FDA label 23477215-fcfc-4b11-a5c3-b2034c31aefb

5. WARNINGS AND PRECAUTIONS Dose-Related Toxicity : Monitor cardiovascular and respiratory vital signs and patient’s state of consciousness after placement of XARACOLL. ( 5.1 ) Methemoglobinemia : Cases of methemoglobinemia have been reported in association with local anesthetic use. See full prescribing information for more detail on managing these risks ( 5.2 ). 5.1 Dose-related Toxicity The safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. The toxic effects of local anesthetics are additive. Avoid additional local anesthetic administration within 96 hours following XARACOLL implantation. If additional local anesthetic administration with XARACOLL cannot be avoided based on clinical need, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be performed after administration of XARACOLL. Possible early warning signs of central nervous system (CNS) toxicity are restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, CNS depression, or drowsiness. Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death. Consider surgical removal of XARACOLL depending on the clinical situation. 5.2 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 CNS and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Consider removal of XARACOLL and discontinue 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. 5.3 Risk of Toxicity in Patients with Hepatic Impairment Because amide local anesthetics such as bupivacaine are metabolized by the liver, consider increased monitoring for bupivacaine systemic toxicity in patients with moderate to severe hepatic impairment who are treated with XARACOLL [see Use in Specific Populations (8.6) ] . 5.4 Risk of Use in Patients with Impaired Cardiovascular Function Patients with impaired cardiovascular function (e.g., hypotension, heart block) may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by XARACOLL. Monitor patients closely for blood pressure, heart rate, and ECG changes. 5.5 Risk of Delayed Bone Healing with Unapproved Use The safety and effectiveness of XARACOLL in surgical procedures other than open inguinal hernia repair have not been established, and XARACOLL is not approved for use in these other surgical procedures (e.g., orthopedic procedures). A study evaluating the effects of bupivacaine HCl implant in rats following an osteotomy procedure demonstrated inhibition of bone healing [see Nonclinical Toxicology (13.2) ] .

6. ADVERSE REACTIONS The following clinically significant adverse reactions have been reported and described in the Warnings section in the labeling: Dose-Related Toxicity [see Warnings and Precautions (5.1) ] Methemoglobinemia [see Warnings and Precautions (5.2) ] Most common adverse reactions in clinical trials (incidence ≥2% and higher than placebo) included incision site swelling, dysgeusia, headache, tremor, vision blurred, seroma, scrotal swelling, pyrexia, hypoesthesia oral, and post procedural discharge. ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Innocoll at 1-833-606-1421 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety of XARACOLL was evaluated in 11 clinical studies, including two Phase 3 double-blind, placebo implant-controlled studies in patients undergoing open, unilateral inguinal hernia repair. Overall, 612 patients were treated with a single dose of XARACOLL, total dose ranged from 100 mg to 300 mg bupivacaine HCl. Patients treated with XARACOLL ranged in age from 18 to 85 years (median age 51 years), with 88% male, 88% White, 9% African-American, and 3% all other races. Across the XARACOLL drug development program, which included evaluations in various surgery models, there was one patient death reported in the placebo implant treatment group, and 16 patients who experienced one or more serious adverse events; 11 patients in the XARACOLL treatment group and 5 patients in the placebo implant or comparator treatment groups. Serious adverse reactions reported in the XARACOLL treatment group included wound infection and seroma. There was a single patient who experienced signs and symptoms consistent with local anesthetic systemic toxicity (LAST) approximately four hours after administration of an early formulation of the bupivacaine collagen implant 150 mg during bladder sling surgery. LAST treatment included administration of lipid emulsion and surgical removal of the XARACOLL implants. The most common adverse reactions (incidence greater than or equal to 2% and higher than placebo implant) following XARACOLL administration were dysgeusia, headache, scrotal swelling, tremor, pyrexia, vision blurred, and seroma. Common incision site adverse reactions (incidence greater than or equal to 2% and higher in either the XARACOLL or placebo implant groups compared to non-implant comparator treatment groups) were swelling pain, other complication, post-procedural discharge, erythema, dehiscence, and inflammation. Adverse Reactions Reported in Phase 3 Placebo-controlled Trials There were 619 patients who underwent open inguinal hernia repair in the two Phase 3 studies. Patients received general anesthesia intra-operatively, and a standard acetaminophen regimen, in addition to intravenous and oral morphine as needed, post-operatively. The most common adverse reactions (incidence greater than or equal to 2% and higher than placebo implants) following XARACOLL administration were incision site swelling, dysgeusia, headache, tremor, vision blurred, seroma, scrotal swelling, pyrexia, hypoesthesia oral, and post procedural discharge shown in Table 1. Table 1: Adverse Reactions (ARs) with Incidence Greater Than or Equal to 2% and Greater Than Placebo Reported in the Phase 3 Placebo-controlled Studies XARACOLL 300 mg N=411 n (%) Placebo Placebo consisted of three collagen implants. N=208 n (%) Subjects Reporting Treatment Emergent Adverse Events 256 (62.3%) 143 (68.8%) Injury, Poisoning and Procedural Complications Incision Site Swelling 60 (14.6%) 30 (14.4%) Post Procedural Discharge 20 (4.9%) 10 (4.8%) Seroma 12 (2.9%) 5 (2.4%) Nervous System Disorders Dysgeusia 31 (7.5%) 13 (6.3%) Headache 17 (4.1%) 1 (0.5%) Tremor 15 (3.6%) 6 (2.9%) Gastrointestinal Disorders Hypoaesthesia Oral 9 (2.2%) 4 (1.9%) Reproductive System and Breast Disorders Scrotal Swelling 12 (2.9%) 2 (1.0%) General Disorders and Administration Site Conditions Pyrexia 10 (2.4%) 1 (0.5%) Eye Disorders Vision Blurred 15 (3.6%) 6 (2.9%) 6.2 Postmarketing Experience The following adverse reactions from voluntary reports have been reported with various formulations of bupivacaine, administered via different routes and for different indications. Because many of these reactions were 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. Adverse reactions to bupivacaine are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation. The most commonly encountered acute adverse reactions that demand immediate counter-measures were related to the CNS and the cardiovascular system. These adverse reactions were generally dose-related and due to high plasma levels, which may have resulted from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. Nervous System Disorders : Adverse reactions were characterized by excitation and/or depression of the central nervous system and included restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, drowsiness, unconsciousness, respiratory arrest, nausea, vomiting, chills, pupillary constriction. Neurological effects following routes of administration other than epidural or caudal have included persistent anesthesia, paresthesia, weakness, and paralysis, all with slow, incomplete, or no recovery. The incidence of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Cardiac Disorders: High doses have led to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest. Immune System Disorders : Allergic-type reactions have occurred as a result of sensitivity to bupivacaine or to other formulation ingredients. These reactions were characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and severe hypotension. Cross sensitivity among members of the amide-type local anesthetic group has been reported.

<table width="100%"><caption> Table 1: Adverse Reactions (ARs) with Incidence Greater Than or Equal to 2% and Greater Than Placebo Reported in the Phase 3 Placebo-controlled Studies</caption><tbody><tr><td/><td align="center"><content styleCode="bold"> XARACOLL 300 mg</content> <content styleCode="bold">N=411</content> <content styleCode="bold">n (%)</content></td><td align="center"><content styleCode="bold"> Placebo<footnote ID="L92b4da30-0977-4200-b78d-f8faa3fe2663">Placebo consisted of three collagen implants.</footnote></content> <content styleCode="bold">N=208</content> <content styleCode="bold">n (%)</content></td></tr><tr><td> Subjects Reporting Treatment Emergent Adverse Events</td><td align="center"> 256 (62.3%)</td><td align="center"> 143 (68.8%)</td></tr><tr><td> Injury, Poisoning and Procedural Complications</td><td/><td/></tr><tr><td> Incision Site Swelling</td><td align="center"> 60 (14.6%)</td><td align="center"> 30 (14.4%)</td></tr><tr><td> Post Procedural Discharge</td><td align="center"> 20 (4.9%)</td><td align="center"> 10 (4.8%)</td></tr><tr><td> Seroma</td><td align="center"> 12 (2.9%)</td><td align="center"> 5 (2.4%)</td></tr><tr><td> Nervous System Disorders</td><td/><td/></tr><tr><td> Dysgeusia</td><td align="center"> 31 (7.5%)</td><td align="center"> 13 (6.3%)</td></tr><tr><td> Headache</td><td align="center"> 17 (4.1%)</td><td align="center"> 1 (0.5%)</td></tr><tr><td> Tremor</td><td align="center"> 15 (3.6%)</td><td align="center"> 6 (2.9%)</td></tr><tr><td> Gastrointestinal Disorders</td><td/><td/></tr><tr><td> Hypoaesthesia Oral</td><td align="center"> 9 (2.2%)</td><td align="center"> 4 (1.9%)</td></tr><tr><td> Reproductive System and Breast Disorders</td><td/><td/></tr><tr><td> Scrotal Swelling</td><td align="center"> 12 (2.9%)</td><td align="center"> 2 (1.0%)</td></tr><tr><td> General Disorders and Administration Site Conditions</td><td/><td/></tr><tr><td> Pyrexia</td><td align="center"> 10 (2.4%)</td><td align="center"> 1 (0.5%)</td></tr><tr><td> Eye Disorders</td><td/><td/></tr><tr><td> Vision Blurred</td><td align="center"> 15 (3.6%)</td><td align="center"> 6 (2.9%)</td></tr></tbody></table>