Diclofenac Epolamine

6 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) ] The most common adverse reactions in DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % and placebo-treated adult patients were pruritus (5% and 8%, respectively) and nausea (3% and 2%, respectively) ( 6.1 ). The most common adverse reactions in DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % treated pediatric patients were headache (9%) and application site pruritus (7%) ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Yaral Pharma Professional Information Service at 1-866-218-9009 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. Adult Clinical Trials Experience In controlled trials during the premarketing development of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, approximately 600 patients with minor sprains, strains, and contusions were treated with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% for up to two weeks. Adverse Events Leading to Discontinuation of Treatment In the controlled trials, 3% of patients in both the DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and placebo groups discontinued treatment due to an adverse event. The most common adverse events leading to discontinuation were application site reactions, occurring in 2% of both the DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and placebo groups. Application site reactions leading to dropout included pruritus, dermatitis, and burning. Common Adverse Events Overall, the most common adverse events associated with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% treatment were skin reactions at the site of treatment. Table 1 lists all adverse events, regardless of causality, occurring in ≥ 1% of patients in controlled trials of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%. A majority of patients treated with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% had adverse events with a maximum intensity of "mild" or "moderate." Table 1. Common Adverse Events (by body system and preferred term) in ≥ 1% of Patients treated with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% or Placebo The table lists adverse events occurring in placebo-treated patients because the placebo-was comprised of the same ingredients as DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% except for diclofenac. Adverse events in the placebo group may therefore reflect effects of the non-active ingredients. Category Diclofenac N=572 Placebo N=564 N Percent N Percent Application Site Conditions 64 11 70 12 Pruritus 31 5 44 8 Dermatitis 9 2 3 <1 Burning 2 <1 8 1 Other Includes: application site dryness, irritation, erythema, atrophy, discoloration, hyperhidriosis, and vesicles. 22 4 15 3 Gastrointestinal Disorders 49 9 33 6 Nausea 17 3 11 2 Dysgeusia 10 2 3 <1 Dyspepsia 7 1 8 1 Other Includes: gastritis, vomiting, diarrhea, constipation, upper abdominal pain, and dry mouth. 15 3 11 2 Nervous System Disorders 13 2 18 3 Headache 7 1 10 2 Paresthesia 6 1 8 1 Somnolence 4 1 6 1 Other Includes: hypoesthesia, dizziness, and hyperkinesias. 4 1 3 <1 Foreign labeling describes that dermal allergic reactions may occur with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% treatment. Additionally, the treated area may become irritated or develop itching, erythema, edema, vesicles, or abnormal sensation. Pediatric Clinical Trials Experience In one open-label trial, 104 male and female pediatric patients 6 years and older presenting with minor strains, sprains, and contusions received DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % twice a day for as many as 16 days. The most commonly reported adverse events (incidence ≥ 2%) were headache (9%), application site pruritus (7%), nausea (3%), and dyspepsia (3%). No adverse events led to discontinuation of treatment.

4 CONTRAINDICATIONS DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [ see Warnings and Precautions (5.7 , 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 (5.7 , 5.8 ) ] In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions (5.1) ] DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is contraindicated for use on non-intact or damaged skin resulting from any etiology, including exudative dermatitis, eczema, infection lesions, burns or wounds. Known hypersensitivity to diclofenac or any components of the drug product ( 4 ) History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 ) In the setting of CABG surgery ( 4 ) For use on non-intact or damaged skin ( 4 )

11 DESCRIPTION DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is a nonsteroidal anti-inflammatory drug for topical application. DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is a 10 cm × 14 cm topical system comprised of an adhesive material containing 1.3% diclofenac epolamine which is applied to a non-woven polyester felt backing and covered with a polypropylene film release liner. The release liner is removed prior to topical application to the skin. The chemical name of diclofenac epolamine is 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, (2-(pyrrolidin-1-yl) ethanol salt, with a molecular formula of C 20 H 24 Cl 2 N 2 O 3, and molecular weight 411.3, an n-octanol/water partition coefficient of 8 at pH 8.5, and the following chemical structure: Each adhesive topical system contains 180 mg of diclofenac epolamine (13 mg per gram adhesive) in an aqueous base. It also contains the following inactive ingredients: butylene glycol, carboxymethylcellulose sodium, dihydroxyaluminum aminoacetate, edetate disodium, fragrance (Dalin PH), gelatin, kaolin, methylparaben, polysorbate 80, povidone, propylene glycol, propylparaben, sodium polyacrylate, sorbitol solution, tartaric acid, titanium dioxide, and purified water. Chemical Structure

2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for shortest duration consist with the individual patient treatment goals ( 2.1 ) The recommended dose of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% for adults and pediatric patients 6 years and older is one (1) topical system to the most painful area twice a day. ( 2 ) DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% should not be applied to damaged or non-intact skin. ( 2 ) 2.1 General Dosing Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions (5) ]. The recommended dose of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is one (1) topical system to the most painful area twice a day both in adults and pediatric patients 6 years of age and older. 2.2 Special Precautions Inform patients that, if DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% begins to peel-off, the edges of the topical system may be taped down. If problems with adhesion persist, patients may overlay the topical system with a mesh netting sleeve, where appropriate (e.g. to secure topical systems applied to ankles, knees, or elbows). The mesh netting sleeve (e.g. Curad® Hold Tite™, Surgilast® Tubular Elastic Dressing) must allow air to pass through and not be occlusive (non-breathable). Do not apply DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% to non-intact or damaged skin resulting from any etiology e.g. exudative dermatitis, eczema, infected lesion, burns or wounds. Do not wear a DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% when bathing or showering. Wash your hands after applying, handling or removing the topical system. Avoid eye contact. Do not use combination therapy with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.

1 INDICATIONS AND USAGE DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is indicated for the topical treatment of acute pain due to minor strains, sprains, and contusions in adults and pediatric patients 6 years and older. DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is a nonsteroidal anti-inflammatory drug (NSAID), and is indicated for the topical treatment of acute pain due to minor strains, sprains, and contusions in adults and pediatric patients 6 years and older. ( 1 )

10 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. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

7 DRUG INTERACTIONS 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. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.12) ]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2) ]. Intervention: Concomitant use of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.12) ]. DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6) ] . When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., 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 EPOLAMINE TOPICAL SYSTEM 1.3% 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 of digoxin. Intervention: During concomitant use of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% 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 EPOLAMINE TOPICAL SYSTEM 1.3% and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., 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 salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% 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 EPOLAMINE TOPICAL SYSTEM 1.3% and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly using DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% with drugs that interfere with hemostasis. Concomitant use of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and analgesic doses of aspirin is not generally recommended ( 7 ) ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% may diminish the antihypertensive effect of these drugs. Monitor blood pressure ( 7 ) ACE Inhibitors and ARBs : Concomitant use with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% 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 EPOLAMINE TOPICAL SYSTEM 1.3% may increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of diclofenac, 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. 12.2 Pharmacodynamics DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% applied to intact skin provides local analgesia by releasing diclofenac epolamine from the topical system into the skin. 12.3 Pharmacokinetics Absorption - Adults Following a single application of the DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% on the upper inner arm, peak plasma concentrations of diclofenac (range 0.7 – 6 ng/mL) were noted between 10 – 20 hours of application. Plasma concentrations of diclofenac in the range of 1.3 – 8.8 ng/mL were noted after five days with twice-a-day DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% application. Systemic exposure (AUC) and maximum plasma concentrations of diclofenac, after repeated dosing for four days with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, were lower (<1%) than after a single oral 50-mg diclofenac sodium tablet. The pharmacokinetics of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% has been tested in healthy volunteers at rest or undergoing moderate exercise (cycling 20 min/h for 12 h at a mean HR of 100.3 bpm). No clinically relevant differences in systemic absorption were observed, with peak plasma concentrations in the range of 2.2 – 8.1 ng/mL while resting, and 2.7 – 7.2 ng/mL during exercise. Absorption – Pediatrics Diclofenac plasma concentration was assessed in pediatric patients 6 years and older at a fixed time point 24-hours after the initial application and at the final visit (Day 3 – 15). The resulting average concentrations were 1.65 ng/mL and 1.80 ng/mL, respectively, both of which are similar to the values observed in adults. Distribution Diclofenac has a very high affinity (>99%) for human serum 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 The plasma elimination half-life of diclofenac after application of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is approximately 12 hours. 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. Specific Populations The pharmacokinetics of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% has not been investigated in children less than 6 years old, patients with hepatic or renal impairment, or specific racial groups. Drug Interaction Studies 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 1 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions (7) ] .

12.1 Mechanism of Action Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of diclofenac, 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.

12.2 Pharmacodynamics DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% applied to intact skin provides local analgesia by releasing diclofenac epolamine from the topical system into the skin.

12.3 Pharmacokinetics Absorption - Adults Following a single application of the DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% on the upper inner arm, peak plasma concentrations of diclofenac (range 0.7 – 6 ng/mL) were noted between 10 – 20 hours of application. Plasma concentrations of diclofenac in the range of 1.3 – 8.8 ng/mL were noted after five days with twice-a-day DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% application. Systemic exposure (AUC) and maximum plasma concentrations of diclofenac, after repeated dosing for four days with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, were lower (<1%) than after a single oral 50-mg diclofenac sodium tablet. The pharmacokinetics of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% has been tested in healthy volunteers at rest or undergoing moderate exercise (cycling 20 min/h for 12 h at a mean HR of 100.3 bpm). No clinically relevant differences in systemic absorption were observed, with peak plasma concentrations in the range of 2.2 – 8.1 ng/mL while resting, and 2.7 – 7.2 ng/mL during exercise. Absorption – Pediatrics Diclofenac plasma concentration was assessed in pediatric patients 6 years and older at a fixed time point 24-hours after the initial application and at the final visit (Day 3 – 15). The resulting average concentrations were 1.65 ng/mL and 1.80 ng/mL, respectively, both of which are similar to the values observed in adults. Distribution Diclofenac has a very high affinity (>99%) for human serum 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 The plasma elimination half-life of diclofenac after application of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is approximately 12 hours. 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. Specific Populations The pharmacokinetics of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% has not been investigated in children less than 6 years old, patients with hepatic or renal impairment, or specific racial groups. Drug Interaction Studies 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 1 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions (7) ] .

20231201

6

3 DOSAGE FORMS AND STRENGTHS Diclofenac Epolamine Topical System is a 10 cm × 14 cm topical system that contains 1.3% diclofenac epolamine, and is debossed with YARAL 1.3%. DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, for topical use. Each individual topical system is debossed. ( 3 )

Diclofenac Epolamine Diclofenac Epolamine BUTYLENE GLYCOL CARBOXYMETHYLCELLULOSE SODIUM, UNSPECIFIED DIHYDROXYALUMINUM AMINOACETATE EDETATE DISODIUM GELATIN, UNSPECIFIED KAOLIN METHYLPARABEN POLYSORBATE 80 POVIDONE, UNSPECIFIED PROPYLENE GLYCOL PROPYLPARABEN SORBITOL TARTARIC ACID TITANIUM DIOXIDE WATER DICLOFENAC EPOLAMINE DICLOFENAC

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of either diclofenac epolamine or DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%. Mutagenesis Diclofenac epolamine is not mutagenic in Salmonella typhimurium strains, nor does it induce an increase in metabolic aberrations in cultured human lymphocytes, or the frequency of micronucleated cells in the bone marrow micronucleus test performed in rats. Impairment of Fertility Male and female Sprague Dawley rats were administered 1, 3, or 6 mg/kg/day diclofenac epolamine via oral gavage (males treated for 60 days prior to conception and during mating period, females treated for 14 days prior to mating through day 19 of gestation). Diclofenac epolamine treatment with 6 mg/kg/day resulted in increased early resorptions and post-implantation losses; however, no effects on the mating and fertility indices were found. The 6 mg/kg/day dose corresponds to 3 times the maximum recommended daily exposure in humans based on a body surface area comparison.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of either diclofenac epolamine or DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%. Mutagenesis Diclofenac epolamine is not mutagenic in Salmonella typhimurium strains, nor does it induce an increase in metabolic aberrations in cultured human lymphocytes, or the frequency of micronucleated cells in the bone marrow micronucleus test performed in rats. Impairment of Fertility Male and female Sprague Dawley rats were administered 1, 3, or 6 mg/kg/day diclofenac epolamine via oral gavage (males treated for 60 days prior to conception and during mating period, females treated for 14 days prior to mating through day 19 of gestation). Diclofenac epolamine treatment with 6 mg/kg/day resulted in increased early resorptions and post-implantation losses; however, no effects on the mating and fertility indices were found. The 6 mg/kg/day dose corresponds to 3 times the maximum recommended daily exposure in humans based on a body surface area comparison.

NDA021234

Diclofenac Epolamine

Diclofenac Epolamine

82347-0405

HUMAN PRESCRIPTION DRUG

TOPICAL

PRINCIPAL DISPLAY PANEL - 30 Topical System Pouch Carton NDC 82347-0405-5 diclofenac epolamine topical system 1.3% 30 TOPICAL SYSTEMS (10 CM X 14 CM EACH) Dispense with enclosed Medication Guide Change diclofenac epolamine topical system once every 12 hours Fold used topical systems so that the adhesive side sticks to itself and safely discard used topical systems where children and pets cannot get them. Rx only YARAL Pharma carton-box

Warning and Precautions, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) ( 5.10 ) 04/2021 Warning and Precautions: Fetal Toxicity ( 5.11 ) 04/2021

Distributed by: YARAL Pharma, Inc., Parsippany, NJ 07054 USA Manufacturer: Altergon Italia Srl, Zona Industriale ASI, Morra de Sanctis, Avellino 83040, Italy (ITA) Manufactured for: IBSA Institut Biochimique SA, 6912 Pazzallo, Switzerland Revised: February, 2023

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed, as well as the Directions for Use on the product packaging. Inform patients, families, or their caregivers of the following information before initiating therapy with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [ see Warnings and Precautions (5.1) ]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [ see Warnings and Precautions (5.2) ]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and seek immediate medical therapy [ see Warnings and Precautions (5.3) ]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [ see Warnings and Precautions (5.5) ]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [ see Contraindications (4) and Warnings and Precautions (5.7) ]. Serious Skin Reactions including DRESS Advise patients to stop using DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [ see Warnings and Precautions ( 5.10 5.9) ]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Use in Specific Populations (8.3) ] Fetal Toxicity Inform pregnant women to avoid use of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and other NSAIDs starting at 30 weeks of gestation because of the risk of the premature closure of the fetal ductus arteriosus. If treatment with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1) ] . Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7) ]. Alert patients that NSAIDs may be present in "over the counter" medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% until they talk to their healthcare provider [see Drug Interactions (7) ]. Eye Exposure Instruct patients to avoid contact of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% with the eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour [see Warnings and Precautions (5.16) ]. Special Application Instructions Instruct patients that, if DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% begins to peel-off, the edges of the topical system may be taped down. If problems with adhesion persist, patients may overlay the topical system with a mesh netting sleeve, where appropriate (e.g. to secure topical systems applied to ankles, knees, or elbows). The mesh netting sleeve (e.g. Curad® Hold Tite™, Surgilast® Tubular Elastic Dressing) must allow air to pass through and not be occlusive (non-breathable). Instruct patients not to apply DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% to non-intact or damaged skin resulting from any etiology e.g. exudative dermatitis, eczema, infected lesion, burns or wounds. Instruct patients not to wear a DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% when bathing or showering. Instruct patients to wash hands after applying, handling or removing the topical system.

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 . This risk may happen early in treatment and may increase: 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 longer use of NSAIDs smoking drinking alcohol older age poor health advanced liver disease 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. NSAIDs and some other medicines can interact with each other and cause serious side effects. 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: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get 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 taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: nausea more tired or weaker than usual diarrhea itching your skin or eyes look yellow indigestion or 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, legs, hands and feet 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 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. Manufactured for: IBSA Institut Biochimique SA, 6912 Pazzallo, Switzerland Distributed by: YARAL Pharma, Inc., Parsippany, NJ 07054 USA For more information, call 1-866-218-9009 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: February, 2023 1320 edition IV

14 CLINICAL STUDIES 14.1 Strains, Sprains, and Contusions Efficacy of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% was demonstrated in two of four studies of patients with minor strains, sprains, and contusions. Patients were randomly assigned to treatment with the DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, or a placebo identical to the DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% minus the active ingredient. In the first of these two studies, patients with ankle sprains were treated once daily for a week. In the second study, patients with strains, sprains and contusions were treated twice daily for up to two weeks. Pain was assessed over the period of treatment. Patients treated with the DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% experienced a greater reduction in pain as compared to patients randomized to placebo as evidenced by the responder curves presented below ( Figures 1-4 ). Figure 1: Patients Achieving Various Levels of Pain Relief at Day 3; 14-Day Study Figure 2: Patients Achieving Various Levels of Pain Relief at End of Study; 14-Day Study Figure 3: Patients Achieving Various Levels of Pain Relief at Day 3; 7-Day Study Figure 4: Patients Achieving Various Levels of Pain Relief at End of Study; 7-Day Study Figure 1 Figure 2 Figure 3 Figure 4

8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Warnings and Precautions (5.1 , 5.2 , 5.3 , 5.6 , 5.14 )]. Clinical studies of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

8.4 Pediatric Use The safety and effectiveness of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% have been established in pediatric patients 6 years and older based on evidence from adequate and well-controlled studies with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % in adults, as well as an open-label study in pediatric patients 6 years and older. The pediatric study enrolled 104 patients, 6 years of age and older with minor soft tissue injuries. One DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % was applied to the injury site twice daily for a maximum of 14 days or until treatment was no longer required for pain management, whichever occurred first. Based on the available data from the pediatric study, the safety profile of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % topical system in pediatric patients is similar to that in adults. The safety and effectiveness of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % has not been investigated in pediatric patients less than 6 years old. [ see Clinical Trials Experience (6.1) , Clinical Pharmacology (12.3) ].

8.1 Pregnancy Risk Summary Use of NSAIDs, including DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, 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 EPOLAMINE TOPICAL SYSTEM 1.3% use between about 20 and 30 weeks of gestation, and avoid DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% 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 EPOLAMINE TOPICAL SYSTEM 1.3%, 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, diclofenac epolamine administered orally to pregnant rats and rabbits during the period of organogenesis produced embryotoxicity at approximately 3 and 7 times, respectively, the topical exposure from the maximum recommended human dose (MRHD) of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%. In rats, increased incidences of skeletal anomalies and maternal toxicity were also observed at this dose. Diclofenac epolamine administered orally to both male and female rats prior to mating and throughout the mating period, and during gestation and lactation in females produced embryotoxicity at doses approximately 3 and 7 times, respectively, the topical exposure from the MRHD (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, 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 is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, 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 EPOLAMINE TOPICAL SYSTEM 1.3% treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and follow up according to clinical practice ( see Data ). 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 Pregnant Sprague Dawley rats were administered 1, 3, or 6 mg/kg diclofenac epolamine via oral gavage daily from gestation days 6 to 15. Maternal toxicity, embryotoxicity, and increased incidence of skeletal anomalies were noted with 6 mg/kg/day diclofenac epolamine, which corresponds to 3 times the maximum recommended daily exposure in humans based on a body surface area comparison. Pregnant New Zealand White rabbits were administered 1, 3, or 6 mg/kg diclofenac epolamine via oral gavage daily from gestation days 6 to 18. No maternal toxicity was noted; however, embryotoxicity was evident at 6 mg/kg/day group which corresponds to 7 times the maximum recommended daily exposure in humans based on a body surface area comparison. Male rats were orally administered diclofenac epolamine (1, 3, 6 mg/kg) for 60 days prior to mating and throughout the mating period, and females were given the same doses 14 days prior to mating and through mating, gestation, and lactation. Embryotoxicity was observed at 6 mg/kg diclofenac epolamine (3 times the maximum recommended daily exposure in humans based on a body surface area comparison), and was manifested as an increase in early resorptions, post-implantation losses, and a decrease in live fetuses. The number of live born and total born were also reduced as was F1 postnatal survival, but the physical and behavioral development of surviving F1 pups in all groups was the same as the deionized water control, nor was reproductive performance adversely affected despite a slight treatment-related reduction in body weight.

8 USE IN SPECIFIC POPULATIONS Infertility : NSAIDs are associated with reversible infertility. Consider withdrawal of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% in women who have difficulties conceiving ( 8.3 ) 8.1 Pregnancy Risk Summary Use of NSAIDs, including DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, 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 EPOLAMINE TOPICAL SYSTEM 1.3% use between about 20 and 30 weeks of gestation, and avoid DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% 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 EPOLAMINE TOPICAL SYSTEM 1.3%, 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, diclofenac epolamine administered orally to pregnant rats and rabbits during the period of organogenesis produced embryotoxicity at approximately 3 and 7 times, respectively, the topical exposure from the maximum recommended human dose (MRHD) of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%. In rats, increased incidences of skeletal anomalies and maternal toxicity were also observed at this dose. Diclofenac epolamine administered orally to both male and female rats prior to mating and throughout the mating period, and during gestation and lactation in females produced embryotoxicity at doses approximately 3 and 7 times, respectively, the topical exposure from the MRHD (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, 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 is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, 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 EPOLAMINE TOPICAL SYSTEM 1.3% treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and follow up according to clinical practice ( see Data ). 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 Pregnant Sprague Dawley rats were administered 1, 3, or 6 mg/kg diclofenac epolamine via oral gavage daily from gestation days 6 to 15. Maternal toxicity, embryotoxicity, and increased incidence of skeletal anomalies were noted with 6 mg/kg/day diclofenac epolamine, which corresponds to 3 times the maximum recommended daily exposure in humans based on a body surface area comparison. Pregnant New Zealand White rabbits were administered 1, 3, or 6 mg/kg diclofenac epolamine via oral gavage daily from gestation days 6 to 18. No maternal toxicity was noted; however, embryotoxicity was evident at 6 mg/kg/day group which corresponds to 7 times the maximum recommended daily exposure in humans based on a body surface area comparison. Male rats were orally administered diclofenac epolamine (1, 3, 6 mg/kg) for 60 days prior to mating and throughout the mating period, and females were given the same doses 14 days prior to mating and through mating, gestation, and lactation. Embryotoxicity was observed at 6 mg/kg diclofenac epolamine (3 times the maximum recommended daily exposure in humans based on a body surface area comparison), and was manifested as an increase in early resorptions, post-implantation losses, and a decrease in live fetuses. The number of live born and total born were also reduced as was F1 postnatal survival, but the physical and behavioral development of surviving F1 pups in all groups was the same as the deionized water control, nor was reproductive performance adversely affected despite a slight treatment-related reduction in body weight. 8.2 Lactation Risk Summary Data from published literature reports with oral preparations of diclofenac indicate the presence of small amounts of diclofenac in human milk (see Data ) . There are no data on the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and any potential adverse effects on the breastfed infant from the DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% 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). The relative bioavailability for DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is <1% of a single 50 mg diclofenac tablet. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Clinical Pharmacology (12.1) ]. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% have been established in pediatric patients 6 years and older based on evidence from adequate and well-controlled studies with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % in adults, as well as an open-label study in pediatric patients 6 years and older. The pediatric study enrolled 104 patients, 6 years of age and older with minor soft tissue injuries. One DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % was applied to the injury site twice daily for a maximum of 14 days or until treatment was no longer required for pain management, whichever occurred first. Based on the available data from the pediatric study, the safety profile of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % topical system in pediatric patients is similar to that in adults. The safety and effectiveness of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % has not been investigated in pediatric patients less than 6 years old. [ see Clinical Trials Experience (6.1) , Clinical Pharmacology (12.3) ]. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Warnings and Precautions (5.1 , 5.2 , 5.3 , 5.6 , 5.14 )]. Clinical studies of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

16 HOW SUPPLIED/STORAGE AND HANDLING The DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is supplied in resealable envelopes, each containing 5 topical systems (10 cm × 14 cm), with 6 envelopes per box (NDC 82347-0405-5). Each individual topical system is debossed with "YARAL < DICLOFENAC EPOLAMINE TOPICAL SYSTEM > 1.3%". The product is intended for topical use only. Keep out of reach of children and pets. Envelopes should be sealed at all times when not in use. Curad® Hold Tite™ is a trademark of Medline Industries, Inc., and Surgilast® Tubular Elastic Dressing is a trademark of Derma Sciences, Inc. Storage 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) [see USP Controlled Room Temperature].

Storage 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) [see USP Controlled Room Temperature].

WARNING: RISK OF SERIOUS CARDIOVASCULAR and GASTROINTESTINAL EVENTS WARNING: RISK OF SERIOUS CARDIOVASCULAR and GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use ( 5.1 ) DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is contraindicated in the setting of coronary artery bypass graft (CABG) surgery ( 4 , 5.1 ) NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events ( 5.2 ) Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [ see Warnings and Precautions (5.1) ]. DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [ see Contraindications (4) and Warnings and Precautions (5.1) ] . Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [ see Warnings and Precautions (5.2) ].