PLIAGLIS

5 WARNINGS AND PRECAUTIONS Methemoglobinemia : Cases of methemoglobinemia have been reported in association with local anesthetic use. ( 5.1 ) Overexposure : To avoid overexposure that could lead to adverse effects, do not use for longer duration or over larger surface areas than recommended. ( 5.2 ) consider total amount of local anesthetics absorbed from all formulations. ( 5.2 ) do not apply to mucous membranes or broken or inflamed skin. ( 5.2 ) use with caution in patients who may be more sensitive to systemic effects of PLIAGLIS, including acutely ill or debilitated or those with severe hepatic disease or pseudocholinesterase deficiency. ( 5.2 ) Risk of Secondary Exposure to Children and Pets : Store and dispose of PLIAGLIS out of reach of children and pets due to the risk of accidental exposure and resulting toxicity. ( 5 ) Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs. ( 5.4 ) Eye Irritation : Avoid contact with eyes. ( 5.5 ) 5.1 Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue PLIAGLIS and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. 5.2 Overexposure Application of PLIAGLIS for longer times than those recommended or application of PLIAGLIS over larger surface areas than those recommended could result in absorption of lidocaine and tetracaine at doses that could lead to serious adverse effects [see Overdosage (10) ] . When PLIAGLIS is used concomitantly with other products containing local anesthetic agents, consider the amount absorbed from all formulations since the systemic toxic effects are thought to be additive and potentially synergistic with lidocaine and tetracaine. PLIAGLIS is not recommended for use on mucous membranes or on areas with a compromised skin barrier because these uses have not been adequately studied. Application to broken or inflamed skin may result in toxic blood concentrations of lidocaine and tetracaine from increased absorption. Use PLIAGLIS with caution in patients who may be more sensitive to the systemic effects of lidocaine and tetracaine, including the acutely ill or debilitated. Patients with severe hepatic disease or pseudocholinesterase deficiency, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations of lidocaine and tetracaine. 5.3 Risks of Secondary Exposure to Children and Pets Used PLIAGLIS contains a large amount of lidocaine and tetracaine. The potential exists for a small child or pet to suffer serious adverse effects from ingesting PLIAGLIS, although this risk with PLIAGLIS has not been evaluated. After use, replace the cap securely on the tube. It is important to store and dispose of PLIAGLIS out of the reach of children and pets. 5.4 Anaphylactic Reactions Allergic or anaphylactic reactions have been associated with lidocaine and tetracaine and may occur with other components of PLIAGLIS. They are characterized by urticaria, angioedema, bronchospasm, and shock. If an allergic reaction occurs, seek emergency help immediately. 5.5 Eye Irritation Avoid contact of PLIAGLIS with the eyes based on the findings of severe eye irritation with the use of similar products in animals. Also, the loss of protective reflexes may predispose to corneal irritation and potential abrasion. If eye contact occurs, immediately wash out the eye with water or saline and protect the eye until sensation returns. 5.6 Vaccinations Lidocaine has been shown to inhibit viral and bacterial growth. The effect of PLIAGLIS on intradermal injections of live vaccines has not been determined.

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: Methemoglobinemia [see Warnings and Precautions (5.1) ] Overexposure [see Warnings and Precautions (5.2) ] Risks of Secondary Exposure in Children and Pets [see Warnings and Precautions (5.3) ] Anaphylactic Reactions [see Warnings and Precautions (5.4) ] Eye Irritation [see Warnings and Precautions (5.5) ] Most common local reactions were erythema (47%), skin discoloration (16%), and edema (14%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact IPG Pharmaceuticals, Inc. at 1-888-711-7116 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 clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. However, the adverse reaction information from clinical trials does provide a basis for identifying the adverse events that appear to be related to drug use and for approximating their incidence in clinical practice. PLIAGLIS has been evaluated for safety in 2159 persons undergoing a superficial dermal procedure. PLIAGLIS was studied in 11 placebo-controlled and 1 active-controlled trials, and in open-label safety trials. All 2159 persons were exposed to only a single application of PLIAGLIS. Adverse reactions were assessed by collecting spontaneously reported adverse reactions, and observations made on formal evaluation of the skin for specific reactions. Most common adverse reactions in clinical trials Localized Reactions: In clinical studies, the most common local reactions were erythema (47%), skin discoloration (e.g., blanching, ecchymosis, and purpura) (16%), and edema (14%). There were no serious adverse reactions. However, one patient withdrew due to burning pain at the treatment site. Other Localized Reactions: The following dermal adverse reactions occurred in 1% or less of PLIAGLIS-treated patients: ecchymosis, petechial rash, vesiculobullous rash, perifollicular erythema, perifollicular edema, pruritus, rash, maculopapular rash, dry skin, contact dermatitis, and acne. Systemic (Dose-Related) Reactions: Across all trials, 19 subjects experienced a systemic adverse reaction, 15 of whom were treated with PLIAGLIS and 4 with placebo. The frequency of systemic adverse reactions was greater for the PLIAGLIS group (1%) than the placebo group (0.3%). The most common systemic adverse events were headache, vomiting, dizziness, and fever, all of which occurred with a frequency of <1%. Other systemic reactions were syncope, nausea, confusion, dehydration, hyperventilation, hypotension, nervousness, paresthesia, pharyngitis, stupor, pallor, and sweating. Systemic adverse reactions of lidocaine and tetracaine are similar in nature to those observed with other amide and ester local anesthetic agents, including CNS excitation and/or depression (lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensation of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest). Excitatory CNS reactions may be brief or not occur at all, in which case the first manifestation may be drowsiness merging into unconsciousness. Signs of CNS toxicity may start at plasma concentrations of lidocaine at 1000 ng/mL. The plasma concentrations at which tetracaine toxicity may occur are less well characterized; however, systemic toxicity with tetracaine is thought to occur with much lower plasma concentrations compared with lidocaine. The toxicity of co-administered local anesthetics is thought to be at least additive. Cardiovascular manifestations may include bradycardia, hypotension and cardiovascular collapse leading to arrest. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of PLIAGLIS. 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. Eye disorders: Eyelid swelling Skin: Pruritus, Rash, Skin Burning Sensation, Erythema, Urticaria Other: Drug ineffective