Posimir

SIDE EFFECTS

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]
• Methemoglobinemia [see WARNINGS AND PRECAUTIONS]
• Chondrolysis with Intra-Articular Infusion [see WARNINGS AND PRECAUTIONS]
• Cardiovascular System Reactions [see WARNINGS AND PRECAUTIONS]

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).

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).

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.

Table 4: 18-Month Follow-up Safety Data from Subacromial Decompression Study 2.

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)

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 laparoscopicallyassisted 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).

Table 7: Incidence of Surgical Site Adverse Reactions from Laparoscopic Cholecystectomy Study with Saline Placebo and Bupivacaine HCl Controls.

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.

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).

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.

Read the entire FDA prescribing information for Posimir (Bupivacaine Solution)