LICART

1 INDICATIONS AND USAGE LICART is indicated for the topical treatment of acute pain due to minor strains, sprains, and contusions in adults and pediatric patients 6 years of age and older. LICART contains diclofenac epolamine, which 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 )

2 DOSAGE AND ADMINISTRATION . Use the lowest effective dose for shortest duration consistent with individual patient treatment goals ( 2.1 ) See the Full Prescribing Information for important administration instructions ( 2.1 ) Do not apply to damaged or non-intact skin ( 2.1 ) The recommended dose is one (1) LICART to the most painful area once daily ( 2.2 ) 2.1 Important Dosage and Administration Information Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5) ] . LICART is intended for topical use only. Convey the following important administration instructions to the patient and caregivers: If LICART 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 (i.e., non-breathable) Curad ® Hold Tite™ is a trademark of Medline Industries, Inc., and Surgilast ® Tubular Elastic Dressing is a trademark of Derma Sciences, Inc. . Do not apply LICART to non-intact or damaged skin resulting from any etiology, e.g., exudative dermatitis, eczema, infected lesion, burns or wounds. Do not wear a LICART topical system when bathing or showering. Wash your hands after applying, handling, or removing the topical system. Avoid contact with eyes. Do not use LICART in combination with an oral NSAID unless the benefit outweighs the risk and periodic laboratory evaluations are conducted. 2.2 Recommended Dose The recommended dose is one (1) LICART topical system to the most painful area once daily both in adults and pediatric patients 6 years and older. .

5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop ( 5.3 ) Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.4 , 7 ) Heart Failure and Edema : Avoid use of LICART in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.5 ) Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of LICART in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function ( 5.6 ) Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs ( 5.7 ) Exacerbation of Asthma Related to Aspirin Sensitivity : LICART is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8 ) Serious Skin Reactions : Discontinue LICART at first appearance of skin rash or other signs of hypersensitivity ( 5.9 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically ( 5.10 ). Fetal Toxicity: Limit use of NSAIDs, including LICART, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus ( 5.11 , 8.1 ) Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.12 , 7 ) 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2) ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4) ] . Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated wi…

4 CONTRAINDICATIONS LICART 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) ]. On non-intact or damaged skin resulting from any etiology, including exudative dermatitis, eczema, infected lesions, burns or wounds. Known hypersensitivity to diclofenac or any components of the drug product ( 4 ) History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs ( 4 ) In the setting of CABG surgery ( 4 ) For use on non-intact or damaged skin ( 4 )

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 LICART 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 LICART and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12) ] . LICART 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 LICART and ACE-inhibitors, ARBs, or betablockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of LICART 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 LICART 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 LICART 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 LICART and…

8.1 Pregnancy Risk Summary Use of NSAIDs, including LICART, 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 LICART use between about 20 and 30 weeks of gestation, and avoid LICART use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations and Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including LICART, 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 LICART. 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(s) 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 LICART, 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 LICART treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue LICART 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 repor…

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) ] Most common adverse reactions for LICART are application site pruritus and other application site reactions ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact IBSA Pharma Inc. at 1-800-587-3513 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. A total of 874 subjects were exposed to one or more doses of LICART in eleven clinical studies, including approximately 500 subjects who were treated with LICART in six controlled multiple-dose trials. Approximately 400 of these were exposed to the once-a-day 24-hour application, for up to one week in 288 subjects and up to two weeks in 121 subjects. Adverse Reactions Leading to Discontinuation of Treatment In the controlled trials, none of the patients given LICART discontinued treatment due to an adverse reaction. Common Adverse Reactions Localized Reactions Overall, the most common adverse reactions associated with LICART treatment were application site skin reactions. Table 1 lists all adverse reactions occurring in ≥ 1% of patients in nine studies (excluding the two dermatologic safety studies) of LICART. A majority of patients treated with LICART experienced adverse reactions with a maximum intensity of "mild" or "moderate". Table 1. Common Adverse Reactions (by System Organ Class) in ≥ 1% of Patients Treated with LICART or Placebo The placebo was comprised of the same ingredients as LICART except for diclofenac and may inform adverse reactions associated with the non-active ingredients contained in LICART. based on Data Pooled from Single-Dose and Multiple-Dose Studies LICART N=573 Placebo N=492 N Percent N Percent General Disorders and Administration Site Conditions 8 1.4 19 3.9 Application Site Pruritus 5 0.9 11 2.2 Other Application Site Reactions Includes application site irritation (6 subjects), application site erythema (3 subjects), application site reaction (4 subjects), application site rash (1 subject), application site inflammation (1 subject), blister (1 subject). 5 0.9 11 2.2 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of LICART or other diclofenac topical system products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. LICART Cases suggesting dermal allergic reactions and photoallergic reactions have been reported. Diclofenac Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), fixed drug eruption (FDE) [see Warnings and Precautions ( 5.9 )]