Safety | POSIMIR®

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PHARMACOKINETICS

Long Half-Life of 26.1 Hours in Arthroscopic Subacromial Decompression

POSIMIR bupivacaine plasma levels were detected at the first time point measured and through the entire 96-hour observational period¹
POSIMIR mean C_max was below levels associated with signs and symptoms of bupivacaine toxicity^3,4
- 2000 ng/mL for CNS toxicity
- 4000 ng/mL for cardiovascular toxicity

MEAN PLASMA BUPIVACAINE
CONCENTRATION 0 TO 96 HOURS
AFTER POSIMIR ADMINISTRATION¹

Mean plasma bupivacaine concentration 0 to 96 hours after POSIMIR® administration

Systemic plasma levels do not correlate
with local efficacy and safety.

SAFETY

STUDY 1¹

Commonly reported adverse reactions with an incidence ≥2% and more
frequent than bupivacaine HCl or Vehicle Control from Study 1

Adverse Reaction (%)	POSIMIR (n=53)	Bupivacaine HCI (n=29)	Vehicle Control (n=25)
Headache	3 (5.7%)	1 (3.4%)	1 (4.0%)
ElectrocardiogramECG 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

ECG=electrocardiogram.

STUDIES 2 & 3¹

Commonly reported adverse reactions with an incidence ≥2% and
more frequent than Vehicle Control in pooled data from Study 2 and Study 3

Adverse Reaction (%)*	POSIMIR (n=75)	Vehicle Control (n=44)
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

Percentages adjusted to account for the different sizes of the pooled studies.

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administration instructions and respond to your questions.

INDICATIONS AND USAGE

POSIMIR is a bupivacaine solution indicated in adults for administration into the subacromial space under direct arthroscopic visualization to produce post-surgical analgesia for up to 72 hours following arthroscopic subacromial decompression.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: RISK OF POTENTIAL ADVERSE EMBOLIC EFFECTS RESULTING FROM INADVERTENT INTRAVASCULAR INJECTION.

INDICATIONS AND USAGE

POSIMIR is a bupivacaine solution indicated in adults for administration into the subacromial space under direct arthroscopic visualization to produce post-surgical analgesia for up to 72 hours following arthroscopic subacromial decompression.

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.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: 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.

Contraindications

POSIMIR is contraindicated in patients with a known hypersensitivity to any amide local anesthetic or to other components of POSIMIR, and in patients undergoing obstetrical paracervical block anesthesia.

Warnings and Precautions

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. Direct arthroscopic visualization must be used to conﬁrm proper placement of the needle tip in the subacromial space before injecting POSIMIR.

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 of POSIMIR in dogs following an intra-articular administration demonstrated joint cartilage necrosis.

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.

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.

Avoid additional use of local anesthetics within 168 hours following administration of POSIMIR. Consider increased monitoring for systemic toxicity in debilitated, elderly, or acutely ill patients.

Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use. If local anesthetics must be used in patients known to be more susceptible to methemoglobinemia, close monitoring for symptoms and signs of methemoglobinemia is recommended.

Chondrolysis with Intra-Articular Infusion of Local Anesthetics: There have been reports of chondrolysis (mostly in the shoulder joint) following intra-articular infusion of local anesthetics, which is an unapproved use. Do not inject POSIMIR intra-articularly.

Risk of Toxicity in Patients with Hepatic Impairment: Consider reduced dosing and increased monitoring for bupivacaine systemic toxicity in patients with moderate to severe hepatic impairment.

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). Consider reduced dosing. Monitor patients closely for blood pressure, heart rate, and ECG changes.

Adverse Reactions

Adverse events 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.

Adverse events 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.

Drug Interactions

Do not dilute or mix POSIMIR with local anesthetics or other drugs or diluents.

Special Populations

Hepatic Impairment: Consider reduced dosing and increased monitoring for bupivacaine toxicity in patients with moderate to severe hepatic impairment.

Renal Impairment: Consider increased monitoring for local anesthetic systemic toxicity when administering POSIMIR to patients with impaired renal function.

For additional safety information, please see full Prescribing Information, including BOXED WARNING.

References: 1. Data on File. Innocoll Pharmaceuticals Limited. 2. Shah J, Ellis D, Verity N. Pharmacokinetic characteristics of SABER^® Bupivacaine in humans demonstrate sustained drug delivery for up to 72 hours in a variety of surgical models. Poster presented at: 39th Annual American Society of Regional Anesthesia and Pain Medicine Meeting. Chicago, IL; Apr 5, 2014. 3. Bardsley H, Gristwood R, Baker H, Watson N, Nimmo W. A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol. 1998;46(3):245-249. 4. Kastrissios H, Triggs EJ, Sinclair F, Moran P, Smithers M. Plasma concentrations of bupivacaine after wound infiltration of an 0.5% solution after inguinal herniorrhaphy: a preliminary study. Eur J Clin Pharmacol. 1993;44(6):555-557.