Administration Treatment C max (ng/mL) Mean ± SD % of Oral (CI) T max (hr) Median (range) AUC 0-24 (ng•h/mL) Mean ± SD % of Oral (CI) Diclofenac sodium topical gel 4 x 4 g per day (=160 mg diclofenac sodium per day) 15 ± 7.3 0.6% (0.5-0.7) 14 (0-24) 233 ± 128 5.8% (5-6.7) Diclofenac sodium topical gel 4 x 12 g per day (=480 mg diclofenac sodium per day) 53.8 ± 32 2.2% (1.9-2.6) 10 (0-24) 807 ± 478 19.7% (17-22.8) Diclofenac sodium tablets, orally 3 x 50 mg per day (=150 mg diclofenac sodium per day) 2270 ± 778 100% 6.5 (1-14) 3890 ± 1710 100% C max = maximum plasma concentration; T max = time of C max ; AUC 0-24 = area under the concentration time curve; SD = standard deviation; CI = confidence interval. Systemic exposure (area under the concentration-time curve) and maximum plasma concentrations of diclofenac are significantly lower with diclofenac sodium topical gel than with comparable oral treatment of diclofenac sodium. Systemic exposure with recommended use of diclofenac sodium topical gel (4 x 4 g per day applied to 1 knee) is on average 17 times lower than with oral treatment. (Basis: treatment with diclofenac sodium topical gel of 1 knee, 4 times a day versus 50 mg, 3 times a day of oral diclofenac tablets.) The amount of diclofenac sodium that is systemically absorbed from diclofenac sodium topical gel is on average 6% of the systemic exposure from an oral form of diclofenac sodium. The average peak plasma concentration with recommended use of diclofenac sodium topical gel (4 x 4 g per day applied to 1 knee) is 158 times lower than with the oral treatment. The pharmacokinetics of diclofenac sodium topical gel has been tested under conditions of moderate heat (application of a heat patch for 15 minutes prior to gel application) and of moderate exercise (first gel application followed by a 20-minute treadmill exercise). No clinically relevant differences of systemic absorption and of tolerability were found between applications of diclofenac sodium topical gel (4 x 4 g per day on 1 knee) with and under the conditions tested. However, the pharmacokinetics of diclofenac sodium topical gel were not tested under the condition of heat application following gel application. Therefore, concurrent use of diclofenac sodium topical gel and heat is not recommended.

12.1 Mechanism of Action The mechanism of action of diclofenac is similar to that of other non-steroidal anti-inflammatory drugs. Diclofenac inhibits the enzyme, cyclooxygenase (COX), an early component of the arachidonic acid cascade, resulting in the reduced formation of prostaglandins, thromboxanes and prostacylin. It is not completely understood how reduced synthesis of these compounds results in therapeutic efficacy.

12.2 Pharmacodynamics Diclofenac, the active component of diclofenac sodium topical gel has anti-inflammatory, anti-nociception, and anti-pyretic effects.

12.3 Pharmacokinetics The pharmacokinetics of diclofenac sodium topical gel were assessed in healthy volunteers following repeated applications during 7 days of diclofenac sodium topical gel to 1 knee (4 x 4 g per day) or to 2 knees and 2 hands (4 x 12 g per day) versus the recommended oral dose of diclofenac sodium for the treatment of osteoarthritis (3 x 50 mg per day). A summary of the pharmacokinetic parameters is presented in Table 2. Table 2. Pharmacokinetic Parameters and Comparison of Diclofenac Sodium Topical Gel to Oral Diclofenac Sodium Tablets After Repeated Administration Treatment C max (ng/mL) Mean ± SD % of Oral (CI) T max (hr) Median (range) AUC 0-24 (ng•h/mL) Mean ± SD % of Oral (CI) Diclofenac sodium topical gel 4 x 4 g per day (=160 mg diclofenac sodium per day) 15 ± 7.3 0.6% (0.5-0.7) 14 (0-24) 233 ± 128 5.8% (5-6.7) Diclofenac sodium topical gel 4 x 12 g per day (=480 mg diclofenac sodium per day) 53.8 ± 32 2.2% (1.9-2.6) 10 (0-24) 807 ± 478 19.7% (17-22.8) Diclofenac sodium tablets, orally 3 x 50 mg per day (=150 mg diclofenac sodium per day) 2270 ± 778 100% 6.5 (1-14) 3890 ± 1710 100% C max = maximum plasma concentration; T max = time of C max ; AUC 0-24 = area under the concentration time curve; SD = standard deviation; CI = confidence interval. Systemic exposure (area under the concentration-time curve) and maximum plasma concentrations of diclofenac are significantly lower with diclofenac sodium topical gel than with comparable oral treatment of diclofenac sodium. Systemic exposure with recommended use of diclofenac sodium topical gel (4 x 4 g per day applied to 1 knee) is on average 17 times lower than with oral treatment. (Basis: treatment with diclofenac sodium topical gel of 1 knee, 4 times a day versus 50 mg, 3 times a day of oral diclofenac tablets.) The amount of diclofenac sodium that is systemically absorbed from diclofenac sodium topical gel is on average 6% of the systemic exposure from an oral form of diclofenac sodium. The average peak plasma concentration with recommended use of diclofenac sodium topical gel (4 x 4 g per day applied to 1 knee) is 158 times lower than with the oral treatment. The pharmacokinetics of diclofenac sodium topical gel has been tested under conditions of moderate heat (application of a heat patch for 15 minutes prior to gel application) and of moderate exercise (first gel application followed by a 20-minute treadmill exercise). No clinically relevant differences of systemic absorption and of tolerability were found between applications of diclofenac sodium topical gel (4 x 4 g per day on 1 knee) with and under the conditions tested. However, the pharmacokinetics of diclofenac sodium topical gel were not tested under the condition of heat application following gel application. Therefore, concurrent use of diclofenac sodium topical gel and heat is not recommended.

20191101

3

3 DOSAGE FORMS AND STRENGTHS 1% gel • 1% gel (3)

Diclofenac Sodium diclofenac sodium DICLOFENAC SODIUM DICLOFENAC AMMONIA CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) COCO-CAPRYLATE/CAPRATE ISOPROPYL ALCOHOL MINERAL OIL POLYOXYL 20 CETOSTEARYL ETHER PROPYLENE GLYCOL WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent for 2 years at doses up to 2 mg/kg/day resulted in no significant increases in tumor incidence corresponding to a human equivalent dose approximately 0.5- and 1-fold (mouse and rat, respectively) of the maximum human topical dose of diclofenac sodium topical gel (based on bioavailability and body surface area comparison). In a dermal carcinogenicity study conducted in albino mice, daily topical applications of a diclofenac sodium gel product for two years at concentrations up to 0.035% diclofenac sodium (a 29-fold lower diclofenac sodium concentration than present in diclofenac sodium topical gel) did not increase neoplasm incidence. In a photococarcinogenicity study conducted in hairless mice, topical application of a diclofenac sodium gel product at doses up to 0.035% diclofenac sodium (a 29-fold lower diclofenac sodium concentration than present in diclofenac sodium topical gel) 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 mouse lymphoma point mutation assay, chromosomal aberration studies in Chinese hamster ovarian cells in vitro , and in vivo rat chromosomal aberration assay of bone marrow cells. Diclofenac did not affect male or female fertility in rats at doses up to 4 mg/kg/day which induced toxicity, corresponding to a human equivalent dose approximately 2-fold greater than the maximum human topical dose of diclofenac sodium topical gel (based on bioavailability and body surface area comparison).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent for 2 years at doses up to 2 mg/kg/day resulted in no significant increases in tumor incidence corresponding to a human equivalent dose approximately 0.5- and 1-fold (mouse and rat, respectively) of the maximum human topical dose of diclofenac sodium topical gel (based on bioavailability and body surface area comparison). In a dermal carcinogenicity study conducted in albino mice, daily topical applications of a diclofenac sodium gel product for two years at concentrations up to 0.035% diclofenac sodium (a 29-fold lower diclofenac sodium concentration than present in diclofenac sodium topical gel) did not increase neoplasm incidence. In a photococarcinogenicity study conducted in hairless mice, topical application of a diclofenac sodium gel product at doses up to 0.035% diclofenac sodium (a 29-fold lower diclofenac sodium concentration than present in diclofenac sodium topical gel) 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 mouse lymphoma point mutation assay, chromosomal aberration studies in Chinese hamster ovarian cells in vitro , and in vivo rat chromosomal aberration assay of bone marrow cells. Diclofenac did not affect male or female fertility in rats at doses up to 4 mg/kg/day which induced toxicity, corresponding to a human equivalent dose approximately 2-fold greater than the maximum human topical dose of diclofenac sodium topical gel (based on bioavailability and body surface area comparison).

NDA022122

Diclofenac Sodium

diclofenac sodium

63187-753

HUMAN PRESCRIPTION DRUG

TOPICAL

5.16 Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have a CBC and a chemistry profile checked periodically. If abnormal liver tests or renal tests persist or worsen, diclofenac sodium topical gel should be discontinued.

Package/Label Display Panel See Medication Guide and Patient Instructions Inside of Carton NDC 63187-753-00 Diclofenac Sodium Topical Gel 1% For Topical Use Only Rx only Net Wt 100 g Use the Dosing Card Attached Inside Carton 63187-753-00

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (NSAIDs Medication Guide and Instructions for Use) prior to using diclofenac sodium topical gel. Inform patients of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Cardiovascular Effects Diclofenac sodium topical gel, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Advise patients of the importance of this follow-up [see Warnings and Precautions (5.1)] . Gastrointestinal Effects Diclofenac sodium topical gel, like other NSAIDs, can cause GI discomfort and, rarely, more serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding. Instruct patients to ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up [see Warnings and Precautions (5.2)] . Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy with diclofenac sodium topical gel and seek immediate medical therapy [see Warnings and Precautions (5.3)] . Adverse Skin Reactions Diclofenac sodium topical gel, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching. Instruct patients to ask for medical advice when observing any indicative signs or symptoms [see Warnings and Precautions (5.8)] . Advise patients to stop diclofenac sodium topical gel immediately if they develop any type of rash and contact their physicians as soon as possible. Instruct patients not to apply diclofenac sodium topical gel to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug. Instruct patients to avoid concomitant use of diclofenac sodium topical gel with other topical products, including sunscreens, cosmetics, lotions, moisturizers, and insect repellants. Concomitant use may result in skin reactions or change the absorption of diclofenac sodium topical gel. Instruct patients to minimize or avoid exposure of treated areas to natural or artificial sunlight. Weight Gain and Edema Instruct patients to report to their physicians signs or symptoms of unexplained weight gain or edema following treatment with diclofenac sodium topical gel [see Warnings and Precautions (5.5)] . Anaphylactoid Reactions Inform patients of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help [see Warnings and Precautions (5.7)] . Effects During Pregnancy In late pregnancy, as with other NSAIDs, diclofenac sodium topical gel should be avoided because it will cause premature closure of the ductus arteriosus [see Warnings and Precautions (5.9)] . Eye Exposure Instruct patients to avoid contact of diclofenac sodium topical gel with the eyes and mucosa, although not studied, should be avoided. Patients should be advised that if eye contact occurs, they should immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour. Proper Application Instruct patients how to use the dosing card to measure the proper dose of diclofenac sodium topical gel to apply. If the patient loses their dosing card, instruct them that they can call 1-800-398-5876 to request a replacement dosing card or ask their pharmacist for a new dosing card. Instruct patients how to correctly measure the 2.25 inches (2 g) dose or 4.5 inches (4 g) dose while waiting for a replacement dosing card. Comments or Questions? Call toll-free 1-800-398-5876 Marketed by: Par Pharmaceutical Chestnut Ridge, NY 10977 Manufactured by: Novartis Pharma Produktions GmbH Wehr, Germany Revised: February 2016

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases: • with longer use of NSAID medicines • in people who have heart disease NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).” NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding: • can happen without warning symptoms • may cause death The chance of a person getting an ulcer or bleeding increases with: • taking medicines called “corticosteroids” and “anticoagulants” • longer use • smoking • drinking alcohol • older age • having poor health NSAID medicines should only be used: • exactly as prescribed • at the lowest dose possible for your treatment • for the shortest time needed What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines are 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 a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine: • if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine • for pain right before or after heart bypass surgery Tell your healthcare provider: • about all of your medical conditions. • about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist. • if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. • if you are breast-feeding. Talk to your healthcare provider. What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? Serious side effects include: • heart attack • stroke • high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma Other side effects include: • stomach pain • constipation • diarrhea • gas • heartburn • nausea • vomiting • dizziness Get emergency help right away if you have any of the following symptoms: • shortness of breath or trouble breathing • chest pain • weakness in one part or side of your body • slurred speech • swelling of the face or throat Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms: • nausea • more tired or weaker than usual • itching • your skin or eyes look yellow • stomach pain • flu-like symptoms • vomit blood • there is blood in your bowel movement or it is black and sticky like tar • unusual weight gain • skin rash or blisters with fever • swelling of the arms and legs, hands and feet These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. NSAID medicines that need a prescription Generic Name Tradename Celecoxib Celebrex ® Diclofenac Flector ® , Cataflam ® , Cambia ® , Voltaren ® , VOLTAREN ® GEL, Arthrotec ® (combined with misoprostol), Pennsaid ® , Zipsor ® , Zorvolex™ Diflunisal Dolobid ® Etodolac Lodine ® , Lodine ® XL Fenoprofen Nalfon ® , Nalfon ® 200 Flurbirofen Ansaid ® Ibuprofen Motrin ® , Tab-Profen ® , Vicoprofen ®* (combined with hydrocodone), Combunox™ (combined with oxycodone), Duexis ® (combined with famotidine) Indomethacin Indocin ® , Indocin ® SR, Indo-Lemmon™, Indomethagan™ Ketoprofen Oruvail ® , Nexcede™ Ketorolac Toradol ® , Sprix ® Mefenamic Acid Ponstel ® Meloxicam Mobic ® Nabumetone Relafen ® Naproxen Naprosyn ® , Anaprox ® , Anaprox ® DS, EC-Naprosyn ® , Naprelan ® , Naprapac ® (co-packaged with lansoprazole), Treximet ® (combined with sumatriptan succinate), Vimovo ® (combined with esomeprazole magnesium) Oxaprozin Daypro ® Piroxicam Feldene ® Sulindac Clinoril ® Tolmetin Tolectin ® , Tolectin ® DS, Tolectin ® 600 *Vicoprofen ® contains the same dose of ibuprofen as over-the-counter (OTC) NSAID, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long-term continuous use may increase the risk of heart attack or stroke.

14 CLINICAL STUDIES 14.1 Pivotal Studies in Osteoarthritis of the Superficial Joints of the Extremities Study 1 evaluated the efficacy of diclofenac sodium topical gel for the treatment of osteoarthritis of the knee in a 12-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group trial. Diclofenac sodium topical gel was administered at a dose of 4 g, 4 times daily, on 1 knee (16 g per day). Pain as assessed by the patients at Week 12 using the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) Pain Subindex was lower in the diclofenac sodium topical gel group than the placebo group. Study 2 evaluated the efficacy of diclofenac sodium topical gel for the treatment of osteoarthritis in subjects with osteoarthritis of the hand in an 8-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group study. Diclofenac sodium topical gel was administered at a dose of 2 g per hand, 4 times daily, on both hands (16 g per day). Pain in the target hand as assessed by the patients at Weeks 4 and 6 on a visual analog scale from 0 to 100 was lower in the diclofenac sodium topical gel group than the placebo group. Table 3. Efficacy outcomes of Diclofenac Sodium Topical Gel in Studies 1 and 2 Diclofenac Sodium Topical Gel Placebo (Vehicle) Adjusted Difference (Placebo - Diclofenac Sodium TopicalGel ) Study 1 (Knee) WOMAC Pain * # at Week 12 Sample Size 127 119 Mean Outcome 28 37 ∆ = 7 † 95% Confidence Interval (1, 12) Study 2 (Hand) Pain Intensity # at Week 4 Sample Size 198 187 Mean Outcome 43 50 ∆ = 7 ‡ 95% Confidence Interval (2, 12) Study 2 (Hand) Pain Intensity # at Week 6 Sample Size 198 187 Mean Outcome 40 47 ∆ = 7 ‡ 95% Confidence Interval (1, 13) * WOMAC = Western Ontario McMaster Osteoarthritis Index. # Scale from 0 (best) to 100 (worst). † Difference is adjusted using an analysis of covariance (ANCOVA) model with main effects of treatment and center and baseline covariate. ‡ Difference is adjusted using an analysis of covariance (ANCOVA) model with main effects of treatment, center, indicator for pain in the CMC-1 joint, and baseline as a covariate, and the treatment-by-CMC-1 indicator interaction. Difference is weighted by size of CMC-1 strata.

8.5 Geriatric Use Of the total number of subjects treated with diclofenac sodium topical gel in clinical studies, 498 were 65 years of age and over. No overall differences in effectiveness or safety were observed between these subjects and younger subjects, but greater sensitivity to the effect of NSAIDs in some older individuals cannot be ruled out. Diclofenac, as with any NSAID, is known to be substantially excreted by the kidney, and the risk of toxic reactions to diclofenac sodium topical gel may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when using diclofenac sodium topical gel in the elderly, and it may be useful to monitor renal function.

8.2 Labor and Delivery In rat studies with oral NSAIDs, including diclofenac, as with other drugs known to inhibit prostaglandin synthesis, there is an increased incidence of dystocia and delayed parturition corresponding to a human equivalent dose approximately similar to the maximum recommended clinical dose (based on bioavailability and body surface area comparison). The effects of diclofenac sodium topical gel on labor and delivery in pregnant women are unknown.

8.3 Nursing Mothers It is not known whether diclofenac is excreted in human milk; however, studies in animals detected diclofenac in the milk after oral administration. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from diclofenac sodium topical gel a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.1 Pregnancy The safety of diclofenac sodium topical gel has not been established during pregnancy. There are no well-controlled studies of diclofenac in pregnant women. Human and animal studies indicate that diclofenac crosses the placenta. In late pregnancy, as with other NSAIDs, diclofenac sodium topical gel should be avoided because it may cause premature closure of the ductus arteriosus. Teratogenic Effects Pregnancy Category C: Studies in mice, rats, and rabbits in which diclofenac was administered orally throughout gestation revealed no evidence of teratogenicity despite the induction of maternal toxicity and fetal toxicity corresponding to a human equivalent dose approximately 4.5-, 2-, and 9-fold (mouse, rat, rabbit, respectively) of the maximum human topical dose of diclofenac sodium topical gel (based on bioavailability and body surface area comparison). Nonteratogenic Effects The use of diclofenac, as with other NSAIDs, is associated with the adverse fetal cardiovascular effect of premature closure of the ductus arteriosus.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy The safety of diclofenac sodium topical gel has not been established during pregnancy. There are no well-controlled studies of diclofenac in pregnant women. Human and animal studies indicate that diclofenac crosses the placenta. In late pregnancy, as with other NSAIDs, diclofenac sodium topical gel should be avoided because it may cause premature closure of the ductus arteriosus. Teratogenic Effects Pregnancy Category C: Studies in mice, rats, and rabbits in which diclofenac was administered orally throughout gestation revealed no evidence of teratogenicity despite the induction of maternal toxicity and fetal toxicity corresponding to a human equivalent dose approximately 4.5-, 2-, and 9-fold (mouse, rat, rabbit, respectively) of the maximum human topical dose of diclofenac sodium topical gel (based on bioavailability and body surface area comparison). Nonteratogenic Effects The use of diclofenac, as with other NSAIDs, is associated with the adverse fetal cardiovascular effect of premature closure of the ductus arteriosus. 8.2 Labor and Delivery In rat studies with oral NSAIDs, including diclofenac, as with other drugs known to inhibit prostaglandin synthesis, there is an increased incidence of dystocia and delayed parturition corresponding to a human equivalent dose approximately similar to the maximum recommended clinical dose (based on bioavailability and body surface area comparison). The effects of diclofenac sodium topical gel on labor and delivery in pregnant women are unknown. 8.3 Nursing Mothers It is not known whether diclofenac is excreted in human milk; however, studies in animals detected diclofenac in the milk after oral administration. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from diclofenac sodium topical gel a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of subjects treated with diclofenac sodium topical gel in clinical studies, 498 were 65 years of age and over. No overall differences in effectiveness or safety were observed between these subjects and younger subjects, but greater sensitivity to the effect of NSAIDs in some older individuals cannot be ruled out. Diclofenac, as with any NSAID, is known to be substantially excreted by the kidney, and the risk of toxic reactions to diclofenac sodium topical gel may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when using diclofenac sodium topical gel in the elderly, and it may be useful to monitor renal function.

16 HOW SUPPLIED/STORAGE AND HANDLING Diclofenac sodium topical gel is available in tubes containing 100 g of the topical gel in each tube. Each tube contains diclofenac sodium in a gel base (10 mg of diclofenac sodium per gram of gel or 1%). 100 g tube……………………………………NDC 63187-753-00 Storage Store at 20°C to 25°C (68°F to 77°F). Keep from freezing. Store the dosing card with your diclofenac sodium topical gel.

WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISK Cardiovascular Risk • Non-steroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk [see Warnings and Precautions (5.1)] . • Diclofenac sodium topical gel is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4)] . Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events [see Warnings and Precautions (5.2)] . WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISK See full prescribing information for complete boxed warning. Cardiovascular Risk • Non-steroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. ( 5.1 ) • Diclofenac sodium topical gel is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. Gastrointestinal Risk ( 4 , 5.1 ) • Non-steroidal anti-inflammatory drugs (NSAIDs), including diclofenac sodium topical gel, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. Elderly patients are at greater risk for serious gastrointestinal events. ( 5.2 )