Exparel

Local Analgesia via Infiltration in Adults

The recommended dose of EXPAREL for local infiltration in adults is up to a maximum dose of 266 mg, and is based on the following factors:

• Size of the surgical site
• Volume required to cover the area
• Individual patient factors that may impact the safety of an amide local anesthetic

As general guidance in selecting the proper EXPAREL dose for local infiltration in adults, two examples are provided [see Clinical Studies (14.2)]. In adult patients undergoing:

• Bunionectomy, a total of 106 mg (8 mL) of EXPAREL was administered, with 7 mL infiltrated into the tissues surrounding the osteotomy, and 1 mL infiltrated into the subcutaneous tissue.
• Hemorrhoidectomy, a total of 266 mg (20 mL) of EXPAREL was diluted with 10 mL of saline, for a total of 30 mL, divided into six 5 mL aliquots, injected by visualizing the anal sphincter as a clock face and slowly infiltrating one aliquot to each of the even numbers to produce a field block.

Local Analgesia via Infiltration in Pediatric Patients

The recommended dose of EXPAREL for one-time infiltration in pediatric patients, aged 6 to less than 17 years, is 4 mg/kg (up to a maximum of 266 mg), and is based upon two studies of pediatric patients undergoing either spine surgery or cardiac surgery [see Use in Specific Populations (8.4)].

Regional Analgesia via Interscalene Brachial Plexus Nerve Block in Adults

The recommended dose of EXPAREL for interscalene brachial plexus nerve block in adults is 133 mg and is based upon one study of patients undergoing either total shoulder arthroplasty or rotator cuff repair [see Clinical Studies (14.3)].

Regional Analgesia via Sciatic Nerve Block in the Popliteal Fossa in Adults

The recommended dose of EXPAREL for sciatic nerve block in the popliteal fossa in adults is 133 mg and is based upon one study of patients undergoing bunionectomy [see Clinical Studies (14.3)].

Regional Analgesia via Adductor Canal Block in Adults

The recommended dose of EXPAREL for adductor canal block in adults is 133 mg (10 mL) admixed with 50 mg (10 mL) 0.5% bupivacaine HCl, for a total volume of 20 mL, and is based upon one study of patients undergoing total knee arthroplasty [see Clinical Studies (14.3)].

Risk Summary

There are no studies conducted with EXPAREL in pregnant women. In animal reproduction studies, embryo-fetal deaths were observed with subcutaneous administration of bupivacaine to rabbits during organogenesis at a dose equivalent to 1.6 times the maximum recommended human dose (MRHD) of 266 mg. Subcutaneous administration of bupivacaine to rats from implantation through weaning produced decreased pup survival at a dose equivalent to 1.5 times the MRHD [see Data]. Based on animal data, advise pregnant women of the potential risks to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Clinical Considerations

Data

Risk Summary

Limited published literature reports that bupivacaine and its metabolite, pipecoloxylidide, are present in human milk at low levels. There is no available information on effects of the drug in the breastfed infant or effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for EXPAREL and any potential adverse effects on the breastfed infant from EXPAREL or from the underlying maternal condition.

Central Nervous System Reactions

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. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. Neurologic effects following infiltration of soft tissue may include persistent anesthesia, paresthesia, weakness, and paralysis, all of which may have slow, incomplete, or no recovery.

Central nervous system reactions are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered.

Cardiovascular System Reactions

Toxic blood concentrations depress cardiac conductivity and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and 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 [See Overdosage (10)].

Allergic Reactions

Allergic-type reactions are rare and may occur as a result of hypersensitivity to the local anesthetic or to other formulation ingredients. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly anaphylactoid-like symptoms (including severe hypotension). Cross-sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitively established.

Chondrolysis

Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been postmarketing 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 not associated with these findings. 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.

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. 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 EXPAREL and 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.

Adverse Reactions Reported in All Local Infiltration Clinical Studies in Adults

The safety of EXPAREL (local administration into the surgical site) was evaluated in 10 randomized, double-blind, clinical studies (including Studies 1 and 2 [see Clinical Studies (14.2)]) that included 823 adult patients who had various surgical procedures. Patients were administered an EXPAREL dose ranging from 66 to 532 mg (two times the maximum recommended dose of 266 mg). In these studies, following EXPAREL administration, the:

• Most common adverse reactions (incidence greater than or equal to 10%) were nausea, constipation, and vomiting.
• Common adverse reactions (incidence greater than or equal to 2% to less than 10%) were pyrexia, dizziness, peripheral edema, anemia, hypotension, pruritus, tachycardia, headache, insomnia, postoperative anemia, muscle spasms, hemorrhagic anemia, back pain, somnolence, and procedural pain.
• Less common adverse reactions (incidence less than 2%) were chills, erythema, bradycardia, anxiety, urinary retention, pain, edema, tremor, postural dizziness, paresthesia, syncope, incision site edema, procedural hypertension, procedural hypotension, procedural nausea, muscular weakness, neck pain, generalized pruritus, pruritic rash, hyperhidrosis, cold sweat, urticaria, palpitations, sinus bradycardia, supraventricular extrasystoles, ventricular extrasystoles, ventricular tachycardia, hypertension, pallor, anxiety, confusional state, depression, agitation, restlessness, hypoxia, laryngospasm, apnea, respiratory depression, respiratory failure, increased body temperature, increased blood pressure (BP), decreased BP, decreased oxygen saturation, urinary incontinence, blurred vision, tinnitus, drug hypersensitivity, and hypersensitivity.

Adverse Reactions Reported in All Local Infiltration Clinical Studies in Pediatric Patients Aged 6 to Less Than 17 Years

The safety of EXPAREL in 110 pediatric patients between the age of 6 and 17 years old who had spine or cardiac surgical procedures was evaluated in one randomized, open-label, clinical study in which EXPAREL was administered by infiltration into the surgical site (Study Peds-1) and one single-arm, open-label study in which EXPAREL was administered by infiltration into the surgical site (Study Peds-2) [see Use in Specific Populations (8.4)]. Patients were administered a weight-based dose of EXPAREL at 4 mg/kg (maximum dose of 266 mg) or bupivacaine HCl 2 mg/kg (maximum dose of 175 mg).

In these studies, following EXPAREL administration the:

• Most common adverse reactions (incidence greater than or equal to 10%) were nausea, vomiting, constipation, hypotension, anemia, muscle twitching, blurred vision, pruritus, and tachycardia.
• Common adverse reactions (incidence greater than or equal to 2% to less than 10%) were bradycardia, muscle spasms, tachypnea, oral hypoesthesia, postoperative anemia, dizziness, pyrexia, diarrhea, hypoacusis, hypoesthesia, back pain, hematuria, incontinence, muscular weakness, and visual impairment.
• Less common adverse reactions (incidence less than 2%) were flatulence, abdominal pain, dyspepsia, lip swelling, pain in extremity, musculoskeletal pain, flank pain, musculoskeletal chest pain, hypertension, sinus tachycardia, ventricular extrasystoles, dysgeusia, paresthesia, burning sensation, syncope, diplopia, eye swelling, dyspnea, atelectasis, hypopnea, hypoxia, chest pain, face edema, gait disturbance, generalized pruritus, rash, delayed recovery from anesthesia, fall, incision site hemorrhage, joint dislocation, seroma, hypomagnesemia, acidosis, hyperglycemia, metabolic acidosis, ear discomfort, decreased urine output, increased heart rate (HR), anxiety, panic attack, ear infection, and fungal wound infection.

Adverse Reactions Reported in Placebo-Controlled Nerve Block Clinical Studies in Adults

The safety of EXPAREL was evaluated in four randomized, double-blind, placebo-controlled nerve block clinical studies (Studies 3, 6, 7, 8) [see Clinical Studies (14.3, 14.4)] involving 469 EXPAREL-treated adult patients and 357 placebo-treated patients who had various surgical procedures. Patients were administered placebo or an EXPAREL dose of either 133 or 266 mg (two times the maximum recommended dose for these nerve blocks). In these studies, following EXPAREL administration via nerve block (perineural use) the:

• Most common adverse reactions (incidence greater than or equal to 10%) were nausea, pyrexia, and constipation.
• Common adverse reactions (incidence greater than or equal to 2% to less than 10%) were muscle twitching, dysgeusia, urinary retention, fatigue, headache, confusional state, hypotension, hypertension, oral hypoesthesia, generalized pruritus, hyperhidrosis, tachycardia, sinus tachycardia, anxiety, fall, increased body temperature, peripheral edema, sensory loss, increased hepatic enzyme, hiccups, hypoxia, and post-procedural hematoma.
• Less common adverse reactions (incidence less than 2%) were arrhythmia, atrial fibrillation, first degree atrioventricular block, bradycardia, left bundle branch block, right bundle branch block, cardiac arrest, impaired hearing, blurred vision, visual impairment, asthenia, chills, hyperthermia, cellulitis, lung infection, pneumonia, procedural nausea, wound dehiscence, wound secretion, electrocardiogram QT prolonged, white blood cell count increased, arthralgia, back pain, joint swelling, decreased mobility, muscle spasms, muscular weakness, musculoskeletal pain, paraesthesia, presyncope, sedation, somnolence, syncope, delirium, dysuria, urinary incontinence, atelectasis, cough, dyspnea, lung infiltration, blister, drug eruption, erythema, rash, urticaria, deep vein thrombosis, hematoma, and orthostatic hypotension.

The most common and common adverse reactions for the four randomized, double-blind, placebo-controlled nerve block clinical studies (Studies 3, 6, 7, 8) are shown in Table 3.

Adverse Reactions Reported in Active-Controlled Nerve Block Clinical Studies in Approved Populations

The safety of EXPAREL was evaluated in two randomized, double-blind, active-controlled nerve block clinical studies in 189 adult patients who had a bunionectomy or a total knee arthroplasty (Studies 4 and 5) [see Clinical Studies (14.3)]. Via nerve block, patients received 133 mg of EXPAREL, 266 mg of EXPAREL (two times the maximum recommended EXPAREL dose) [see Dosage and Administration (2.3)] or 133 mg of EXPAREL admixed with 50 mg of bupivacaine HCl. In both of these studies the active comparator was 50 mg of bupivacaine HCl.

The most common adverse reactions (incidence greater than or equal to 10%) in Studies 4 and 5 following:

• EXPAREL administration as a nerve block were nausea and constipation.
• Administration of EXPAREL admixed with bupivacaine as a nerve block were nausea, constipation, muscle spasms, and headache.

The common adverse reactions (incidence greater than or equal to 2% to less than 10%) in Studies 4 and 5 following:

• EXPAREL administration as a nerve block were pruritus, vomiting, dyspepsia, headache, peroneal nerve palsy, rash and hypertension.
• Administration of EXPAREL admixed with bupivacaine as a nerve block were vomiting, dyspepsia, heart rate increased, hypokalaemia, hyponatraemia, back pain, disorientation, oropharyngeal pain, hypoaesthesia, pruritus, dizziness, insomnia, hypertension, hypoxia, hypotension, pyrexia, and tachycardia.

The less common adverse reactions (incidence less than 2%) in Studies 4 and 5 following:

• EXPAREL administration as a nerve block were increased BP, pyrexia, arthralgia, insomnia, muscle spasms, asthenia, increased systolic BP, diarrhea, facial pain, migraine, muscle twitching, throat irritation, post procedural erythema, post procedural edema, dizziness, hypoesthesia, rhinorrhea, and paresthesia.
• Administration of EXPAREL admixed with bupivacaine as a nerve block were increased BP, procedural pain, rash, pruritic rash, anemia, anxiety, arthralgia, atrial fibrillation, decreased blood potassium, decreased BP, increased systolic BP, increased body temperature, bradycardia, confusional state, decreased appetite, diarrhea, dysarthria, fall, feeling cold, decreased HR, hot flush, joint swelling, leukocytosis, mental status changes, neuralgia, orthostatic hypotension, decreased oxygen saturation, pneumonia, post procedural hematoma, post procedural inflammation, post procedural swelling, pruritic rash, positive staphylococcus test, syncope, and urinary tract infection .

The most common and common adverse reactions in adult patients in the active-controlled clinical studies are shown in Table 4.

Notable Adverse Reactions from Active-Controlled Studies in Unapproved Populations

The safety of EXPAREL was evaluated in a multicenter, randomized, double-blind, active-controlled trial in 119 patients undergoing foot and ankle procedures (Study 9) [see Clinical Studies (14.3)]. Patients were administered a dose of either 266 mg EXPAREL, 266 mg EXPAREL admixed with 50 mg bupivacaine HCl, or 100 mg bupivacaine HCl. The following adverse reactions were observed following administration of EXPAREL or EXPAREL admixed with bupivacaine in Study 9 that either were not observed in Studies 4 and 5, or were observed at a higher frequency than was observed in Studies 4 and 5. These include:

• The most common adverse reactions (incidence greater than 10%) observed in Study 9 at higher frequencies than Studies 4 and 5: hypoesthesia (21% vs. 1% and 0%, respectively), paresthesia (10% vs. 1% and 0%, respectively).
• The common adverse reactions (incidence greater than or equal to 2% to less than 10%) observed in Study 9 but not in Studies 4 and 5: epistaxis, motor dysfunction, pain in extremity, skin abrasion, infusion site pain, muscular weakness.

Absorption

The rate of systemic absorption of bupivacaine is dependent upon the total dose of EXPAREL administered, the route of administration, and the vascularity of the administration site.

Pharmacokinetic parameters of EXPAREL after local infiltration, and following an interscalene brachial plexus nerve block, sciatic nerve block in the popliteal fossa, and adductor canal block were evaluated following surgical procedures. Descriptive statistics of pharmacokinetic parameters of representative EXPAREL doses in each study are provided in Table 5 for adult patients after administration of single doses of EXPAREL via local infiltration; Table 6 for adult patients after administration of single doses of EXPAREL via nerve block; and in Table 7 for pediatric patients aged 6 to less than 17 years old after administration of single doses of EXPAREL via local infiltration.

Distribution

After bupivacaine has been released from EXPAREL and is absorbed systemically, bupivacaine distribution is expected to be the same as for any bupivacaine HCl solution formulation.

Local anesthetics including bupivacaine are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.

Local anesthetics including bupivacaine appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Bupivacaine with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, non-ionized drugs such as bupivacaine readily enter the fetal blood from the maternal circulation.

Elimination

Specific Populations

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine have not been conducted.

Mutagenesis

The mutagenic potential of bupivacaine has not been determined.

Impairment of Fertility

The effect of bupivacaine on fertility has not been determined.

Study 1: Infiltration for Bunionectomy in Adults

A multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (NCT00890682) (Study 1) evaluated the safety and efficacy of 106 mg (8 mL) EXPAREL in 193 adult patients undergoing bunionectomy. The mean age was 43 years (range 18 to 72).

Study medication was administered directly into the site at the conclusion of the surgery, prior to closure. There was an infiltration of placebo or 7 mL of EXPAREL into the tissues surrounding the osteotomy and 1 mL into the subcutaneous tissue.

Pain intensity was rated by the patients on a 0 to 10 numeric rating scale (NRS) out to 72 hours. Postoperatively, patients were allowed rescue medication (5 mg oxycodone/325 mg acetaminophen orally every 4 to 6 hours as needed) or, if that was insufficient within the first 24 hours, ketorolac (15 to 30 mg IV). The primary outcome measure was the area under the curve (AUC) of the NRS pain intensity scores (cumulative pain scores) collected over the first 24-hour period. There was a significant treatment effect for EXPAREL compared to placebo. EXPAREL demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours. There was no significant difference in the amount of morphine equivalents used through 72 hours post-surgery, 43 mg versus 42 mg for placebo and EXPAREL, respectively. In addition, there was not a significant difference in the percentage of patients that used ketorolac, 43% versus 31% for placebo and EXPAREL, respectively.

Study 2: Infiltration for Hemorrhoidectomy in Adults

A multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (NCT00890721) (Study 2) evaluated the safety and efficacy of 266 mg (20 mL) EXPAREL in 189 adult patients undergoing hemorrhoidectomy. The mean age was 48 years (range 18 to 86).

EXPAREL or placebo were administered directly into the site (greater than or equal to 3 cm) at the conclusion of the surgery. Dilution of 20 mL of EXPAREL with 10 mL of saline, for a total of 30 mL, was divided into six 5-mL aliquots. A field block was performed by visualizing the anal sphincter as a clock face and slowly infiltrating one aliquot to each of the even numbers.

Pain intensity was rated by the patients on a 0 to 10 NRS at multiple time points up to 72 hours. Postoperatively, patients were allowed rescue medication (morphine sulfate 10 mg intramuscular every 4 hours as needed).

The primary outcome measure was the AUC of the NRS pain intensity scores (cumulative pain scores) collected over the first 72-hour period.

There was a significant treatment effect for EXPAREL compared to placebo. See Figure 1 for the mean pain intensity over time for the EXPAREL and placebo treatment groups for the 72-hour efficacy period.

There were statistically significant, but small differences in the amount of opioid rescue analgesia used across the treatment groups, the clinical benefit of which has not been established. The median time to rescue analgesic use was 15 hours for patients treated with EXPAREL and one hour for patients treated with placebo. Twenty-eight percent of patients treated with EXPAREL required no rescue medication at 72 hours compared to 10% treated with placebo. For those patients who did require rescue medication, the mean amount of morphine sulfate intramuscular injections used over 72 hours was 22 mg for patients treated with EXPAREL and 29 mg for patients treated with placebo.

Study 3: Interscalene Brachial Plexus Nerve Block for Total Shoulder Arthroplasty or Rotator Cuff Repair in Adults

A multicenter, randomized, double-blind, placebo-controlled study (NCT02713230) (Study 3) was conducted in 156 adult patients undergoing primary unilateral total shoulder arthroplasty or rotator cuff repair with general anesthesia. The mean age was 61 years (range 33 to 80). Prior to the surgical procedure, patients received 133 mg (10 mL) of EXPAREL expanded with normal saline to 20 mL or placebo as a brachial plexus nerve block (perineural use) via interscalene or supraclavicular approach with ultrasound guidance. Only two patients received nerve block with EXPAREL by supraclavicular approach. Postsurgically, patients were administered acetaminophen/paracetamol up to 1,000 mg orally or intravenously every 8 hours unless contraindicated. Patients were allowed opioid rescue medication administered initially as oral immediate-release oxycodone (initiating at 5-10 mg every 4 hours or as needed). If a patient could not tolerate oral medication, intravenous morphine (2.5-5 mg) or hydromorphone (0.5-1 mg) could be administered every 4 hours or as needed.

In Study 3, there was a statistically significant treatment effect for EXPAREL compared to placebo in cumulative pain scores through 48 hours as measured by the AUC of the visual analog scale (VAS) pain intensity scores. There were statistically significant, but small differences in the amount of opioid consumption through 48 hours, the clinical benefit of which has not been demonstrated. For those patients who required rescue medication, the mean amount of morphine-equivalent opioid rescue used over 48 hours was 12 mg for EXPAREL-treated patients and 54 mg for placebo-treated patients and 23 mg with EXPAREL-treated patients vs. 70 mg for placebo-treated patients over 72 hours.

Although at 48 hours, 9 patients (13%) in the EXPAREL group remained opioid-free compared to 1 patient (1%) in the placebo group, a difference which was statistically significant, at 72 hours, there were 4 (6%) patients in the EXPAREL group who remained opioid-free compared to 1 (1%) patient in the placebo group, a difference that is not statistically significant.

Study 4: Sciatic Nerve Block in the Popliteal Fossa for Bunionectomy in Adults

A multicenter, randomized, double-blind, active controlled study (NCT05157841) (Study 4) was conducted in 185 adult patients undergoing bunionectomy. The mean age was 49 years (range 18 to 76).

Prior to the surgical procedure, patients received 133 mg of EXPAREL mixed with 20 mL saline OR 50 mg (20 mL) of 0.25% bupivacaine HCl mixed with 10 mL saline via sciatic nerve block (perineural use) in the popliteal fossa. All patients received 100 mg (20 mL) of 0.5% immediate-release bupivacaine HCl as a Mayo field block after study drug administration (i.e., in the operating room immediately prior to surgical incision). All patients also received a dose of 1,000 mg of intravenous (IV) acetaminophen at the time of surgical incision. IV fentanyl was allowed for intraoperative pain control (not exceeding 1 mcg/kg unless deemed medically necessary).

Postsurgically, all patients received one post-operative dose of 1,000 mg IV acetaminophen, administered approximately 8 hours after the first dose (approximately 8 hours after incision). Patients were administered pain medications on an as needed basis; opioids were not given on a pre-determined schedule. Patients were allowed opioid rescue medication administered initially as oral immediate-release oxycodone (initiating at 5 mg and increasing the dose to 10 mg if initial opioid dose was insufficient). If a patient could not tolerate oral medication or the oral oxycodone pain relief was insufficient, IV morphine (initiated at 2 mg) or hydromorphone (initiated at 0.2 mg) could be administered. No NSAIDs or other opioids including tramadol were allowed for the breakthrough pain management and no acetaminophen (other than the scheduled IV acetaminophen) was used for breakthrough pain.

In Study 4, there was a statistically significant treatment effect for EXPAREL (with 0.5% immediate-release bupivacaine HCl as a Mayo field block) compared to bupivacaine HCl (with 0.5% immediate-release bupivacaine HCl as a Mayo field block) in cumulative pain scores through 96 hours as measured by AUC of the NRS pain intensity scores. There were statistically significant differences in the total amount of postsurgical opioid medication used through 96 hours, the clinical benefit of which has not been demonstrated. For those patients who required postsurgical opioid medication, the mean amount of morphine-equivalent opioid rescue used over 96 hours was 18 mg for patients treated with EXPAREL + Mayo field block and 45 mg for patients treated with bupivacaine HCl + Mayo field block. There was also a statistically significant difference in the percentage of opioid-free patients through 96 hours compared with bupivacaine HCl (24% in the EXPAREL + Mayo field block vs. 6% in the bupivacaine HCl + Mayo field block).

See Figure 2 for the LS mean pain intensity scores after administration of either 133 mg of EXPAREL or 50 mg of 0.25% bupivacaine HCl.

Figure 2. NRS Pain Intensity After Administration of Study Drug by Sciatic Nerve Block in the Popliteal Fossa.

Study 5: Adductor Canal Block for Total Knee Arthroplasty in Adults

A multicenter, randomized, double-blind, active controlled study (NCT05139030) (Study 5) was conducted in 166 adult patients undergoing primary unilateral total knee arthroplasty. The mean age was 62 years (range 37 to 83).

Prior to the surgical procedure, patients received (via adductor canal block) (perineural use):

• 133 mg (10 mL) of 1.3% EXPAREL admixed with 50 mg (10 mL) of 0.5% bupivacaine HCl or
• 50 mg (10 mL) of 0.5% bupivacaine HCl mixed with 10 mL normal saline.

All patients also received 37.5 mg (15 mL) of 0.25% immediate-release bupivacaine HCl as an infiltration between the popliteal artery and capsule of the knee (IPACK) block immediately following study drug administration. All patients received spinal anesthesia immediately prior to surgery with 0.5% bupivacaine HCl (up to 15 mg). All patients also received a dose of 1,000 mg of intravenous (IV) acetaminophen at the time of surgical incision. IV fentanyl was allowed for intraoperative pain control (not exceeding 1 ug/kg unless deemed medically necessary).

Postsurgically, all patients received one post-operative dose of 1,000 mg IV acetaminophen, administered approximately 8 hours after the first dose (approximately 8 hours after incision). Patients were administered pain medications on an as needed basis for breakthrough pain; opioids were not given on a pre-determined schedule. Patients were allowed opioid rescue medication administered initially as oral immediate-release oxycodone (initiating at 5 mg and increasing the dose to 10 mg if initial opioid dose was insufficient). If a patient could not tolerate oral medication or the oral oxycodone pain relief was insufficient, IV morphine (initiated at 2 mg) or hydromorphone (initiated at 0.2 mg) could be administered. No NSAIDs or other opioids including tramadol were allowed for the breakthrough pain management and no acetaminophen (other than the scheduled IV acetaminophen) was used for breakthrough pain.

In Study 5, there was a statistically significant treatment effect for EXPAREL + IPACK block compared to bupivacaine HCl + IPACK in cumulative pain scores through 96 hours as measured by AUC of the NRS pain intensity scores. There were statistically significant differences in the total amount of postsurgical opioid medication used through 96 hours, the clinical benefit of which has not been demonstrated. For those patients who required postsurgical opioid medication, the mean amount of morphine-equivalent opioid rescue used over 96 hours was 102 mg for patients treated with EXPAREL + IPACK and 133 mg for patients treated with bupivacaine HCl+ IPACK. The median time to first postsurgical use was 4.2 hours for patients treated with EXPAREL + IPACK and 3.6 hours for patients treated with bupivacaine HCl + IPACK.

See Figure 3 for LS mean pain intensity scores after administration of either 133 mg of 1.3% EXPAREL admixed with 50 mg) of 0.5% bupivacaine HCl or 50 mg of 0.5% bupivacaine HCl.

Figure 3. NRS Pain Intensity After Administration of Study Drug by Adductor Canal Block

Studies 6 and 7: Inadequate Demonstration of Efficacy and Safety in Femoral Nerve Block in Total Knee Arthroplasty

EXPAREL was administered via a femoral nerve block in two placebo-controlled studies in adults (Studies 6 and 7). The results of these studies did not support a femoral nerve block indication due to inadequate safety data (Study 6) and/or due to inadequate efficacy findings (Study 7). In addition, patient falls were reported only in the EXPAREL treatment groups, and none was reported in placebo groups.

Study 8: Lack of Efficacy in Intercostal Nerve Block for Posterolateral Thoracotomy

A multicenter, randomized, double-blind, placebo-controlled study was conducted in 191 adult patients undergoing posterolateral thoracotomy under general anesthesia (NCT01802411) (Study 8). The mean age was 58 years (range 18 to 82).

After the surgical procedure was completed but prior to the surgical site closure, 266 mg (20 mL) of EXPAREL was administered by the surgeon as an intercostal nerve block divided into three equal doses in three syringes of approximately 88 mg in 6.6 mL volume per nerve, and administered to each of three nerve segments (index nerve, nerve above, and nerve below). Postsurgically, patients were allowed opioid rescue medication administered initially by intravenous fentanyl 100 mcg, which was to be administered once via bolus only. For the US sites, the second rescue medication was to be PCA-administered morphine or hydromorphone. For the European sites, the second rescue medication was to be intramuscular administered morphine up to 10 mg every 4 hours. At all sites, once a patient was tolerating oral medication, oral immediate-release oxycodone was administered (but not more than 10 mg every 4 hours). Patients who did not achieve adequate pain relief with this regimen were to be withdrawn from the study and followed for safety only.

In this study there were no statistically significant treatment effects for EXPAREL 266 mg compared to placebo in cumulative pain intensity scores or total opioid consumption. Four percent of patients treated with EXPAREL required no rescue medication at 72 hours compared to 1% treated with placebo. For those patients who did require rescue medication, the mean amount of opioid rescue used over 72 hours was 71 mg for patients treated with EXPAREL and 71 mg for patients treated with placebo. The median Tmax of bupivacaine observed in this study was 1 hour with a range of 0.5 hours to 50 hours.

Study 9: Lack of Efficacy in Combined Sciatic (in popliteal fossa) and Saphenous (in adductor canal) Nerve Block Study in Lower Extremity Surgeries

A multicenter, randomized, double-blind, active-controlled trial (NCT04518462) (Study 9) was conducted in 119 adult patients who underwent foot and ankle procedures (bunionectomy, first metatarsophalangeal fusion, forefoot & hindfoot fusion, total ankle arthroplasty). The mean age was 48 years (range 20 to 72). Prior to the surgical procedure, patients received one of the following three treatments under ultrasound guidance as a sciatic nerve block in the popliteal fossa and a saphenous nerve block in the adductor canal:

• 266 mg of EXPAREL (20 mL) admixed with 20 mL of 0.9% Sodium Chloride Injection (referred to as normal saline (NS)),
• 266 mg of EXPAREL (20 mL) admixed with 50 mg of 0.25% bupivacaine HCl (20 mL), or
• 100 mg of 0.25% bupivacaine (40 mL).

The total volume (40 mL) was divided evenly between the two blocks. All patients received general anesthesia or nonopioid sedation (except fentanyl); were allowed medication for intraoperative nausea/vomiting prevention; and were allowed medication for breakthrough pain postsurgery which followed a step-wise approach starting with acetaminophen or a nonsteroidal anti-inflammatory drug (not exceeding the maximum dose), and, if needed escalating to an initial 5 mg dose of oxycodone, then to a 10 mg dose of oxycodone, and finally to intravenous morphine (initiated at 2 mg) or intravenous hydromorphone (initiated at 0.2 mg).

In Study 9 there was no significant difference in the primary endpoint [least square mean (LSM) area under the curve (AUC) numerical rating scale (NRS) pain score from 0 to 96 hours after surgery] between EXPAREL + NS and the 0.25% bupivacaine HCl treatment groups. Cumulative opioid consumption differences between groups were nonsignificant 0-96 hours after surgery. The LSM amount of opioids received over 96 hours was 21 mg in EXPAREL group and 20 mg in bupivacaine HCl group.