EXPAREL. An Innovative Non-Opioid Option for the Management of Postsurgical Pain. Presenter s Name Affiliation Date

Transcription

1 EXPAREL An Innovative Non-Opioid Option for the Management of Postsurgical Pain Presenter s Name Affiliation Date

2 Disclosures The speaker has a consulting relationship with Pacira Pharmaceuticals, Inc. This program is sponsored and approved by Pacira Pharmaceuticals, Inc.

3 A Multimodal Approach Uses a Variety of Therapeutics to Minimize Opioid Use and ORAEs 1-4 Simultaneous use of a combination of 2 analgesics that act at different sites within the central and peripheral nervous systems in an effort to - Reduce pain - Minimize opioid use and ORAEs ORAE, opioid-related adverse event; NSAID, nonsteroidal anti-inflammatory drug; NMDA, N-methyl-D-aspartate; COX, cyclooxygenase. Pain Ascending input via spinothalamic tract Dorsal horn 1. Gottschalk A, Smith DS. Am Fam Physician. 2001;63(10): ; 2. Gandhi K, Viscusi E. The Journal of New York School of Regional Anesthesia. 2009;13:1-10; 3. Kehlet H, Dahl JB. The value of mulitmodal or balanced analgesia in postoperative pain treatment. Anesth Analg. 1993;77(5): ; 4. Yu H, Li Q, Wang D, et al. Mapping the central effects of chronic ketamine administration in an adolescent primate model by functional magnetic resonance imaging (fmri). Neurotoxicology. 2012;33(1): Peripheral nerve Tissue Injury Descending modulation Peripheral nociceptors Opioids 1-3 Alpha-2 agonists 1,2 Acetaminophen 2 Anti-inflammatory agents 2 Ketamine 4 Local anesthetics (epidural) 1-3 Opioids 1-3 Alpha-2 agonists 1-3 NMDA antagonists 2 Local anesthetics (peripheral nerve block) 1,2 Local anesthetics (field block) 1-3 NSAIDs 1,2 COX-2 inhibitors 2 Opioids 3

4 Role of Local Anesthetics Act as Membrane Stabilizers rate of depolarization and repolarization of excitable membranes, including nociceptors Inhibit sodium influx through sodium-specific ion channels in the neuronal cell membrane Thus, an action potential cannot arise, and signal conduction is inhibited Techniques for Administering Local Anesthetics Surgical site infiltration 1 Single injection Catheters Peripheral nerve blocks 2 Single injection Catheters Epidural 1. Badner NH, et al. J Bone Joint Surg Am. 1996;78(5): ; 2. Richman JM, et al. Anesth Analg. 2006;102(1):

5 Use of Local Analgesics for Postsurgical Pain Target pain at the source Postsurgical pain is mostly nociceptive pain caused by stimulation of peripheral receptors responding to the surgical insult 1 Infiltrating the surgical site is a simple, effective means of providing analgesia in a variety of surgical procedures 1 Not typically associated with severe side effects 1 Local toxicity, wound infection, and wound healing When delivered in single doses, the duration of traditional local anesthetics can be a limiting factor 2 1. Scott NB. Anaesthesia. 2010;65(Suppl 1):67-75; 2. Gupta A. Curr Opin Anesthesiol. 2010;23(6):

6 EXPAREL: Indicated for Single-Dose Administration Into the Surgical Site to Produce Postsurgical Analgesia Provides long acting pain control with a reduced reliance on opioids 30% reduction in cumulative pain scores and a 45% reduction in opioid consumption No need for catheters or pumps The clinical benefit of the attendant decrease in opioid consumption was not demonstrated EXPAREL is contraindicated in obstetrical paracervical block anesthesia In clinical trials, the most common adverse reactions (incidence 10%) following EXPAREL administration were nausea, constipation, and vomiting

7 EXPAREL Uses DepoFoam to Release Bupivacaine Over Time By utilizing the DepoFoam product delivery platform, EXPAREL delivers therapeutic levels of bupivacaine over time DepoFoam is a multivesicular liposomal product delivery technology that encapsulates drugs without altering their molecular structure and then releases them over a desired period of time 1 DepoFoam utilizes membrane components that are based on natural and well tolerated sources and are cleared by normal metabolic pathways DepoFoam is <3% lipid, biodegradable, and biocompatible 1. Lambert WJ, Los K. In: Rathbone MJ et al, eds. Modified-Release Drug Delivery Technology. Volume 2. 2nd ed. New York: Informa Healthcare; 2008:

8 Pharmacokinetics Demonstrate Plasma Levels of Bupivacaine That Can Persist for 96 Hours 1 Plasma Bupivacaine Concentration (ng/ml) EXPAREL 266 mg Peak P1: 0-2 hours P2: hours Duration 96 hours Second peak due to slow release of bupivacaine from DepoFoam Initial peak largely due to extraliposomal bupivacaine Time (Hours) Other formulations of bupivacaine should not be administered within 96 hours following administration of EXPAREL Systemic plasma levels of bupivacaine following administration of EXPAREL are not correlated with local efficacy The rate of systemic absorption of bupivacaine is dependent upon the total dose of drug administered, the route of administration, and the vascularity of the administration site The blood plasma level for central nervous system effects is 2000 ng/ml The blood plasma level for cardiac effects is 4000 ng/ml 1. Hu D, et al. Clin Drug Investig. 2013;33(22):

9 Clinical Program for FDA Approval Evidence of efficacy and safety with EXPAREL is available from two pivotal Phase 3 trials (one soft tissue and one orthopedic model) The safety of EXPAREL was evaluated in 10 randomized, double-blind, local administration into the surgical site clinical studies involving 823 patients undergoing various surgical procedures including Hemorrhoidectomy Bunionectomy Inguinal hernia repair Breast augmentation Total knee arthroplasty

10 Safety Evaluated in Broad Clinical Development Program 21 clinical studies, 1307 patients received EXPAREL 10 wound infiltration studies: 823 patients Various surgical procedures; EXPAREL doses ranged from 66 mg to 532 mg The maximum dose of EXPAREL should not exceed 266 mg (one 20 ml vial) The most common adverse reactions (incidence 10%) following EXPAREL administration were nausea, constipation, and vomiting Cardiac Safety No QTc prolongation Even at supratherapeutic doses 1 No signal of any clinically important cardiac events from development program Additional Safety Findings No events of chondrolysis No hepatic dosing adjustment for mild to moderate disease No abnormal findings reflecting improper wound healing 2 1. Naseem A, et al. J Clin Pharmacol. 2012;52(9): ; 2. Golf M, et al. Adv Ther. 2011;28(9):

11 Clinical Experience to Date With EXPAREL The safety and efficacy of EXPAREL have only been demonstrated in bunionectomy and hemorrhoidectomy Broad label indication: Used in more than 1,000,000 patients since its launch in April 2012 Soft tissue Bariatric procedures Anorectal procedures Ventral and inguinal herniorrhaphy Open and laparoscopic colorectal procedures Ileostomy reversal Cosmetic plastic surgery: breast augmentation, breast reduction, abdominoplasty Plastic reconstructive surgery Transversus abdominis plane (TAP) infiltration Orthopedic Total knee arthroplasty Total hip arthroplasty Laminectomy Thoracotomy 11

12 Dosing EXPAREL is available as 266 mg, 1.3%/20 ml single-use vials Recommended dose of EXPAREL is based on the surgical site and the volume required to cover the area Dosing is not weight based Maximum dose of EXPAREL should not exceed 266 mg (one 20 ml vial)

13 Administration EXPAREL should be injected slowly into the soft tissues of the surgical site with frequent aspiration to check for blood and minimize the risk of intravascular injection Administer with a 25-gauge or larger needle Following withdrawal from the vial, EXPAREL may be stored at controlled room temperature of 20 C to 25 C (68 F to 77 F) for up to 4 hours prior to administration Soft Tissue Infiltration TAP Infiltration EO=External oblique IO=Internal oblique TA=Transversus abdominis LA=Local anesthetic Adapted from: Journal of New York School of Regional Anesthesia

14 Expanding the Volume The volume of EXPAREL can be expanded as necessary to accommodate administration into a larger surgical site without impacting efficacy EXPAREL can be expanded up to a total volume of 300 ml with normal (0.9%) saline for injection or lactated Ringer s solution Volumes used in clinical practice range from 20 to 300 ml depending on the size of the surgical site

15 Administration Technique Is Important EXPAREL does not diffuse throughout tissues in the same manner as bupivacaine Meticulous infiltration technique is important to ensure best results EXPAREL requires more injections to cover the same area EXPAREL Bupivacaine Note: graphic is for illustrative purposes only.

16 Administration Precautions Wait 20 minutes after administering lidocaine or other nonbupivacaine-based local anesthetics before administering EXPAREL into the same surgical site Allow topical antiseptics to dry before administering EXPAREL into the same surgical site When using bupivacaine HCl before EXPAREL, the dose of bupivacaine HCl should be <50% of the dose of EXPAREL. As a reference: One 20 ml vial of EXPAREL contains 266 mg of free base bupivacaine; 266 mg of free base bupivacaine is equivalent to 300 mg of bupivacaine HCl One 30 ml vial of 0.5% bupivacaine HCl contains 150 mg bupivacaine HCl Toxic effects of these drugs are additive and their administration should be used with caution, including monitoring for neurological and cardiovascular effects related to toxicity

17 Compatibility With Medications and Implantable Materials Commonly Used During Surgery No significant interaction with the following materials: Stainless steel Titanium Polypropylene Silicone Liposomal bupivacaine should not be admixed with other compounds In vivo compatibility studies have not been conducted, but when the following classes of compounds were tested in vitro with EXPAREL they did not cause excessive release of bupivacaine from the liposomal formulation: NSAIDs Opioids Epinephrine Tranexamic acid Corticosteroids Antibiotics Kharitonov V. Postgrad Med. 2014;126(1):

18 Cardiovascular and Central Nervous System Risks Associated With Local Anesthetics As with other local anesthetic products, monitoring of cardiovascular and neurological status, as well as vital signs should be performed during and after injection of EXPAREL The incidences 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

19 One Dose of EXPAREL Provides Significant Pain Control With Reduced Opioid Consumption Indicated for administration into the surgical site for postsurgical analgesia Requires no catheter or additional device Supplied in a ready-to-use aqueous suspension or the volume can be expanded to accommodate larger surgical sites Administered using a single-dose deep tissue infiltration technique

20 Important Safety Information EXPAREL is contraindicated in obstetrical paracervical block anesthesia EXPAREL has not been studied for use in patients younger than 18 years of age Non-bupivacaine-based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. Other formulations of bupivacaine should not be administered within 96 hours following administration of EXPAREL Monitoring of cardiovascular and neurological status, as well as vital signs should be performed during and after injection of EXPAREL as with other local anesthetic products Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, EXPAREL should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations In clinical trials, the most common adverse reactions (incidence 10%) following EXPAREL administration were nausea, constipation, and vomiting PP-EX-US-0750