Limitations of Use

Safety and effectiveness have not been established in other surgical procedures, including soft tissue surgical procedures, other orthopedic procedures, including for intra-articular administration, and boney procedures, or when used for neuraxial or peripheral nerve blockade.

2.1 Important Dosage and Administration Information

• POSIMIR is intended for single-dose administration only.
• Do not dilute or mix POSIMIR with local anesthetics or other drugs or diluents.
• As there is a potential risk of severe, life-threatening adverse reactions associated with the administration of bupivacaine, POSIMIR should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurological or cardiac toxicity.
• Different formulations of bupivacaine are not bioequivalent to POSIMIR even if the milligram dosage is the same. It is not possible to convert dosing from any other formulations of bupivacaine to POSIMIR and vice versa. Do not substitute.
• The toxic effects of local anesthetics are additive. Avoid additional use of local anesthetics within 168 hours following administration of POSIMIR.
• Avoid intravascular administration of POSIMIR. Convulsions and cardiac arrest have occurred following accidental intravascular injection of bupivacaine and other amide-containing products.
• POSIMIR is not indicated for the following routes of administration.
  • Epidural
  • Intrathecal
  • Intravascular
  • Intra-articular use [see Nonclinical Toxicology ( 13.2)]
  • Regional nerve blocks
  • Pre-incisional or pre-procedural locoregional anesthetic techniques that require deep and complete sensory block in the area of administration.

2.2 Recommended Dose

The recommended dose of POSIMIR is 660 mg (5 mL).

2.3 Preparation, Administration, and Dosing Instructions

• POSIMIR is ready to use and does not require dilution or mixing.
• Prior to administration, draw up POSIMIR into a 5 mL syringe using a large bore needle (16 gauge or larger). Once the syringe has been filled, discard the large bore needle.
• At the close of surgery, administer the entire 5 mL dose of POSIMIR into the subacromial space using an 18 gauge or larger-bore needle. The needle may be inserted through an existing arthroscopic port or through intact skin to reach the subacromial space. Confirm correct placement of the needle tip within the subacromial space by direct arthroscopic visualization.
• Do not administer POSIMIR into the glenohumeral intra-articular space.

2.4 Compatibility Considerations

POSIMIR is compatible with:

• Commonly implantable materials, such as polypropylene and polyester
• Silk, nylon, gut, polypropylene, polydioxanone, and polyglycolic acid sutures

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.

6.1 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.

7.1 Drugs Associated with Methemoglobinemia

Patients who are administered POSIMIR are at increased risk of developing methemoglobinemia when concurrently exposed to following drugs, which could include other local anesthetics [see Warnings and Precautions ( 5.4)].

Examples of Drugs Associated with Methemoglobinemia:

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of POSIMIR in pediatric patients below the age of 18 have not been established.

8.5 Geriatric Use

Of the total number of patients enrolled in the POSIMIR clinical studies (N=1463), 167 patients were older than 65 years and 32 patients were older than 75 years.

In bupivacaine clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger adult patients. Bupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to bupivacaine may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Elderly patients may require lower doses of POSIMIR. Consider increased monitoring for local anesthetic systemic toxicity when administering POSIMIR to elderly patients.

8.6 Hepatic Impairment

Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, these drugs should be used with caution in patients with hepatic impairment. Patients with severe hepatic impairment, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity. Care should be taken when considering the use of POSIMIR in patients with impaired hepatic function and consider reduced dosing. Consider increased monitoring for local anesthetic systemic toxicity in patients with moderate to severe hepatic impairment when administering POSIMIR.

8.7 Renal Impairment

Bupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Care should be taken when considering the use of POSIMIR in patients with impaired renal function. Consider increased monitoring for local anesthetic systemic toxicity when administering POSIMIR to patients with impaired renal function.

12.1 Mechanism of Action

Bupivacaine blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

12.2 Pharmacodynamics

Systemic absorption of bupivacaine produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. These cardiovascular changes are more likely to occur after unintended intravascular injection of liquid formulations of bupivacaine.

Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. Apparent central stimulation is usually manifested as restlessness, tremors and shivering, progressing to convulsions, followed by depression and coma, progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage.

12.3 Pharmacokinetics

Infiltration of POSIMIR into the surgical wound results in plasma levels of bupivacaine that can persist for 168 hours. Systemic plasma levels of bupivacaine following administration of POSIMIR are not correlated with local efficacy.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Necrosis of the joint cartilage was observed following intra-articular injection of a single dose of POSIMIR or POSIMIR vehicle in the dog model.

Study 1

Study 1 was a randomized, multicenter, assessor blinded, placebo-controlled (vehicle) clinical trial in 107 patients undergoing arthroscopic subacromial decompression surgery with an intact rotator cuff. Associated procedures included inspection of the glenohumeral joint, distal clavicle excision, bursectomy, synovectomy, removal of loose body, resection of coracoacromial ligament and subacromial spurs, rotator cuff debridement, and minor debridement of articular cartilage. There were no open surgical procedures performed during this study. The mean age was 50 years (range 21 to 70 years), 60% of treated patients were female, 96% were White, 2% were Hispanic, 1% were Asian, and 1% were Other.

Patients were randomized 2:1:1 to receive POSIMIR, vehicle placebo, or bupivacaine HCl 50 mg, and all patients received general anesthesia. No analgesic pre-medication or local anesthetics were administered. POSIMIR and vehicle placebo were administered under direct arthroscopic visualization as single injections into the subacromial space through one of the arthroscopic portals at the end of the surgery. Bupivacaine HCl 50 mg was administered subacromially as a single dose. Post-operatively, patients received acetaminophen 500 mg or 1000 mg every six hours, depending on body weight, through 72 hours, and were allowed morphine rescue medication as needed, either 2 mg IV or 10 mg orally. Pain intensity was rated by the patients using a 0 to 10 numerical rating scale (NRS) at multiple time points up to 72 hours.

The primary outcome measures were the normalized area under the curve (nAUC) of mean pain intensity on movement scores collected at specified intervals over the first 72 hours after surgery and total opioid rescue analgesia (IV morphine-equivalent dose) through 72 hours. In this clinical study, POSIMIR 5 mL demonstrated a significant reduction in mean pain intensity compared with placebo of 1.3 points on a 0 to 10 NRS scale over 72 hours ( Figure 1).

Figure 1. Mean Pain Intensity on Movement Through 72 Hours After Surgery,
Subacromial Decompression Study 1

The median total use of opioid rescue analgesia (IV morphine equivalent dose) from 0 to 72 hours for the POSIMIR treatment group (4 mg) was statistically lower than for the placebo treatment group (12 mg). The median use of opioid rescue analgesia in the bupivacaine treatment group was 8 mg.

Study 2

Study 2 was a randomized, double-blind, placebo-controlled (vehicle) clinical trial in 60 patients undergoing arthroscopic subacromial decompression, inspection of glenohumeral joint, synovectomy, removal of loose body, minor debridement of articular cartilage, minor debridement or minor repair of rotator cuff, open distal clavicle excision, bursectomy, and resection of coracoacromial ligament and subacromial spurs. The mean age was 48 years (range 27 to 68 years), 55% of treated patients were female, 95% were White, 2% were Asian, and 2% were Other.

Patients were randomized 2:1 to receive POSIMIR or vehicle placebo, and all patients received general anesthesia. Post-operatively, patients were allowed morphine rescue medication as needed, either 3 mg IV or 10 mg to 15 mg orally, or acetaminophen. Pain intensity was rated by the patients using a 0 to 10 numerical rating scale (NRS) at multiple time points up to 72 hours.

The primary outcome measures were mean pain intensity on movement AUC through 72 hours and total opioid rescue analgesia (IV morphine-equivalent dose) through 72 hours. There was no statistically significant difference in either primary endpoint between the POSIMIR and vehicle placebo treatment groups ( Figure 2).

Figure 2: Mean Pain Intensity on Movement Through 72 Hours After Surgery,
Subacromial Decompression Study 2

Study 3

Study 3 was a randomized, double-blind, placebo-controlled (vehicle) and open-label PK clinical trial in 92 patients undergoing a variety of shoulder surgical procedures, including rotator cuff repair, subacromial decompression, glenoid labrum repair or debridement, and biceps tendon repair. The majority of patients underwent arthroscopic procedures; however, six patients underwent a combination of arthroscopic and open procedures. The mean age was 54 years (range 20 to 82 years), 59% of treated patients were male, 87% were White, 8% were African American, 3% were Other, and 2% were Asian.

An equal number of patients were randomized to two cohorts. The routes of POSIMIR or vehicle placebo administration in Cohort 1 were subacromial or subcutaneous injection or a combination. In Cohort 2, POSIMIR or vehicle placebo was administered via injection under direct arthroscopic visualization into the subacromial space. Surgical procedures were completed either under local or general anesthesia. Post-operatively, patients were allowed morphine IV, oxycodone orally, or acetaminophen orally as needed.

The primary outcome measures were mean pain intensity on movement and at rest through 120 hours and pain control through day seven. There was no statistically significant difference in either primary endpoint between POSIMIR and vehicle placebo treatment groups ( Figure 3).

Figure 3: Mean Pain Intensity on Movement Through 120 Hours After Surgery,
Subacromial Decompression Study 3

Storage

POSIMIR vial should be stored at a controlled room temperature of 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature]. Vial should be protected from light and retained in carton until time of use.

Handling

• Do not administer any solution which contains particulate matter.
• Do not autoclave.
• Do not dilute.
• Discard any unused portion in an appropriate manner.