FDA label efa9d516-d353-d315-e053-2a95a90ab12c

WARNING: RISK OF POTENTIAL ADVERSE EMBOLIC EFFECTS RESULTING FROM INADVERTENT INTRAVASCAULAR INJECTION Inadvertent intravascular injection could cause POSIMIR droplets to be deposited in the pulmonary and other capillary beds. Administer POSIMIR into the subacromial space at the end of arthroscopic shoulder surgery. Direct arthroscopic visualization must be used to confirm proper placement of the needle tip before injecting POSIMIR. [see Warnings and Precautions ( 5.1 )] . WARNING: RISK OF POTENTIAL ADVERSE EMBOLIC EFFECTS RESULTING FROM INADVERTENT INTRAVASCULAR INJECTION See full prescribing information for complete boxed warning. Inadvertent intravascular injection could cause POSIMIR droplets to be deposited in the pulmonary and other capillary beds. Administer POSIMIR into the subacromial space at the end of arthroscopic shoulder surgery. Direct arthroscopic visualization must be used to confirm proper placement of the needle tip before injecting POSIMIR. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Risk of Joint Cartilage Necrosis with Unapproved Intra-articular Use: A study evaluating the effects of POSIMIR and POSIMIR vehicle in dogs following an intra-articular administration demonstrated joint cartilage necrosis ( 5.2 , 13.2 ). Risk of 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 injection of bupivacaine. ( 5.3 ) Methemoglobinemia : Cases of methemoglobinemia have been reported in association with local anesthetic use. See Full Prescribing Information for more detail on managing these risks. ( 5.4 ) Chondrolysis with Intra-Articular Infusion : Intra-articular infusions of local anesthetics including POSIMIR following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. ( 5.5 ) 5.1 Risk of Potential Adverse Embolic Effects Resulting from Inadvertent Intravascular Injection Inadvertent intravascular injection could cause POSIMIR droplets to be deposited in the pulmonary and other capillary beds. Administer POSIMIR into the subacromial space at the end of arthroscopic shoulder surgery. Direct arthroscopic visualization must be used to confirm proper placement of the needle tip before injecting POSIMIR. 5.2 Risk of Joint Cartilage Necrosis with Unapproved Intra-articular Use The safety and effectiveness of POSIMIR in surgical procedures other than subacromial decompression have not been established, and POSIMIR is not approved for use via intra-articular injection. A study evaluating the effects of POSIMIR and POSIMIR vehicle in dogs following an intra-articular administration demonstrated joint cartilage necrosis [ see Nonclinical Toxicology ( 13.2 ) ]. 5.3 Risk of Systemic Toxicity Unintended intravascular injection of POSIMIR may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Direct arthroscopic visualization must be used to confirm proper placement of the needle tip in the subacromial space before injecting POSIMIR. The safety and effectiveness of bupivacaine depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state of consciousness should be performed after injection of bupivacaine. 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 systemic toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death. Avoid additional use of local anesthetics within 168 hours following administration of POSIMIR. Injection of repeated doses of bupivacaine may cause significant increases in plasma levels due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation. Tolerance to elevated blood levels varies with the status of the patient. Consider increased monitoring for systemic toxicity in debilitated, elderly, or acutely ill patients. 5.4 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 [ see Drug Interactions ( 7 ) ]. 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 any 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. 5.5 Chondrolysis with Intra-Articular Infusion of Local Anesthetics Intra-articular infusions of local anesthetics including bupivacaine following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric patients and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are associated with chondrolysis. The time of onset of symptoms, such as joint pain, stiffness, and loss of motion can be variable, but may begin as early as the second month after surgery. Currently, there is no effective treatment for chondrolysis; patients who have experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. 5.6 Risk of Toxicity in Patients with Hepatic Impairment Because amide local anesthetics such as bupivacaine are metabolized by the liver, consider reduced dosing and increased monitoring for bupivacaine systemic toxicity in patients with moderate to severe hepatic impairment who are treated with POSIMIR [see Use in Specific Populations ( 8.6 ) ]. 5.7 Risk of Use in Patients with Impaired Cardiovascular Function Care should be taken when considering the use of POSIMIR in patients with impaired cardiovascular function (e.g., hypotension, heartblock) because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by bupivacaine. Consider reduced dosing. Monitor patients closely for blood pressure, heart rate, and ECG changes.

6 ADVERSE REACTIONS The following adverse reactions to bupivacaine hydrochloride are described in other sections of the prescribing information: Systemic Toxicity with Intravascular Injection [see Warnings and Precautions ( 5.3 ) ] Methemoglobinemia [see Warnings and Precautions ( 5.4 ) ] Chondrolysis with Intra-Articular Infusion [see Warnings and Precautions ( 5.5 ) ] Cardiovascular System Reactions [see Warnings and Precautions ( 5.7 ) ] Adverse reactions reported with an incidence greater than or equal to 10% and greater than control following POSIMIR administration in shoulder surgery were dizziness, dysgeusia, dysuria, headache, hypoesthesia, paresthesia, tinnitus, and vomiting ( 6.1 ). Adverse reactions reported with an incidence greater than or equal to 10% and greater than control following POSIMIR administration in soft tissue surgical procedures were anemia, bradycardia, constipation, C-reactive protein increased, diarrhea, dizziness, dysgeusia, headache, nausea, post procedural contusion (bruising), procedural pain, pruritus, pyrexia, somnolence, surgical site bleeding, visible bruising, and vomiting ( 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 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 to rates observed in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of POSIMIR, doses ranging from 2.5 mL to 5 mL, was evaluated in 10 randomized, double-blind, controlled trials. Overall, POSIMIR 5 mL, the recommended dose, has been administered to a total of 735 patients in clinical trials using a variety of administration methods, including the recommend method of infiltration. Three trials were controlled with bupivacaine HCl, two trials were controlled with bupivacaine HCl and vehicle placebo, and five trials were controlled with vehicle placebo. An additional 47 patients were treated with saline placebo in one of the bupivacaine HCl-controlled trials. The evaluated surgical procedures included inguinal hernia repair, subacromial decompression of the shoulder, abdominal hysterectomy, laparotomy, laparoscopic cholecystectomy, and laparoscopically-assisted colectomy. Shoulder surgical procedures There were three studies evaluating the safety of POSIMIR administered during shoulder surgery. In Study 1, one of three treatments was administered into the subacromial space at the end of surgery: POSIMIR, vehicle placebo, or bupivacaine HCl. Table 1 presents commonly-reported adverse reactions from Study 1. Table 1. Commonly Reported Adverse Reactions from Study 1 (Incidence ≥ 2% and More Frequent than Bupivacaine HCl or Vehicle Placebo). Preferred Term, n (%) Posimir (N=53) Bupivacaine HCl (n=29) Vehicle Placebo (N=25) Headache 3 (5.7%) 1 (3.4%) 1 (4.0%) Electrocardiogram T wave inversion 2 (3.8%) 0 0 Hypoesthesia 2 (3.8%) 1 (3.4%) 1 (4.0%) Pruritus generalized 2 (3.8%) 0 0 In Study 2 and Study 3, patients were administered either POSIMIR or vehicle placebo into the subacromial space at the end of surgery. Table 2 presents commonly-reported adverse reactions from Studies 2 and 3. Table 2. Commonly Reported Adverse Reactions Pooled from Study 2 and Study 3 (Incidence ≥ 2% and More Frequent than Vehicle Placebo). Preferred Term, n (%)* Posimir (N=75) Vehicle Placebo (N=44) * Percentages adjusted to account for the different sizes of the pooled studies. Dizziness 30 (40.3%) 17 (38.3%) Vomiting 22 (29.0%) 12 (26.6%) Headache 17 (23.3%) 7 (16.3%) Paresthesia 14 (18.4%) 7 (15.4%) Dysgeusia 13 (17.6%) 7 (14.9%) Hypoesthesia 13 (17.3%) 7 (15.8%) Tinnitus 10 (13.2%) 3 (6.7%) Dysuria 8 (10.1%) 4 (10.1%) Pyrexia 7 (9.3%) 2 (4.6%) Insomnia 5 (7.1%) 0 Dyspnea 3 (3.8%) 0 Muscle twitching 3 (3.8%) 0 Peripheral swelling 3 (3.9%) 0 Urinary retention 2 (2.7%) 1 (2.1%) Contusion 2 (2.5%) 0 Dysmenorrhea 2 (2.7%) 0 Incision site pruritus 2 (2.7%) 0 Nasal congestion 2 (2.5%) 0 Pruritus generalized 2 (2.5%) 0 Less common adverse reactions (incidence less than 2% and more frequent than either bupivacaine HCl or vehicle placebo) following POSIMIR administration in shoulder surgical procedures were angina pectoris, blepharospasm, electrocardiogram T wave amplitude decreased, fatigue, osteoarthritis, procedural nausea, procedural pain, and pulmonary arterial hypertension. Additional follow-up safety data consisting of shoulder MRI, physical examination of the shoulder, and assessments of wound healing were collected at 6 months in Study 1 and at 18 months in Study 2. There were no specific long-term follow-up evaluations for patients treated in Study 3; however, study investigators did not report any cases of chondrolysis in follow-up surveys. All surgical incisions were found to have healed as expected in all three studies. Table 3 presents the results of the MRI and physical examinations for Study 1. Table 4 presents the results of the MRI and physical examinations for Study 2. Table 3. 6-Month Follow-up Safety Data from Subacromial Decompression Study 1. Safety Evaluation Posimir Vehicle Placebo Bupivacaine HCl [1] Compared with pre-surgical MRI Number enrolled 53 25 29 Shoulder MRI Number at 6-month follow-up 51 25 25 Improved [1] , n (%) 6 (11.8%) 2 (8.0%) 6 (24.0%) No change [1] , n (%) 31 (60.8%) 14 (56.0%) 9 (36.0%) Worsened [1] , n (%) 14 (27.4%) 9 (36%) 10 (40%) Constant-Murley score Number at 6-month follow-up 52 25 26 Pre-surgery, mean (SD) 44.7 (12.5%) 41.7 (11.7%) 42 (11.3%) Follow-up, mean (SD) 61.6 (15.2%) 63.2 (12.4%) 65.6 (6.8%) Decreased from baseline. n (%) 5 (9.6%) 2 (8.0%) 0 (0%) Table 4. 18-Month Follow-up Safety Data from Subacromial Decompression Study 2. Safety Evaluation Posimir Vehicle Placebo [1] The humeral head cartilage thinning was unchanged from baseline. [2] Two POSIMIR patients were positive for signal abnormalities at baseline and negative at 18 months. Two POSIMIR patients were negative for signal abnormalities at baseline and positive at 18 months. One placebo patient was positive for signal abnormality at baseline and negative at 18 months. Two placebo patients were positive for signal abnormalities at both baseline and 18 months. [3] Two POSIMIR patients had joint effusion/synovitis that improved from moderate at baseline to mild at 18 months. One POSIMIR patient had joint effusion/synovitis that improved from severe at baseline to mild at 18 months. Four patients (1 POSIMIR, 3 placebo) had joint effusion/synovitis that worsened from mild at baseline to moderate at 18 months. One placebo patient had joint effusion/synovitis that worsened from mild at baseline to severe at 18 months. [4] One placebo patient had bursitis/excess fluid that was severe at baseline and mild at 18 months. Number enrolled 40 20 Shoulder MRI Number at 18-month follow-up 27 14 Overall assessment Unexpected injuries or findings compared with pre-surgical MRI, n (%) 0 0 New-onset cartilage or bone lesions of concern (not present at baseline and unrelated to surgery or natural disease progression), n (%) 0 0 Glenohumeral joint and humeral head Presence of cartilage thinning - humeral head, n (%) Grade 0: normal/none 26 (96.3%) 14 (100%) Grade 1: mild 0 0 Grade 2: moderate 1 (3.7%) [1] 0 Grade 3: severe 0 0 Rotator cuff and labrum Supraspinatus tendon tear, n (%) No tear 16 (59.3%) 5 (35.7%) Partial 7 (25.9%) 7 (50.0%) Full thickness 1 (3.7%) 0 Other findings 3 (11.1%) 2 (14.3%) Supraspinatus - other findings, n (%) Interstitial tear 0 0 Tendinosis 2 (7.4%) 1 (7.1%) Surgically repaired tendon 0 1 (7.1%) Interstitial tear/tendinosis 1 (3.7%) 0 (blank) 24 (88.9%) 12 (85.7%) Subacromial space - acromion Acromion bony spur, n (%) Yes 1 (3.7%) 0 No 26 (96.3%) 14 (100%) Acromion bone resection, n (%) Yes 18 (66.7%) 9 (64.3%) No 9 (33.3%) 5 (35.7%) Acromion signal abnormality (edema, fibrosis), n (%) Yes 2 (7.4%) [2] 2 (14.3%) [2] No 25 (92.6%) [2] 12 (85.7%) [2] Acromioclavicular joint Bone resection at acromioclavicular joint/postoperative changes, n (%) Yes 10 (37.0%) 4 (28.6%) No 16 (59.3%) 10 (71.4%) Not evaluable 1 (3.7%) 0 Joint effusion/synovitis, n (%) Grade 0: normal/none 9 (33.3%) 2 (14.3%) Grade 1: mild 9 (33.3%) [3] 7 (50.0%) Grade 2: moderate 3 (11.1%) [3] 3 (21.4%) [3] Grade 3: severe 0 1 (7.1%) [3] Not evaluable 6 (22.2%) 1 (7.1%) Bursa and Soft Tissue Subacromial bursa - bursitis/excess fluid, n (%) Grade 0: normal/none 18 (66.7%) 5 (35.7%) Grade 1: mild 6 (22.2%) 9 (64.3%) [4] Grade 2: moderate 3 (11.1%) 0 Grade 3: severe 0 0 Physical Exam Number at 18-month follow-up 31 16 Clinical assessment, n (%) Normal 27 (87.1%) 13 (81.3%) Abnormal 4 (12.9%) 3 (18.8%) Pain intensity, 0-10 scale Mean (SE) 0.9 (0.4%) 1.2 (0.6%) Positive impingement sign, n (%) Yes 3 (9.7%) 3 (18.8%) No 28 (90.3%) 13 (81.3%) Full passive range of motion, n (%) Yes 27 (87.1%) 13 (81.3%) No 4 (12.9%) 3 (18.8%) Soft tissue surgical procedures There were two studies evaluating the safety of POSIMIR in patients undergoing inguinal hernia repair (hernioplasty). Patients in these studies were administered either POSIMIR 5 mL or vehicle placebo; 2.5 mL administered into the floor of the inguinal canal and 2.5 mL administered into the subcutaneous space. Table 5 presents commonly-reported adverse reactions from these studies. Table 5. Commonly Reported Adverse Reactions Pooled from Studies in Inguinal Hernia Repair (Incidence ≥ 2% and More Frequent than Placebo) Preferred Term, n (%)* Posimir (N=69) Vehicle Placebo (N=53) * Percentages adjusted to account for the different sizes of the pooled studies. † Incision site pruritus, generalized pruritus, and genital pruritus were also reported, but none had incidence ≥2% and more frequent than placebo. Bradycardia 16 (22.9%) 7 (14.2%) Pruritus† 15 (21.6%) 9 (17.5%) Post procedural contusion (bruising) 10 (14.0%) 5 (10.1%) Vomiting 6 (9.4%) 4 (7.4%) Incision site swelling 4 (6.0%) 3 (5.7%) Dyspepsia 4 (5.7%) 2 (3.7%) Pyrexia 4 (6.0%) 2 (4.0%) Contusion 4 (5.7%) 0 Back pain 3 (4.1%) 2 (3.4%) Viral infection 3 (4.1%) 2 (4.0%) Incision site erythema 3 (4.1%) 0 Oropharyngeal pain 3 (4.6%) 0 Tachycardia 3 (4.6%) 0 Upper respiratory tract infection 2 (3.0%) 1 (2.0%) Dry throat 2 (3.2%) 0 Hyperhidrosis 2 (3.0%) 0 Hypertension 2 (2.8%) 0 Local swelling 2 (3.0%) 0 Testicular swelling 2 (3.2%) 0 There were five studies evaluating the safety of POSIMIR in laparoscopic, laparoscopically-assisted, or open abdominal surgeries. In two studies in patients undergoing laparoscopic cholecystectomy, POSIMIR or bupivacaine HCl was administered into the laparoscopic port incisions at the end of surgery. In one of these studies, a subset of patients received either POSIMIR or saline placebo. In a study of patients undergoing laparoscopically-assisted colectomy, POSIMIR or vehicle placebo was administered predominantly into the hand port incision at the end of surgery. In a study of patients undergoing laparotomy, POSIMIR or bupivacaine HCl was administered into the full length of the surgical incision at the end of surgery. Table 6 presents commonly-reported adverse reactions from these four studies. Table 7 and Table 8 present, respectively, surgical-site adverse reactions and early-occurring central nervous system (CNS)-related adverse reactions from the laparoscopic cholecystectomy study that included a saline placebo control arm. Table 6. Commonly Reported Adverse Reactions Pooled from Laparoscopic, Laparoscopically-Assisted, and Open Abdominal Surgery Studies (Incidence ≥ 2% and More Frequent than Bupivacaine HCl or Placebo). Preferred Term, n (%)* Posimir (N=337) Bupivacaine HCl (N=186) Vehicle Placebo (N=78) * Percentages adjusted to account for the different sizes of the pooled studies. † Incision site pruritus, generalized pruritus, eye pruritus, anal pruritus, and infusion site pruritus were also reported, but none had incidence ≥2% and more frequent than placebo. Post procedural contusion (bruising) 231 (71.2%) 119 (61.8%) 41 (52.6%) Nausea 189 (55.8%) 111 (59.6%) 40 (51.3%) Constipation 112 (35.2%) 80 (41.8%) 8 (10.3%) Somnolence 92 (30.4%) 80 (41.0%) 3 (3.8%) Headache 86 (27.2%) 63 (32.3%) 12 (15.4%) Dizziness 75 (23.5%) 58 (30.1%) 6 (7.7%) Vomiting 66 (19.4%) 39 (21.0%) 6 (7.7%) Dysgeusia 50 (16.2%) 33 (16.9%) 2 (2.6%) Pruritus† 45 (14.3%) 36 (18.7%) 5 (6.4%) Procedural pain 35 (11.4%) 35 (17.8%) 0 Diarrhea 34 (9.8%) 10 (5.5%) 10 (12.8%) Incision site hemorrhage 30 (8.7%) 6 (3.0%) 3 (3.8%) Pyrexia 29 (8.2%) 10 (5.7%) 11 (14.1%) Abdominal distension 29 (8.2%) 8 (4.8%) 12 (15.4%) Incision site erythema 29 (8.1%) 5 (2.7%) 10 (12.8%) Post procedural discharge 26 (7.5%) 8 (4.4%) 7 (9.0%) Paresthesia 23 (7.5%) 25 (13.1%) 2 (2.6%) Hypokalemia 22 (5.9%) 2 (1.4%) 10 (12.8%) Incision site hematoma 18 (5.2%) 3 (1.7%) 4 (5.1%) Anemia 17 (4.5%) 1 (0.7%) 7 (9.0%) Flatulence 16 (4.6%) 7 (4.0%) 8 (10.3%) Hypertension 16 (4.6%) 7 (3.6%) 1 (1.3%) Incision site infection 16 (4.5%) 4 (2.5%) 2 (2.6%) Musculoskeletal pain 15 (4.2%) 8 (4.9%) 0 Abdominal pain 15 (4.4%) 1 (0.5%) 1 (1.3%) Insomnia 14 (3.9%) 5 (2.9%) 7 (9.0%) Dyspepsia 13 (3.8%) 3 (1.9%) 4 (5.1%) Wound dehiscence 13 (3.6%) 3 (1.5%) 5 (6.4%) Cough 12 (3.6%) 3 (1.8%) 1 (1.3%) Oropharyngeal pain 12 (3.5%) 2 (1.0%) 0 Urinary retention 10 (2.8%) 2 (1.2%) 4 (5.1%) Chest pain 10 (2.9%) 1 (0.5%) 1 (1.3%) Ileus 10 (2.7%) 1 (0.7%) 3 (3.8%) Body temperature increased 9 (2.4%) 0 2 (2.6%) Abdominal pain upper 8 (2.5%) 2 (1.0%) 0 Rash 7 (2.1%) 7 (3.8%) 1 (1.3%) Pain in extremity 7 (2.1%) 5 (2.8%) 1 (1.3%) Dry mouth 7 (2.2%) 2 (1.0%) 1 (1.3%) Nasopharyngitis 7 (2.1%) 0 0 Table 7. Incidence of Surgical Site Adverse Reactions from Laparoscopic Cholecystectomy Study with Saline Placebo and Bupivacaine HCl Controls. * Terms were prespecified for examination by a blinded assessor on postoperative days 0, 4, 7, 14, 28, and 59. Saline Placebo Control Bupivacaine HCl Control Prespecified Term*, n (%) Posimir (N=45) Saline Placebo (N=47) Posimir (N=148) Bupivacaine HCl (N=148) Visible bruising 41 (91.1%) 33 (70.2%) 142 (95.9%) 105 (70.9%) Surgical site bleeding 22 (48.9%) 20 (42.6%) 19 (12.8%) 24 (16.2%) Drainage from surgical incision(s) 2 (4.4%) 3 (6.4%) 11 (7.4%) 6 (4.1%) Wound hematoma 0 0 6 (4.1%) 2 (1.4%) Wound dehiscence 0 0 2 (1.4%) 3 (2.0%) Surgical site infection 0 0 2 (1.4%) 1 (0.7%) Table 8. CNS-related Adverse Reactions Solicited from Subjects at 6 Hours Post-surgery in Laparoscopic Cholecystectomy Study with Saline Placebo and Bupivacaine HCl Controls. * Patients responded to a 10-symptom checklist (7 symptoms for part of the saline placebo-controlled portion of the study). Saline Placebo Control Bupivacaine HCl Control Dictionary-Derived Term (Symptom)* Posimir (N=45) Saline Placebo (N=47) Posimir (N=148) Bupivacaine HCl (N=148) Entire study, n (%) Somnolence (Drowsiness) 18 (40.0%) 16 (34.0%) 60 (40.5%) 48 (32.4%) Nausea (Nausea) 9 (20.0%) 13 (27.7%) 48 (32.4%) 57 (38.5%) Dizziness (Dizziness) 3 (6.7%) 3 (6.4%) 28 (18.9%) 31 (20.9%) Headache (Headache) 5 (11.1%) 4 (8.5%) 23 (15.5%) 18 (12.2%) Vomiting (Vomiting) 2 (4.4%) 3 (6.4%) 10 (6.8%) 15 (10.1%) Constipation (Constipation) 0 (0.0%) 4 (8.5%) 9 (6.1%) 10 (6.8%) Pruritus (Itching) 1 (2.2%) 1 (2.1%) 6 (4.1%) 5 (3.4%) Subset of study, n (%) N=23 N=22 Dysgeusia (Metallic taste in mouth) 3 (13.0%) 2 (9.1%) 26 (17.6%) 22 (14.9%) Paresthesia (Tingling) 0 0 2 (1.4%) 6 (4.1%) Hypoesthesia (Numbness) 0 0 1 (0.7%) 1 (0.7%) In a study of patients undergoing total abdominal hysterectomy, POSIMIR, vehicle placebo, or bupivacaine HCl was administered into the surgical incision at the end of surgery. Table 9 presents commonly-reported adverse reactions from this study. Table 9. Commonly Reported Adverse Reactions from Total Abdominal Hysterectomy Study (Incidence ≥ 2% and More Frequent than Bupivacaine HCl). Preferred Term Posimir (N=60) Bupivacaine HCl (N=27) Vehicle Placebo (N=27) Post procedural contusion (bruising) 36 (60.0%) 0 9 (33.3%) Anemia 10 (16.7%) 3 (11.1%) 4 (14.8%) Dizziness 9 (15.0%) 4 (14.8%) 3 (11.1%) Vomiting 9 (15.0%) 4 (14.8%) 8 (29.6%) C-reactive protein increased 7 (11.7%) 1 (3.7%) 0 Pyrexia 7 (11.7%) 7 (25.9%) 3 (11.1%) Somnolence 5 (8.3%) 2 (7.4%) 0 Blood potassium decreased 4 (6.7%) 0 1 (3.7%) Hypertension 4 (6.7%) 2 (7.4%) 1 (3.7%) Incision site hematoma 3 (5.0%) 0 0 Electrocardiogram change 2 (3.3%) 0 0 Procedural hemorrhage 2 (3.3%) 0 0 Vaginal hematoma 2 (3.3%) 0 0 Less common adverse reactions (incidence less than 2% and more frequent than either bupivacaine HCl or placebo) following POSIMIR administration in soft tissue surgical procedures were: application site irritation, atrial fibrillation, drug eruption, electrocardiogram QT prolonged, eructation, erythema, excessive granulation tissue, fatigue, genital pain, heart rate increased, hiccups, hypoesthesia, hypogeusia, incision site cellulitis, incision site erosion, incision site hypoesthesia, incision site inflammation, incision site edema, incision site pain, incision site rash, mean arterial pressure increased, micturition urgency, night sweats, overdose, palpitations, procedural hypertension, pruritus generalized, rash generalized, seroma, sinus tachycardia, skin discoloration, tinnitus, and wound hemorrhage.

<table ID="t1" width="100%"><caption>Table 1. Commonly Reported Adverse Reactions from Study 1 (Incidence &#x2265; 2% and More Frequent than Bupivacaine HCl or Vehicle Placebo). </caption><col width="41.335%" align="left"/><col width="19.555%" align="left"/><col width="19.555%" align="left"/><col width="19.555%" align="left"/><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="bottom"><content styleCode="bold">Preferred Term, n (%)</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">Posimir</content><content styleCode="bold"> </content><content styleCode="bold">(N=53)</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">Bupivacaine HCl</content><content styleCode="bold"> </content><content styleCode="bold">(n=29)</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">Vehicle Placebo</content><content styleCode="bold"> </content><content styleCode="bold">(N=25)</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Headache </td><td align="center" styleCode="Botrule Rrule" valign="middle">3 (5.7%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">1 (3.4%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">1 (4.0%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Electrocardiogram T wave inversion </td><td align="center" styleCode="Botrule Rrule" valign="middle">2 (3.8%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">0 </td><td align="center" styleCode="Botrule Rrule" valign="middle">0 </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Hypoesthesia </td><td align="center" styleCode="Botrule Rrule" valign="middle">2 (3.8%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">1 (3.4%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">1 (4.0%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Pruritus generalized </td><td align="center" styleCode="Botrule Rrule" valign="middle">2 (3.8%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">0 </td><td align="center" styleCode="Botrule Rrule" valign="middle">0 </td></tr></tbody></table>

<table ID="t2" width="100%"><caption>Table 2. Commonly Reported Adverse Reactions Pooled from Study 2 and Study 3 (Incidence &#x2265; 2% and More Frequent than Vehicle Placebo). </caption><col width="46.167%" align="left"/><col width="26.900%" align="left"/><col width="26.933%" align="left"/><thead><tr><th align="left" styleCode="Toprule Botrule Lrule Rrule" valign="bottom"><content styleCode="bold">Preferred Term, n (%)*</content></th><th align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">Posimir</content> <content styleCode="bold">(N=75)</content></th><th align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">Vehicle Placebo</content> <content styleCode="bold">(N=44)</content></th></tr></thead><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">* Percentages adjusted to account for the different sizes of the pooled studies. </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Dizziness </td><td align="center" styleCode="Botrule Rrule" valign="bottom">30 (40.3%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">17 (38.3%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Vomiting </td><td align="center" styleCode="Botrule Rrule" valign="bottom">22 (29.0%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">12 (26.6%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Headache </td><td align="center" styleCode="Botrule Rrule" valign="bottom">17 (23.3%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">7 (16.3%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Paresthesia </td><td align="center" styleCode="Botrule Rrule" valign="bottom">14 (18.4%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">7 (15.4%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Dysgeusia </td><td align="center" styleCode="Botrule Rrule" valign="bottom">13 (17.6%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">7 (14.9%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Hypoesthesia </td><td align="center" styleCode="Botrule Rrule" valign="bottom">13 (17.3%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">7 (15.8%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Tinnitus </td><td align="center" styleCode="Botrule Rrule" valign="bottom">10 (13.2%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">3 (6.7%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Dysuria </td><td align="center" styleCode="Botrule Rrule" valign="bottom">8 (10.1%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">4 (10.1%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Pyrexia </td><td align="center" styleCode="Botrule Rrule" valign="bottom">7 (9.3%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">2 (4.6%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Insomnia </td><td align="center" styleCode="Botrule Rrule" valign="bottom">5 (7.1%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">0 </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Dyspnea </td><td align="center" styleCode="Botrule Rrule" valign="bottom">3 (3.8%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">0 </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Muscle twitching </td><td align="center" styleCode="Botrule Rrule" valign="bottom">3 (3.8%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">0 </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Peripheral swelling </td><td align="center" styleCode="Botrule Rrule" valign="bottom">3 (3.9%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">0 </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Urinary retention </td><td align="center" styleCode="Botrule Rrule" valign="bottom">2 (2.7%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">1 (2.1%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Contusion </td><td align="center" styleCode="Botrule Rrule" valign="bottom">2 (2.5%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">0 </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Dysmenorrhea </td><td align="center" styleCode="Botrule Rrule" valign="bottom">2 (2.7%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">0 </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Incision site pruritus </td><td align="center" styleCode="Botrule Rrule" valign="bottom">2 (2.7%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">0 </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Nasal congestion </td><td align="center" styleCode="Botrule Rrule" valign="bottom">2 (2.5%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">0 </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="bottom">Pruritus generalized </td><td align="center" styleCode="Botrule Rrule" valign="bottom">2 (2.5%) </td><td align="center" styleCode="Botrule Rrule" valign="bottom">0 </td></tr></tbody></table>

<table ID="t3" width="100%"><caption>Table 3. 6-Month Follow-up Safety Data from Subacromial Decompression Study 1. </caption><col width="42.250%" align="left"/><col width="19.250%" align="left"/><col width="19.250%" align="left"/><col width="19.250%" align="left"/><thead><tr><th align="left" styleCode="Toprule Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Safety Evaluation</content></th><th align="center" styleCode="Toprule Botrule Rrule" valign="middle"><content styleCode="bold">Posimir</content></th><th align="center" styleCode="Toprule Botrule Rrule" valign="middle"><content styleCode="bold">Vehicle Placebo</content></th><th align="center" styleCode="Toprule Botrule Rrule" valign="middle"><content styleCode="bold">Bupivacaine HCl</content></th></tr></thead><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">[1] Compared with pre-surgical MRI </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle"> Number enrolled </td><td align="center" styleCode="Botrule Rrule" valign="middle">53 </td><td align="center" styleCode="Botrule Rrule" valign="middle">25 </td><td align="center" styleCode="Botrule Rrule" valign="middle">29 </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Shoulder MRI </td><td align="center" styleCode="Botrule Rrule" valign="middle"/><td align="center" styleCode="Botrule Rrule" valign="middle"/><td align="center" styleCode="Botrule Rrule" valign="middle"/></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle"> Number at 6-month follow-up </td><td align="center" styleCode="Botrule Rrule" valign="middle">51 </td><td align="center" styleCode="Botrule Rrule" valign="middle">25 </td><td align="center" styleCode="Botrule Rrule" valign="middle">25 </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle"> Improved ^[1], n (%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">6 (11.8%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">2 (8.0%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">6 (24.0%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle"> No change ^[1], n (%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">31 (60.8%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">14 (56.0%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">9 (36.0%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle"> Worsened ^[1], n (%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">14 (27.4%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">9 (36%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">10 (40%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Constant-Murley score </td><td align="center" styleCode="Botrule Rrule" valign="middle"/><td align="center" styleCode="Botrule Rrule" valign="middle"/><td align="center" styleCode="Botrule Rrule" valign="middle"/></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle"> Number at 6-month follow-up </td><td align="center" styleCode="Botrule Rrule" valign="middle">52 </td><td align="center" styleCode="Botrule Rrule" valign="middle">25 </td><td align="center" styleCode="Botrule Rrule" valign="middle">26 </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle"> Pre-surgery, mean (SD) </td><td align="center" styleCode="Botrule Rrule" valign="middle">44.7 (12.5%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">41.7 (11.7%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">42 (11.3%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle"> Follow-up, mean (SD) </td><td align="center" styleCode="Botrule Rrule" valign="middle">61.6 (15.2%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">63.2 (12.4%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">65.6 (6.8%) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle"> Decreased from baseline. n (%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">5 (9.6%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">2 (8.0%) </td><td align="center" styleCode="Botrule Rrule" valign="middle">0 (0%) </td></tr></tbody></table>