These Highlights Do Not Include All The Information Needed To Use Licart ®

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)] .
• LICART is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [See Contraindications (4) and Warnings and Precautions (5.1)].

Manufactured for: IBSA Institut Biochimique SA, 6912 Pazzallo, Switzerland



Distributed by: IBSA Pharma Inc., Parsippany, NJ 07054 USA

For more information, go to www.licart.com or call 1-800-587-3513



This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2022

1235 edition V 11.22

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]. Once the envelope has been opened, LICART is stable up to 6 months, if stored at room temperature in the re-sealed envelope.

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, call a poison control center (1-800-222-1222).

LICART (diclofenac epolamine) topical system 1.3% is a nonsteroidal anti-inflammatory drug, available for topical application. LICART 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 ₂₀H ₂₄Cl ₂N ₂O ₃ and molecular weight 411.3, an n-octanol/water partition coefficient of 8 at pH 8.5, and the following chemical structure:

Each LICART contains 182 mg of diclofenac epolamine in an aqueous base. Each gram of adhesive contains 13 mg of diclofenac epolamine (equivalent to 9.4 mg diclofenac). Each LICART also contains the following inactive ingredients: butylene glycol, carboxymethylcellulose sodium, dihydroxyaluminum aminoacetate, edetate disodium, gelatin, heparin sodium, kaolin, methylparaben, polysorbate 80, povidone, propylene glycol, propylparaben, sodium polyacrylate, sorbitol solution, tartaric acid, titanium dioxide, and purified water.

NSAIDs, including LICART, can lead to new onset or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)] .

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

Avoid contact of LICART with 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.

The safety and effectiveness of LICART in pediatric patients have not been established.

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 LICART 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.

In clinical trials of oral diclofenac containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies).

In an open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of the 3,700 patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.

In post-marketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Post-marketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.

In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days.

Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and post-marketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac.

If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), LICART should be discontinued immediately.

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 clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue LICART immediately, and perform a clinical evaluation of the patient. To minimize the potential risk for an adverse liver related event in patients treated with LICART, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing LICART with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti-epileptics).

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.

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)]

See Table 2 for clinically significant drug interactions with diclofenac.

The recommended dose is one (1) LICART topical system to the most painful area once daily.

LICART applied to intact skin provides local analgesia by releasing diclofenac epolamine from the topical system into the skin.

LICART is indicated for the topical treatment of acute pain due to minor strains, sprains, and contusions.

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.

Heparin sodium is included in the LICART formulation as an inactive ingredient. In one study in healthy human volunteers activated partial thromboplastin time (aPTT), a measure of coagulation, was unchanged following multiple LICART applications.

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with LICART has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including LICART, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)] .

• 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)

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)] .

Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)].

Seek emergency help if an anaphylactic reaction occurs.

NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening.These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of LICART at the first appearance of skin rash or any other sign of hypersensitivity. LICART is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)] .

• 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)

Topical System: 1.3% diclofenac epolamine (10 cm × 14 cm) debossed with "LICART (diclofenac epolamine) topical system 1.3%".

The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)] .

Avoid the use of LICART in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If LICART is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

The following adverse reactions have been identified during post-approval use of diclofenac topical system. 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 through foreign post-marketing surveillance.

Diclofenac

Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), fixed drug eruption (FDE) [see Warnings and Precautions ( 5.9)]

• Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of LICART in women who have difficulties conceiving ( 8.3)

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.

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 LICART and periodically during the course of ongoing therapy.

The LICART (diclofenac epolamine) topical system 1.3% is supplied in re-sealable envelopes, each containing 5 topical systems (10 cm × 14 cm EACH) (NDC 71858-0305-4), with 3 envelopes per box (NDC 71858-0305-5). Each LICART is debossed with "LICART (diclofenac epolamine) topical system 1.3%".

• Keep out of reach of children and pets.
• Envelopes should be sealed at all times when not in use.

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)].

Even a used LICART contains a large amount of diclofenac epolamine (as much as 170 mg). The potential therefore exists for a small child or pet to suffer serious adverse effects from chewing or ingesting a new or used LICART. It is important for patients to store and dispose of LICART out of the reach of children and pets.

The pharmacological activity of LICART in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infections.

NDC 71858-0305-5

Licart®



(diclofenac epolamine) topical system 1.3%

CHANGE LICART ONCE DAILY 24hr

Rx Only

15 TOPICAL SYSTEMS (10 CM X 14 CM EACH)

Dispense with enclosed Medication Guide

Fold the used topical systems so that the adhesive side sticks to itself and safely discard used topical systems where children and pets cannot get them

IBSA

Concomitant use of oral and topical NSAIDs may result in a higher rate of hemorrhage, more frequent abnormal creatinine, urea and hemoglobin. Do not use LICART in combination with an oral NSAID unless the benefit outweighs the risk and periodic laboratory evaluations are conducted.

The efficacy of LICART was demonstrated in two randomized, double-blind, parallel-arm, placebo- and active-controlled studies in patients with minor sprains, strains, and/or contusions. Patients were randomized equally to receive LICART, placebo, or FLECTOR and treatment was applied as a 24-hour, once daily application for 7 or 14 days. FLECTOR was not administered according to its approved twice daily (BID) dosing regimen; therefore, conclusions regarding comparative efficacy between LICART and FLECTOR cannot be made based on these studies.

One study enrolled 429 adult patients aged 18 to 65 years with ankle sprain who had a mean baseline pain intensity on movement of 72 mm on a 0-100 mm visual analog scale (VAS). The second study enrolled 355 adult patients aged 18-75 years with muscle contusion of the limb who had a mean baseline pain on movement intensity of 68 mm on a 0-100 mm VAS. The primary efficacy endpoint was the mean change from baseline in pain on movement to Day 3 of treatment, where pain on movement was assessed twice daily (i.e., morning and evening) for 7 days in the ankle sprain study (06EU/FHp03) and 14 days in the muscle contusion study (05DCz/FHp11). In both studies, LICART demonstrated a statistically significant difference versus placebo on the primary efficacy endpoint, reduction in pain on movement at Day 3.

Figure 1: Pain on movement intensity score differences from baseline in the muscle contusion study (Protocol 05DCz/FHp11).

Figure 2: Pain on movement intensity score differences from baseline in the ankle sprain study (Protocol 06EU/FHp03).

Based on a clinical study in 28 subjects with LICART applied to the lower leg above the ankle, 28 subjects (100%) had adhesion scores of 0 (≥90% adhered) for all evaluations performed every 4 hours during the 24-hour wear period.

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:

• 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.

NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.

Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2% - 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

A subpopulation of patients with asthma may have aspirin-sensitive asthma, which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, LICART is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)] . When LICART is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as LICART. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue LICART and evaluate the patient immediately .

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 the treatment and may increase with duration of use ( 5.1)
• LICART 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)] .
• LICART is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [See Contraindications (4) and Warnings and Precautions (5.1)].

Manufactured for: IBSA Institut Biochimique SA, 6912 Pazzallo, Switzerland



Distributed by: IBSA Pharma Inc., Parsippany, NJ 07054 USA

For more information, go to www.licart.com or call 1-800-587-3513



This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2022

1235 edition V 11.22

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]. Once the envelope has been opened, LICART is stable up to 6 months, if stored at room temperature in the re-sealed envelope.

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, call a poison control center (1-800-222-1222).

LICART (diclofenac epolamine) topical system 1.3% is a nonsteroidal anti-inflammatory drug, available for topical application. LICART 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 ₂₀H ₂₄Cl ₂N ₂O ₃ and molecular weight 411.3, an n-octanol/water partition coefficient of 8 at pH 8.5, and the following chemical structure:

Each LICART contains 182 mg of diclofenac epolamine in an aqueous base. Each gram of adhesive contains 13 mg of diclofenac epolamine (equivalent to 9.4 mg diclofenac). Each LICART also contains the following inactive ingredients: butylene glycol, carboxymethylcellulose sodium, dihydroxyaluminum aminoacetate, edetate disodium, gelatin, heparin sodium, kaolin, methylparaben, polysorbate 80, povidone, propylene glycol, propylparaben, sodium polyacrylate, sorbitol solution, tartaric acid, titanium dioxide, and purified water.

NSAIDs, including LICART, can lead to new onset or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)] .

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

Avoid contact of LICART with 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.

The safety and effectiveness of LICART in pediatric patients have not been established.

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 LICART 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.

In clinical trials of oral diclofenac containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies).

In an open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of the 3,700 patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.

In post-marketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Post-marketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.

In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days.

Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and post-marketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac.

If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), LICART should be discontinued immediately.

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 clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue LICART immediately, and perform a clinical evaluation of the patient. To minimize the potential risk for an adverse liver related event in patients treated with LICART, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing LICART with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti-epileptics).

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.

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)]

See Table 2 for clinically significant drug interactions with diclofenac.

The recommended dose is one (1) LICART topical system to the most painful area once daily.

LICART applied to intact skin provides local analgesia by releasing diclofenac epolamine from the topical system into the skin.

LICART is indicated for the topical treatment of acute pain due to minor strains, sprains, and contusions.

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.

Heparin sodium is included in the LICART formulation as an inactive ingredient. In one study in healthy human volunteers activated partial thromboplastin time (aPTT), a measure of coagulation, was unchanged following multiple LICART applications.

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with LICART has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including LICART, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)] .

• 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)

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)] .

Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)].

Seek emergency help if an anaphylactic reaction occurs.

NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening.These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of LICART at the first appearance of skin rash or any other sign of hypersensitivity. LICART is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)] .

• 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)

Topical System: 1.3% diclofenac epolamine (10 cm × 14 cm) debossed with "LICART (diclofenac epolamine) topical system 1.3%".

The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)] .

Avoid the use of LICART in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If LICART is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

The following adverse reactions have been identified during post-approval use of diclofenac topical system. 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 through foreign post-marketing surveillance.

Diclofenac

Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), fixed drug eruption (FDE) [see Warnings and Precautions ( 5.9)]

• Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of LICART in women who have difficulties conceiving ( 8.3)

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.

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 LICART and periodically during the course of ongoing therapy.

The LICART (diclofenac epolamine) topical system 1.3% is supplied in re-sealable envelopes, each containing 5 topical systems (10 cm × 14 cm EACH) (NDC 71858-0305-4), with 3 envelopes per box (NDC 71858-0305-5). Each LICART is debossed with "LICART (diclofenac epolamine) topical system 1.3%".

• Keep out of reach of children and pets.
• Envelopes should be sealed at all times when not in use.

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)].

Even a used LICART contains a large amount of diclofenac epolamine (as much as 170 mg). The potential therefore exists for a small child or pet to suffer serious adverse effects from chewing or ingesting a new or used LICART. It is important for patients to store and dispose of LICART out of the reach of children and pets.

The pharmacological activity of LICART in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infections.

NDC 71858-0305-5

Licart®



(diclofenac epolamine) topical system 1.3%

CHANGE LICART ONCE DAILY 24hr

Rx Only

15 TOPICAL SYSTEMS (10 CM X 14 CM EACH)

Dispense with enclosed Medication Guide

Fold the used topical systems so that the adhesive side sticks to itself and safely discard used topical systems where children and pets cannot get them

IBSA

Concomitant use of oral and topical NSAIDs may result in a higher rate of hemorrhage, more frequent abnormal creatinine, urea and hemoglobin. Do not use LICART in combination with an oral NSAID unless the benefit outweighs the risk and periodic laboratory evaluations are conducted.

The efficacy of LICART was demonstrated in two randomized, double-blind, parallel-arm, placebo- and active-controlled studies in patients with minor sprains, strains, and/or contusions. Patients were randomized equally to receive LICART, placebo, or FLECTOR and treatment was applied as a 24-hour, once daily application for 7 or 14 days. FLECTOR was not administered according to its approved twice daily (BID) dosing regimen; therefore, conclusions regarding comparative efficacy between LICART and FLECTOR cannot be made based on these studies.

One study enrolled 429 adult patients aged 18 to 65 years with ankle sprain who had a mean baseline pain intensity on movement of 72 mm on a 0-100 mm visual analog scale (VAS). The second study enrolled 355 adult patients aged 18-75 years with muscle contusion of the limb who had a mean baseline pain on movement intensity of 68 mm on a 0-100 mm VAS. The primary efficacy endpoint was the mean change from baseline in pain on movement to Day 3 of treatment, where pain on movement was assessed twice daily (i.e., morning and evening) for 7 days in the ankle sprain study (06EU/FHp03) and 14 days in the muscle contusion study (05DCz/FHp11). In both studies, LICART demonstrated a statistically significant difference versus placebo on the primary efficacy endpoint, reduction in pain on movement at Day 3.

Figure 1: Pain on movement intensity score differences from baseline in the muscle contusion study (Protocol 05DCz/FHp11).

Figure 2: Pain on movement intensity score differences from baseline in the ankle sprain study (Protocol 06EU/FHp03).

Based on a clinical study in 28 subjects with LICART applied to the lower leg above the ankle, 28 subjects (100%) had adhesion scores of 0 (≥90% adhered) for all evaluations performed every 4 hours during the 24-hour wear period.

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:

• 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.

NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.

Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2% - 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

A subpopulation of patients with asthma may have aspirin-sensitive asthma, which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, LICART is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)] . When LICART is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as LICART. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue LICART and evaluate the patient immediately .

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 the treatment and may increase with duration of use ( 5.1)
• LICART 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)