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Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

1

Bupivacaine Liposome Injectable Suspension

(EXPAREL)

National Drug Monograph

June 2013

VA Pharmacy Benefits Management Services,

Medical Advisory Panel and VISN Pharmacist Executives

The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions.

These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in

the Archive section when the information is deemed to be no longer current.

Executive Summary

Description

 Bupivacaine liposomal injectable suspension (Exparel) is an amide-type local anesthetic in an

encapsulated liposomal formulation developed with the goal of providing a longer duration of

anesthesia compared with its non-liposomal counterpart, bupivacaine hydrochloride or other local

anesthetics.

 The product utilizes the DepoFoam drug delivery system consisting of an aqueous suspension

of multivesicular liposomes containing bupivacaine in a honeycomb-like structure that allows for a

more gradual release.

 The FDA approved bupivacaine liposomal in October 2011 for single-dose infiltration into the

surgical site for postoperative analgesia.

Efficacy

 To date, there have been a limited number of published clinical trials evaluating the safety and

efficacy of liposomal bupivacaine.

 Three phase 3 pivotal trials were reviewed by the FDA for final approval, two of them comparing

liposomal bupivacaine to placebo and one comparing liposomal bupivacaine to unencapsulated

bupivacaine HCl/epinephrine (unpublished). In each of the trials, the primary endpoint was pain

intensity and duration using the numeric pain rating score through a predetermined period of time

postoperatively (24, 72 and 96 hrs). In the placebo-controlled trials (1-bunionectomy4, 1-

hemorrhoidectomy5), liposomal bupivacaine was associated with statistically less intense pain

through the stated time period compared to placebo. In addition, opioid consumption was

statistically less in favor of liposomal bupivacaine versus placebo, but the clinical significance of

the difference is unknown (Golf-3.8 vs. 4.7 tabs of oxycodone 5 mg/APAP 325 mg tablets at 24

hrs, p=0.008 and Gorfine-22.3 mg vs. 29.1 mg morphine equivalents at 72 hrs, p=0.0006). In an

unpublished study, liposomal bupivacaine was not statistically different from unencapsulated

bupivacaine HCl/epinephrine in reducing pain intensity through the specified time points or other

secondary outcome measures in patients following hemorrhoidectomy.

 The FDA reviewer highlighted some important points regarding the results of these three trials as

follows:

 In the two pivotal, placebo controlled trials, liposomal bupivacaine provided postoperative analgesia for up to

24 hours in patients having bunionectormy or hemorrhoidectomy surgery. In these studies, pain intensity

was significantly reduced in patients receiving liposomal bupivacaine compared to placebo for the initial 12

hours after infiltration, but diminished over the subsequent 12 hours resulting in no clinical meaningful

difference in pain between groups beyond 24 hrs.

 Unpublished, active comparison: Based upon the results, investigators failed to show any statistically or

clinically meaningful advantage of liposomal bupivacaine over bupivacaine HCl when used after

hemorrhoidectomy, despite examining over 60 different efficacy endpoints. Both agents were equally well

tolerated.

 The manufacturer did request a priority review. However, that request was denied since the manufacturer

was unable to demonstrate that use of liposomal bupivacaine reduced the use of opioids or their associated

adverse events or a relevant benefit in reduced time to discharge or return to usual activities.

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

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 Since different doses and manner of administration were used in the two types of surgery, extrapolation of

dosing and effectiveness to other surgical interventions is not possible. Additional studies are needed to

answer the question of appropriate dose and manner of administration for use in other surgeries.

 Original recommendation was for the labeling to specifically include postoperative use following

bunionectomy or hemorrhoidectomy. The final labeling was less specific.

 Labeling should contain a strong caution against use of liposomal bupivacaine by other administration routes

(other than single-dose, postoperative wound infiltration) that are commonly used with other local

anesthetics in clinical practice but may be unsafe for this product.

 There have been two published phase 2 trials (1-hemorrhoidectomy9, 1-total knee arthroplasty10)

and two published phase 3 trials (1-total knee arthroplasty11, 1-breast augmentation18) comparing

the cumulative pain scores between liposomal bupivacaine and unencapsulated bupivacaine HCl

(0.25% with epinephrine 1:200,000).

 In the phase-2 studies, the primary endpoint of cumulative pain intensity was met in favor of the

liposomal product9,10 but not in the phase-3 studies11,18. However, since the analysis of pain

intensity was determined over the entire planned study length (through 72 hrs or 4 days), the

differences at the various time points were not entirely consistent between studies making it

difficult to determine the actual length of time the differences between groups existed or if the

differences were clinically important. For example in the pivotal trials, the primary endpoint was

reportedly met through 72 hrs but when the FDA reviewer reported their findings, the statistical

difference from placebo was present only through 24 hours, but not beyond.

 In each of the studies, sample sizes were small, multiple comparisons between groups at a

number of time points were made with some showing statistical benefit of the liposomal product

and others not, and post-hoc changes were made to the analysis of one of the studies, thereby

limiting the strength of the evidence.9

 In three of the studies9,10,11, there was no statistical or clinically important difference in total

consumption of opioids, discharge readiness, proportion of patients who were opioid free or who

were able to return to work or resume normal daily activities between groups.

Safety

 Liposomal bupivacaine was well tolerated and adverse events were not significantly different than

bupivacaine HCl/epinephrine or placebo when administered as a single-dose infiltrated into the

surgical site after bunionectomy or hemorrhoidectomy.

 The most common adverse events reported with bupivacaine liposomal injectable suspension

were constipation, nausea, and vomiting.

 Similar to other local anesthetics, there is a potential for neurologic or cardiovascular adverse

events and is related to the total dose administered. However, other factors may increase the

incidence of these adverse events and include the specific anesthetic used, the route of

administration and the patient’s health status. Early signs of central nervous system toxicity

include restlessness, anxiety, incoherent speech, lightheadedness, numbness, tingling of the

mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, twitching, tremors, depression, or

drowsiness.

 There are no known long-term safety issues that have been identified to date.

 Since liposomal bupivacaine has not been studied or data are limited in patients undergoing other

types of surgery (other than bunionectomy or hemorrhoidectomy), the safety, efficacy and

appropriate doses of liposomal bupivacaine are not known and therefore, use is not

recommended.

 Furthermore, other routes of administration or types of analgesia have not been studied and

therefore, are not recommended (e.g., epidural, intrathecal, regional nerve block or intravascular

or intra-articular use).

Conclusion

 Although liposomal bupivacaine statistically reduced pain intensity in patients undergoing

bunionectomy or hemorrhoidectomy when compared to placebo, there was no difference in the

primary outcome or secondary outcomes when compared to traditional unencapsulated

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

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bupivacaine HCl in an unpublished phase 3 pivotal trial in patients undergoing

hemorrhoidectomy.

 In two phase 2, dose-ranging studies, liposomal bupivacaine was associated with improved

cumulative pain scores compared to bupivacaine HCl but differences in total consumption of

opioids, readiness for discharge, proportion of patients who were opioid free or who were able to

return to work or resume normal activities were not different.

 Since the safety and efficacy of liposomal bupivacaine has been evaluated primarily in patients

undergoing hemorrhoidectomy or bunionectomy (using a single-dose infiltrated into the surgical

site), the safety and efficacy when used after other surgeries; by other routes of administration; or

use for other types of analgesia are unknown and therefore, use after other surgeries is not

recommended.

 Based on the existing evidence, there are no clear or substantive advantages of the liposomal

bupivacaine product over bupivacaine HCl.

 There are no clinical trials comparing liposomal bupivacaine to other local anesthetic agents so

any advantage or disadvantage of liposomal bupivacaine over other local anesthetics is unknown.

Introduction

The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy,

cost, and other pharmaceutical issues that would be relevant to evaluating bupivacaine liposome

injectable suspension for possible addition to the VA National Formulary; (2) define its role in therapy; and

(3) identify parameters for its rational use in the VA.

Pharmacology/Pharmacokinetics1,2

Bupivacaine liposomal injectable suspension is an amide-type local anesthetic in an encapsulated

liposomal formulation developed to provide a longer duration of anesthesia compared with its non-

liposomal counterpart, bupivacaine hydrochloride or other local anesthetics. Anesthesia occurs by

reversibly binding to sodium channels on the neuronal cell wall, preventing the influx of sodium, and

increasing the nerve’s electrical excitation threshold. Action potential firing is reduced and the nerve’s

impulse generation and conduction are blocked. Small unmyelinated C-fibers are blocked first, which

mediate pain, followed by small myelinated Aδ-fibers which mediate pain and temperature sensation, and

lastly large myelinated fibers including Aγ-, Aβ-, and Aα- fibers which mediate touch, pressure, muscle

and postural sensations.

Bupivacaine liposomal injectable suspension utilizes the DepoFoam drug delivery system, an aqueous

suspension of multivesicular liposomes containing bupivacaine, for gradual systemic release. The

multivesicular liposome particles are made up of a honeycomb like structure consisting of many

nonconcentric compartments containing bupivacaine. In vivo, DepoFoam particles release drug over an

extended period of time by erosion of the exterior surface and reorganization of the particles’ lipid

membranes. Bupivacaine liposomal injectable suspension follows a two-compartment model. Initially, first

order short-term release followed by zero-order release over an extended period of time. When

bupivacaine liposomal injectable suspension is administered, free bupivacaine in the solution is

immediately available to anesthetize the surgical site, while the bupivacaine enclosed in the DepoFoam is

released more gradually over an extended period of time.

Once Bupivacaine liposomal injectable suspension is released from the liposome, distribution,

metabolism, and excretion follows the same kinetics as bupivacaine HCl. Of note, bupivacaine liposomal

injectable suspension can have elevated systemic plasma levels for up to 96 hours, but the systemic

plasma levels do not correlate with local efficacy. Duration of local analgesia properties is ~24 hours.

Different formulations of bupivacaine are not bioequivalent and it is not possible to convert dosing from

one formulation to another.1

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

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Table 1. PK Parameters of Bupivacaine Liposomal Injectable Suspension1

Parameters Bunionectomy 106 mg (8 mL)

(N=26)

Hemorrhoidectomy 266 mg (20 mL)

(N=25)

Mean Cmax

(ng/mL)

166(92.7) 867 (353)

Median Tmax

(h)

2 0.5

Mean AUC(0-t)

(h*ng/mL) 5864 (2038) 16,867 (7868)

Mean AUC (inf)

(h*ng/mL) 7105 (2283) 18,289 (7569)

Mean t 1/2 (h)

34.1 (17.0)

23.8 (39.4)

Table adapted from product information

Table 2. PK parameters of bupivacaine liposomal injectable suspension and bupivacaine HCl2,3

PK Parameter EXPAREL Bupivacaine HCl

Metabolism Hepatic conjugation with glucuronic acid;

inactive metabolite pipecoloxylidine (PPX)

Hepatic conjugation with glucuronic acid;

inactive metabolite pipecoloxylidine (PPX)

Elimination Urine (6% unchanged) Urine (6% unchanged)

Half-life 24-34 h 2.7 h

Protein binding 95% 95%

Local onset 2 minutes 1-17 minutes

Duration

Local: 24 h

Systemic: 96 h (does not correlate with local

efficacy)

2-9 h (route and dose dependent)

Time to peak

Bunionectomy: 2 h

Hemorrhoidectomy: 0.5 h

Inguinal hernia: 12 h

Total Knee Arthroplasty: 36 h

0.5 hours-0.75 h

Bupivacaine liposomal injectable suspension is not associated with major motor blockade at doses up to 266 mg.

When motor block did occur, the maximum duration was 4 hours instead of 12 hours as seen with unencapsulated

bupivacaine.17

FDA Approved Indication(s)1

Bupivacaine liposomal injectable suspension is indicated for single-dose infiltration into the surgical site to

produce anesthesia after surgery. The U.S. Food and Drug Administration approved it on October 28,

2011. Of note, the pivotal trials providing the basis for FDA approval consisted of patients having

bunionectomy or hemorroidectomy.

Potential Off-label Uses

This section is not intended to promote any off-label uses. Off-label use should be evidence- based. See

VA PBM-MAP and Center for Medication Safety’s Guidance on “Off-label” Prescribing (available on the

VA PBM Intranet site only).

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

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Bupivacaine liposomal injectable suspension has been studied for use in postoperative local analgesia in

adults having hernia repair, breast augmentation, and total knee arthroplasty. There are also several

phase 4 trials currently recruiting patients. Investigators for these trials will examine bupivacaine

liposomal injectable suspension in comparison to morphine or other opioids for pain associated with

colectomy, ileostomy reversal and robotic assisted laparoscopic prostatectomy.20-22 Most of these trials

are designed as health-economic trials. There is one planned trial to examine femoral nerve block with

liposomal bupivacaine in patients having total knee arthroplasty. At this time, evidence is lacking to

support the efficacy and safety of liposomal bupivacaine for post-operative local anesthesia in

surgeries other than bunionectomy or hemorroidectomy, and therefore use in other surgeries

cannot be recommended. Furthermore, evidence is lacking for use of other types of analgesia or

routes of administration for liposomal bupivacaine (e.g., epidural, intrathecal, regional nerve

blocks, etc.) and therefore should not be used outside of its approved dosage and administration.

Current VA National Formulary Alternatives

Current VA National Formulary Injectable local anesthetics (VA Class CN204) include: bupivacaine HCl*,

chloroprocaine HCL, prilocaine, lidocaine HCl, mepivacaine HCl, ropivacaine HCl, and tetracaine HCl.

Lidocaine, bupivacaine and prilocaine combined with epinephrine are also on the VANF.

*It is important to note that when using non-liposomal bupivacaine, there are multiple formulations with

and without preservative. Bupivacaine multi-dose vials with methylparaben as a preservative can only be

used for peripheral nerve block. The preservative free versions (also referred to as methylparaben free)

are required for caudal or epidural anesthesia. For spinal anesthesia, bupivacaine spinal, which also

contains dextrose, is the only bupivacaine product indicated.

Dosage and Administration1

Bunionectomy (Adult): Inject 106 mg by infiltrating 7 mL into surrounding tissue of the osteotomy and 1

mL into the subcutaneous tissue. Bupivacaine liposomal is intended for single-dose infiltration only and

the maximum dose should not exceed 266 mg. The recommended dose is based on surgical site and

volume needed to cover the surgical area.

Hemorrhoidectomy (Adult): Dilute 20 mL vial of bupivacaine liposome with 10 mL of normal saline for a

total of 30 mL. Inject 266 mg via infiltration by dividing the 30 mL mixture into six 5-mL aliquots. Visualize

the anal sphincter as a clock face and perform anal block by slowly infiltrating one aliquot to each of the

even numbers. Liposomal bupivacaine is intended for single-dose infiltration only and maximum dose

should not exceed 266 mg.

Safety and efficacy of bupivacaine liposome have not been established in patients less than 18 years of

age. Bupivacaine liposomal injectable suspension should be used with caution in patients with hepatic

and renal impairment (Refer to section on Special Populations for additional information).

Administration: Bupivacaine liposomal injectable suspension is indicated for single-dose infiltration only.

 A 25-gauge or larger bore needle should be used to administer bupivacaine liposomal. Do not

filter or heat before use. Invert vials several times to re-suspend particles immediately before

withdrawing drug from vial.

 Do not administer if vial has been frozen (as reflected by the temperature indicator) or exposed to

high temperatures (40C or 104F) for an extended period of time. Freeze indicator turns from

green to white if product has been exposed to freezing temperatures.

 Inspect product for discoloration, do not administer if product is discolored.

 Bupivacaine liposomal should be injected into the surrounding soft tissue of the surgical site.

Frequent aspiration should be done to check for blood and to reduce the risk of intravascular

administration. The maximum dose is 266 mg and should not be exceeded.

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

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 Bupivacaine liposomal can be administered diluted up to 0.89 mg/ml (i.e., 1:14 dilution by

volume) with preservative free normal sterile saline (0.9%) for injection or undiluted.

 Non-bupivacaine based local anesthetics may cause immediate release of bupivacaine from

bupivacaine liposomal injectable suspension if administered together locally. Administration of

bupivacaine liposomal injectable suspension may follow the administration of lidocaine after at

least 20 minutes. Other formulations of bupivacaine should not be used within 96 hours due to

risk of toxicity.

 When a topical antiseptic (povidone iodine) is applied to site, the site should be allowed to dry

before liposomal bupivacaine is administered since topical antiseptics should not come into

contact with liposomal bupivacaine.

Storage: Store refrigerated between 2°C to 8°C. Unopened vials may be kept at room temperature (20 to

25°C) for up to 30 days. Record the date when a vial is removed from refrigeration. Unopened vials

should not be re-refrigerated. After withdrawal from vial, the suspension may be stored up to 4 hours at

room temperature. Diluted suspensions should be used within 4 hours.

Dose conversion: Bupivacaine liposomal injectable suspension is not bioequivalent with other

formulations of bupivacaine, even if the milligram strength is the same. Therefore, dosage conversion

between bupivacaine liposomal and other forms of bupivacaine, and vice versa, is not possible.

Efficacy

For this review, all published studies examining the efficacy and/or safety of bupivacaine liposomal

injectable suspension for producing post-surgical, local anesthesia in humans were included.

Efficacy Measures

Primary Outcome Measure:

 Pain Intensity-Assessed by the cumulative pain score using the numeric rating scale (NRS) area

under the curve (AUC) through a designated period of time (e.g., 0-24 hrs, 0-72 hrs, etc.). At

designated time points, patients rate their pain intensity at rest or with activity on an 11-point

scale (0=no pain, 10=worst pain possible). The pain assessment ratings are then summed during

the time points and the NRS-AUC for the period of time is obtained.

Secondary Outcome Measures:

 Proportion of patients receiving no supplemental opioids

 Total milligrams of opioid rescue medications

 Time to first post-surgical use of opioid rescue medications

 Brief pain inventory (BIP)-Measures the severity of pain and its impact on daily function

 Patient rating of satisfaction with pain control after surgery

 Caregiver assessment of wound healing

 Adverse effects, including those commonly associated with opioid use

Summary of Efficacy Findings4-5, 28

As part of the FDA review process, the manufacturer submitted three clinical trials examining the safety

and efficacy of liposomal bupivacaine. Two of the trials were published and involved a comparison of

liposomal bupivacaine to placebo in patients undergoing bunionectomy (n=193 patients)4 or

hemorrhoidectomy (n=189 patients)5. The third, unpublished trial involved a comparison of liposomal

bupivacaine with bupivacaine HCl in patients having hemorrhoidectomy28. In each of the three trials, the

primary endpoint was the intensity and duration of pain as reported using the area under the curve (AUC)

of the numeric rating scale (NRS) through 24-72 hrs after surgery between treatments. The three trials

are summarized below in Table 3.

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

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Table 3. Clinical Efficacy Trials (Pivotal, Phase 3 Clinical Trials Used for FDA Submission)

Clinical Trial

Exclusion/Intervention

Outcome Measures

Results

Adverse Events/Comments

Golf4

Phase 3, R, MC, PC,

DB

N=193

Inclusion: Adult

patients undergoing

primary unilateral first

metatarsal osteotomy

without hammertoe.

Able to have Mayo

block for

intraoperative local

analgesia and

propofol and/or

midazolam for

sedation.

*Sponsored by Pacira

Pharma

Exclusion: pregnancy, nursing or

planning to become pregnant, chronic

users of analgesics either opioids or

non-opioids, any analgesic within 24

hrs to 3 days prior to surgery,

peripheral neuropathy, hx of hepatitis,

addiction to drugs or etoh past 2 yrs,

peripheral ischemic disease,

diabetes, acute or chronic medical or

psychiatric disease, malignancy in last

2 yrs, sensitivity to amide local

anesthetics or opioids, etc.

Intervention: LBup 8 mL (120 mg) or

Placebo

Rescue meds: 1-2 oxy 5 mg/APAP

325 mg every 4-6 hrs prn. (Max 12/d).

If pain couldn’t be rescued by

oxy/APAP, a single dose of ketorolac

15-30 mg was allowed. If pain still not

controlled, pt removed from efficacy

portion of study. No other analgesics

were allowed for first 72 hrs.

Primary: AUC-NRS

score through 24 hrs

(Measured at 2, 4, 8,

12, 24, 26, 48, 60 and

72 hrs post-op)

Secondary:

*AUC-NRS through 36,

48, 60 and 72 hrs

* Proportion of patients

pain free at 24 hrs and

other time points.

* Proportion of pts

receiving no rescue

pain med

* Total oxy/APAP mg

through 24, 36, 48, 60

and 72 hrs.

* Time to first rescue

Patients were d/c after

24 hrs and staff called

patients to get

assessments beyond

24 hrs.

N=193 randomized, 97 to LBup, 96 to

placebo. 4 pts from each group

withdrew or violated study protocol.

Mean age: 42 years

Primary:

AUC-NRS0-24: LBup 124.9 vs. 146.4

(p=0.0005, LSM difference: -22.297,

95% CI for difference: -34.8 to -9.8)

Secondary:

Adjusted mean AUC-NRS0-36 and 0-48:

LBup 0-36 hr: 196.9 vs. 220.3 placebo

(p=0.0229) and

LBup 0-48 hr: 268.9 vs. 290.5 placebo

(p=0.1316) (NS)

Pts pain free:

Statistical difference in favor of LBup for

2, 4, 8 and 48 hrs but not other time

points. (No diff at 12, 36 or 60 hrs)

Pts receiving no opioids:

Statistical difference in favor of LBup

through 24 hrs, after that, no diff.

Time to first opioid:

LBup: 7.2 hrs vs. 4.3 hrs placebo

(p<0.0001)

Total use of rescue opioids (tabs)

through 24 hrs:

LBup: 3.8 tabs vs. 4.7 tabs placebo

(p=0.008)

Most ADEs were mild-moderate. Systemic ADEs

were higher with LBup vs placebo (9.3% vs.

5.2%, respectively), including somnolence.

Incidence of severe ADEs was also higher with

LBup than placebo (11.3% vs. 5.2%,

respectively), these severe ADEs were not

detailed. Moderate ADEs were higher in the

placebo group (20.8%) vs. LBup (12.4%).

Vomiting was reported more often in the LBup vs.

placebo (27.8% vs. 17.7%, respectively). Reports

of constipation were also numerically higher with

LBup vs. placebo (2.1% vs. 1%, respectively)

Comments/Limitations:

*No active control, only placebo controlled

*Patients left study site after 24 hrs and were

contacted via telephone for follow up pain

assessments.

*Authors cautioned against extrapolation of their

results to other surgical populations, those with

multiple medical problems or those taking other

medications and the controlled conditions of the

study. They also state that interpretation of their

results is limited due to the inherent subjectivity

and intra-patient variability of patient-rated pain

evaluations.

FDA reviewer comments:

*Severe vomiting reported by 9% of LBup vs. 2%

placebo.

*When taking into account individual NRS scores

for entire study period, the analgesic effect of

LBup is greatest during the first 12 hours and

after that differences become less apparent

between groups. At 8 hrs, both groups have NRS

scores indicating at least moderate pain. By 16 h

hrs, the pain intensity is as if no treatment was

received and rescue pain meds are necessary.

Post-hoc Changes to protocol: Addition of % of

patients receiving no rescue meds through 8,

12,16 and 20 hrs was added. And, “pain free:

was originally defined as a NRS score of 0 but

changed to a NSR score of 0, 1 or 2.

FDA Reviewer Conclusion: Superior to placebo

when used with oxycodone, acetaminophen and

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ketorolac for up to 12 hrs and no more than 24

hrs after surgery. Little risk for ADEs when used

at this dose in this surgical setting.

Gorfine5

Phase 3, R MC, PC,

DB

N=189

Inclusion: Adult men

and women

undergoing 2 or 3

column excisional

hemorrhoidectomy

under general

anesthesia. Patients

had ASA physical

exam status of 1, 2 or

3.

*Sponsored by Pacira

Pharma

Exclusion: medical conditions

believed to interfere with study

including hepatitis, etoh/substance

abuse, uncontrolled psychiatric

disorders, know allergy or

contraindication to amide type local

anesthetics, opioids or propofol. Also,

those with body weight of <50 kg,

participation in other study within 30

days, or taking NSAIDs, APAP,

opioids, antidepressants or

glucocorticoids within 3 days of

surgery.

Intervention: LBup 300 mg/30 mL or

placebo. Infiltrated into 6 sites of the

perianal tissues (surrounding external

sphincter), each injection was 5 mL.

Fentanyl was permitted during

surgery but intraoperative use of other

analgesics was not permitted unless

to treat and ADE.

Rescue meds: MS 10 mg IM every 4-

6 hrs prn for 72 hrs post-op.

Patients were allowed antiemetic

meds or low dose aspirin for CV

protection or platelet inhibition. The

use of any topical rectal meds was

prohibited for 72 hrs. Stool softeners

and laxatives were given prn and sitz

baths were at the discretion of the

surgeon.

Primary: AUC-NRS

score through 72 hrs

(Measured at the end

of anesthesia, before

first dose of MS (if

applicable) and at 1, 2,

4, 8, 12, 24, 36, 48, 60

and 72 hrs post-op)

Secondary:

* Proportion of pts

receiving no rescue

opioid pain med

* Total opioid dose

(mg) through 24, 36,

48, 60 and 72 hrs.

* Time to first rescue

dose

*BPI assessment at 24

and 72 hrs and 30 days

post-op

*Patient’s rating of

satisfaction with post-

op analgesia.

*ADEs

*Caregiver satisfaction

with wound healing.

Patients remained at

study site for 72 hrs.

N=189 randomized, 187 analyzed, 186

completed study. LBup: 94, Placebo: 93

(ASA 3 status: 2.1% and 3.2% placebo)

Mean age in both groups: 48 years

Primary:

AUC-NRS 0-72 hr (LSM): 141.8 LBup

vs. 202.5 placebo (p<0.0001)

Secondary:

*Proportion of pts receiving no rescue

opioids: Significant difference favoring

LBup beginning at 12 hrs through 72 hrs

(p<0.0008). At 72 hrs: 28% LBup vs.

10% for placebo (p=0.0007)

*Total opioid dose: Lower total dose at

each time point through 72 hrs in favor

of LBup vs. placebo (p<0.0001 through

48 hrs, p<0.0003 at 60 hrs and

p<0.0006 at 72 hrs). Total dose of

opioid (MS) consumed by 72hrs: LBup

22.3 mg vs. 29.1 mg Placebo

(p=0.0006).

*Median time to first opioid rescue:

LBup: 14 hr and 20 min vs. 1 hr and 10

min placebo (p<0.0001)

*BPI: At 24 hrs, LBup pts reported less

pain and pain-interference with general

activities vs. placebo (no numbers

provided or statistical significance

values). At 72 hrs, LBup pts reported

less pain-interference with general

activities vs. placebo. At 30 days, no

difference.

*Patient Satisfaction with post-op

analgesia:

LBup: 89/94 (94.7%) were satisfied or

extremely satisfied vs. 68/93 (73.1%)

were satisfied or extremely satisfied with

placebo. (p=0.0007)

*Caregiver satisfaction with wound

healing: No difference

No difference in overall number of ADEs between

groups. Most were mild in severity. Anal

hemorrhage and painful defecation were the most

common ADEs reported.

Anal hemorrhage, painful defecation, vomting

and rectal discharged trended towards a higher

percentage of patients in the placebo group.

Comments/Limitations:

*No active control, only placebo controlled

*Relatively young, healthy population of patients.

Authors cautioned against extrapolation of their

results to settings where other modes of

administration are used (e.g., nerve block,

epidural, etc.) or to broader patient populations.

FDA reviewer comments:

After 24 hrs, there is no difference between

placebo and LBup with regard to the primary

endpoint.

Changes to protocol Post-hoc: an exploratory

analysis was added, the NRS pain intensity

scores were summarized using a wWOCF+

LOCF imputation at each specified time point.

FDA reviewer Conclusion: LBup is effective at

reducing post-op pain following

hemorrhoidectomy at the dose and method of

administration used. Clinical and statistical

differences were observed only during the initial

24 hrs. The dose used could result in plasma

concentrations of bupivacaine that have been

reported to lead to neurotoxic ADEs.

Post-hoc, an exploratory analysis was added:

The NRS pain intensity scores were summarized

using a wWOCF+LOCF imputation at each

specified time point.

Unpublished28

Phase 3, R, MC, DB

N=198

Inclusion: Adult men

and women

undergoing 2 or 3

Exclusion: pregnancy, significant

medical conditions believed to

interfere with study results,

etoh/substance abuse within past 2

yrs, uncontrolled psychiatric

disorders, know allergy or

Primary Endpoint:

AUC-NRS through 96

hrs.

Secondary:

*Total post-op use of

N=198 randomized, LBup=99 pts,

Bupivacaine HCl/epi=99 pts

Primary endpoint:

AUC-NRS (mean): LBup: 393 vs.

Bupivacaine HCl/epi: 359

ADEs were similar between groups.

In the LBUP group, flatulence, abdominal pain,

pyrexia, pruritis, and urinary retention were

reported in >5% vs. only headache was the only

ADE with an incidence >5%.

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

9

column excisional

hemorrhoidectomy

under general or

spinal anesthesia.

Hemorrhoids were

either internal or

internal/external.

Patients had ASA

physical exam status

of 1, 2, 3 or 4.

*Sponsored by Pacira

Pharma

contraindication to amide type local

anesthetics, opioids or propofol or

other pain meds planned for post-op

use. Use of long-acting opioids within

3 days of surgery or any opioid within

24 hrs of surgery. Contraindication to

epinephrine, monoamine oxidase

inhibitors or antidepressants of

tryptyline or imipramine types or

conditions where the production or

exacerbation of tachycardia could

prove fatal or any condition that can

be aggravated by epi. Also, those with

body weight of <50 kg and

participation in other study within 30

days, etc.

Intervention: LBup 300 mg/30 mL or

bupivacaine HCl 100 mg/epi as a

single dose. The dose was infiltrated

into 6 sites of the perianal tissues

(surrounding external sphincter), each

injection was 5 mL. Ketorolac IV or

alternative was given at the end of

surgery.

Rescue meds: No specific details on

rescue opioid protocol. APAP was

given as 1000 mg three times a day

for 4 days as soon as oral meds were

tolerated.

opioids through 12, 24,

36, 48, 60, 72 and 96

hrs

* Proportion of pts

receiving no

supplemental opioids

through same time

periods.

*Pain intensity at each

time point assessed.

*Pain with first BM.

*Time to first post-op

use of opioid.

*Quality of life

questionnaire.

*Time to first

occurrence of PONV.

*PONV free through 96

hrs.

*Discharge readiness.

*Subject’s overall

satisfaction with post-

op analgesia.

*Blinded care providers

satisfaction with post-

op analgesia.

*Time to return to work

or normal daily

activities.

ADEs were monitored

through day 8 and

deaths through 30 d.

Unclear length of stay

at study site.

No significant difference through 96 hrs

(p=0.15).

Secondary measures: (Over 60

secondary endpoints). Not all

summarized in FDA review, only the

following points were made:

*Only two time points differed between

groups and in both periods, differences

favored Bupivacaine HCl over LBup.

(Page 137, FDA reviewer report).

*Study failed to show a difference

between LBup and bupivacaine HCl/epi.

This failure to show a difference was not

only in the primary endpoint but also in

nearly all secondary endpoints

examined.

Comments/Limitations:

Unpublished

FDA reviewer comments:

“The study failed to show any statistically or

clinically meaningful advantage of LBup over

bupivacaine HCl when used after

hemorrhoidectomy despite examining over 60

different efficacy endpoints. Both drugs were

tolerated equally well.”

Changes to protocol Post-hoc: Prior to unbinding,

those sites that enrolled <10 patients were

pooled. Only one site used spinal anesthesia so

that mode of anesthesia was not used in the

model.

FDA reviewer Conclusion:

“The study failed to show any statistically or

clinically meaningful advantage of LBup over

bupivacaine HCl when used after

hemorrhoidectomy despite examining over 60

different efficacy endpoints. Both drugs were

tolerated equally well.”

ADE-adverse drug event, ASA=American Society of Anesthesiologists (1=normal, health, 2=mild systemic disease, 3=severe systemic disease, 4=severe systemic disease that is a

constant threat to life), BM=bowel movement, BPI=brief pain inventory, CV=cardiovascular, DB=double-blind, IM=intramuscular, LBup=liposomal bupivacaine, LSM=least squares

mean, MC-multicenter, NS=not significant Oxy/APAP=oxycodone/acetaminophen, PC-placebo-controlled, PONV=post-op nausea and vomiting, PRN=as needed, R=randomized,

wWOCF+LOCF=windowed worst observation carried forward+last observation carried forward.

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10

Additional Information from FDA Reviewer 28

 In the two pivotal, placebo controlled trials, liposomal bupivacaine provided postoperative analgesia

for up to 24 hours in patients having bunionectormy or hemorrhoidectomy surgery. In these studies,

pain intensity was significantly reduced in patients receiving liposomal bupivacaine compared to

placebo for the initial 12 hours after infiltration, but diminished over the subsequent 12 hours

resulting in no clinical meaningful difference in pain between groups beyond 24 hrs.

 Liposomal bupivacaine was compared to the existing formulation of bupivacaine HCl after

hemorrhoidectomy in a third pivotal, unpublished study. In their review, the FDA medical officer

concluded that based upon the results, investigators failed to show any statistically or clinically

meaningful advantage of liposomal bupivacaine over bupivacaine HCl when used after

hemorrhoidectomy, despite examining over 60 different efficacy endpoints. Both agents were equally

well tolerated.

 The manufacturer did request a priority review. However, that request was denied since the

manufacturer was unable to demonstrate that the use of liposomal bupivacaine reduces the use of

opioids or their associated adverse events or has shown relevant benefit in reduced time to

discharge or return to usual activities.

 Since different doses and manner of administration were used in the two studies, extrapolation of

dosing and effectiveness to other surgical interventions is not possible. Additional studies are

needed to answer the question of appropriate dose and manner of administration for use in other

surgeries.

 Original recommendation was for the labeling to specifically include postoperative use following

bunionectomy or hemorrhoidectomy. The final labeling was less specific.

 Labeling should contain a strong caution against use of liposomal bupivacaine by other

administration routes (other than single-dose, postoperative wound infiltration) that are commonly

used with other local anesthetics in clinical practice but may be unsafe for this product.

 Post-marketing studies are recommended in pediatric patients.

In the phase 3 clinical trials submitted to gain FDA approval, liposomal bupivacaine reduced pain intensity

versus placebo for the first 24 hours in patients following bunionectomy or hemorrhoidectomy. In addition,

opioid use was reduced in favor of liposomal bupivacaine vs. placebo but the clinical relevance of the

difference is unknown (Golf-3.8 vs. 4.7 tabs of oxycodone 5 mg/APAP 325 mg tablets, p=0.008 and Gorfine-

22.3 mg vs. 29.1 mg morphine equivalents, p=0.0006). However, liposomal bupivacaine was not statistically

different from unencapsulated bupivacaine HCl in reducing pain intensity or other secondary outcome

measures in patients following hemorrhoidectomy.

Other published clinical trials

There have been two published phase 2 trials (1-hemorrhoidectomy9, 1-total knee arthroplasty10) and two

published phase 3 trials (1-total knee arthroplasty11, 1-breast augmentation18) comparing the cumulative pain

scores between liposomal bupivacaine and unencapsulated bupivacaine HCl (0.25% with epinephrine

1:200,000). In the phase-2 studies, the primary endpoint of cumulative pain intensity was met in favor of the

liposomal product9,10 but not in the phase-3 studies11,18. However, since the analysis of pain intensity was

determined over the entire planned study length (through 72 hrs or 4 days), the differences at the various

time points were not entirely consistent between studies to determine actually how long the differences

between groups existed or if the differences were clinically important. For example in the pivotal trials,4-5,28

the primary endpoint was reportedly met through 72 hrs but when the FDA reviewer reported their findings,

the statistical difference from placebo was present only through 24 hours, but not beyond. In each of the

studies, sample sizes were small, multiple comparisons between groups at a number of time points were

made with some showing statistical benefit of the liposomal product and others not, and post-hoc changes

were made to the analysis of one of the studies, thereby limiting the strength of the evidence.9 In three of the

studies, there was no statistical or clinically important difference in total consumption of opioids, discharge

readiness, proportion of patients who were opioid free or who were able to return to work or resume normal

daily activities. (Details below)

Bupivacaine Liposome Injectable Suspension Monograph

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11

 In a phase 2, dose-ranging study, 100 patients were randomized to receive liposomal bupivacaine 66

mg, 199 mg, 266 mg or unencapsulated bupivacaine HCl 75 mg (0.25% with 1:200,000 epinephrine)

via local infiltration after hemorrhoidectomy. The primary endpoint was cumulative pain intensity

using the numeric rating scale at rest over 72 hrs (AUC-NRS-R0-72) after surgery. Pain intensity was

reported to be significantly less in the 199 mg and 266 mg liposomal bupivacaine groups vs.

bupivacaine HCl at 72 hrs (p=0.001, p<0.001, respectively). A number of post-hoc changes were

made including the decision to make multiple comparisons (study not powered to do so) between

groups so a Bonferroni correction was made so that statistical significance was achieved only if a p-

value of <0.017 was achieved. In addition, differences between groups in incidence of opioid-related

adverse events were determined, post-hoc. Pain intensity scores with first bowel movement (NRS-

BM) were higher in the bupivacaine HCl vs. the liposomal bupivacaine 199 mg and 266 mg groups

(p=0.003), but the mean NRS-BM scores did not differ between groups. Time to first BM was not

different between groups and ranged from 55-64 hours. No significant between-group differences

were reported for use of rescue opioids or proportion of patients who were opioid free through 72

hours. Time to first rescue opioid was statistically different between bupivacaine HCl and favored

only the 266 mg liposomal bupivacaine group (p=0.005). Post-hoc, no difference in opioid

consumption was observed in the first 12 hours but between 12 and 72 hours after dosing, there was

a difference in favor of the 266 mg group vs. bupivacaine HCl (3.7 mg vs. 10.2 mg, respectively,

p=0.019). Authors noted since the analysis was done post-hoc, they did not apply to Bonferroni

adjustment; otherwise the difference would not have been significant. Finally, no differences were

observed in numbers of patients meeting criteria for discharge at 1, 2 or 3 hours after surgery or in

the proportion of patients that were able to return to work or resume normal activities.9

 In another phase 2, dose-ranging study, 138 adults undergoing total knee arthroplasty (TKA) were

randomly assigned to received liposomal bupivacaine 133 mg, 266 mg or 150 mg of bupivacaine HCl

(0.25% with epinephrine 1:200,000) postoperatively, via local infiltration. Investigators planned three

consecutive cohorts with gradually increasing doses of liposomal bupivacaine to identify a

therapeutic dose for use in patients having TKA and further examine its safety and

pharmacokinetics. Cohort 1 involved the doses listed above randomized 1:1:1; Cohort 2 added a 399

mg dose of liposomal bupivacaine randomized 2:2:5:2; and Cohort 3 added a 532 mg dose of the

liposomal product vs. bupivacaine HCl 150 mg, randomized 5:2. At the end of the surgery, patients

were given a single intravenous dose of ketorolac, ketoprofen or diclofenac. If oral medications were

tolerated, 1000 mg of acetaminophen was given three times a day through 96 hours post-op. The

primary outcome measure was the cumulative pain score with activity through the fourth post-op day

(NRS-A AUC). Mean NRS-A AUC through four days after surgery were all stated to be statistically

different than bupivacaine HCl but the cumulative NRS-A score was numerically lower in the

bupivacaine HCl 150 mg vs. liposomal bupivacaine 133 mg group and differed by only 0.9 vs.

liposomal bupivacaine 266 mg. Although the authors state a significant difference in the primary

endpoint in favor of the liposomal product (results section), presentation of the results is misleading

since they later comment in the conclusion section that a statistical difference was not attained in the

primary endpoint. A number of assessment time periods were favorable for liposomal bupivacaine

vs. bupivacaine HCl. However, the mean NRS score with activity (NRS-A), total consumption of

rescue opioids and time to resuming work or normal activities was not different between groups.10

 Bupivacaine liposomal injectable suspension 532 mg and bupivacaine HCl 200 mg were compared

in a phase 3 study in a primarily female population having total knee arthroplasty. The investigators

found that both groups had similar pain intensity during activity. Total opioid consumption after

surgery and quality of life scores were comparable between groups as well as time to physical

recovery and return to daily activities.11

 In a phase 3 study conducted in patients undergoing breast augmentation, 136 patients were

randomly assigned to bupivacaine liposomal injectable suspension 300 mg in each breast or

bupivacaine HCl 100 mg in each breast. The primary endpoint was the cumulative pain intensity with

activity (NRS-A) through 72 hours post-op. The investigators found that there was no difference in

NRS-A AUC0-72 between groups (liposomal bupivacaine 441.5 vs. bupivacaine HCl 468.2,

p=0.3999). Total opioid consumption was lower through 24 hours (p=0.0211) and just reached

Bupivacaine Liposome Injectable Suspension Monograph

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12

statistical significance at 48 hours (p=0.0459) in favor of the liposomal product. The authors note that

the study was underpowered due to early termination, resulting from administrative reasons

unrelated to safety.18

 A manufacturer sponsored analysis of pooled data from nine placebo or active controlled trials

(several trials are published only as abstracts; some are already detailed above) showed a mean

cumulative pain score through 72 hours that was significantly lower with liposomal bupivacaine vs.

bupivacaine HCl (283 vs. 329, respectively, p=0.039); a median time to first opioid rescue that was

prolonged in the liposomal group (10 vs. 3 hours, p<0.0001) and significantly less opioid consumed

(12 mg vs. 19 mg, p<0.0001) during the study period vs. non-liposomal bupivacaine. As already

mentioned in the text above, some of these endpoints were reviewed post-hoc and alterations to the

study were made during the course of the earlier phase studies. No difference in discharge

readiness, time resuming work or normal activities were reported.30

For further details on the efficacy results of the phase 2 and off-label clinical trials, refer to Appendix: Clinical

Trials

Adverse Events (Safety Data)

Safety and effectiveness of liposomal bupivacaine are dependent upon appropriate dose, administration

technique, taking sufficient precautions and readiness to respond to emergency situations if one arises.

Deaths and Other Serious Adverse Events (Sentinel Events)

No deaths have been reported that are attributable to administration of liposomal bupivacaine.

Common Adverse Events

The most common adverse reactions in wound filtration clinical trials were nausea, constipation, and

vomiting. Overall incidence of these common adverse events with bupivacaine liposomal injectable

suspension and bupivacaine HCl was similar (62% vs. 75%). Severity and frequency were also similar.

Other common adverse reactions, defined as incidence between 2 to 10%, include pyrexia (2%), dizziness

(6%), peripheral edema (2-10%), hemorrhagic anemia (2-10%), hypotension (2-10%), pruritus (3%),

tachycardia (4%), headache (4%), insomnia (2-10%), muscle spasms (2-10%), back pain (2-10%),

somnolence (2-5%), and procedural pain (<2%).

Table 4. Adverse events from pivotal trial data1,4-5

Bupivacaine

liposomal injectable

suspension (8 mL)

4 Placebo

Bupivacaine

liposomal injectable

suspension (30 mL)

5

Placebo

Gastrointestinal

Disorders

42.3% 39.6%

7.4%

13.8%

Nausea 40.2% 37.5%

2.1%

1.1%

Vomiting 27.8% 17.7%

2.1%

4.3%

Constipation 2.1% 1%

2.1%

2.1%

Nervous System

Disorders

20.6% 31.3%

0

0

Dizziness 11.3% 26%

0

0

Headache 5.2% 8.3%

0

0

Somnolence 5.2% 1%

0

0

Bupivacaine Liposome Injectable Suspension Monograph

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13

Skin Disorders 8.2% 7.3%

0

0

Pruitus 3.1% 1%

0

0

Other 5.2% 3.1%

--

--

Increased Alanine

Aminotransferase 3.1% 3.1%

1.1%

0

Increased Aspartate

Aminotransferase 3.1% 2.1%

0

0

Serum Creatinine

Increased

2.1% 0%

0

0

Feeling Hot 2.1% 0%

0

0

Post Procedural

Swelling

2.1% 0%

0

0

Adverse events derived from 2 pivotal studies. Table adapted from product information1

Study 1: Bunionectomy4

Study 2: Hemorrhoiddectomy5

Other Adverse Events1,29

Less common adverse events defined as an incidence of less than 2% were chills, erythema, bradycardia,

anxiety, urinary retention, pain, edema, tremor, dizziness postural, paresthesia, syncope, procedural

hypertension, procedural hypotension, muscular weakness, neck pain, pruritus generalized, rash pruritus,

hyperhidrosis, cold sweat, palpitations, supraventricular extrasystoles, ventricular extrasystoles, ventricular

tachycardia, anxiety, confusion, depression, agitation, restlessness, hypoxia, laryngospasm, apnea,

respiratory failure, body temperature increase, oxygen saturation decreased, urinary retention, urinary

incontinence, blurry vision, tinnitus, and hypersensitivity.

Tolerability

Bupivacaine liposomal injectable suspension is generally well tolerated. Common adverse events were

mostly assessed as mild or moderate severity2,29. When compared directly to unencapsulated bupivacaine

HCl, liposomal bupivacaine was equally well tolerated.

For further details on safety results of the clinical trials, refer to Appendix: Clinical Trials.

Contraindications

Use of Bupivacaine liposomal injectable suspension is contraindicated in the setting of obstetrical

paracervical block anesthesia. Bupivacaine liposomal injectable suspension has not been tested using this

technique; however, administration of bupivacaine HCl with this technique has resulted in fetal bradycardia

and death1.

Warnings and Precautions

Potential life-threatening adverse effects: Bupivacaine liposomal injectable suspension should be

administered in a setting where trained personnel and equipment are available to promptly treat patients

displaying evidence of neurological or cardiac toxicity. Cardiovascular, respiratory, and neurological status,

as well as vital signs should be monitored during and after administration.

Central Nervous System Reactions: The occurrence of neurologic adverse events with local anesthetics is

related to the total dose administered. However, other factors may increase the incidence and include the

specific anesthetic used, the route of administration and the patient’s health status. Early signs of central

Bupivacaine Liposome Injectable Suspension Monograph

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14

nervous system toxicity include restlessness, anxiety, incoherent speech, lightheadedness, numbness,

tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, twitching, tremors, depression,

or drowsiness. Symptoms may proceed to convulsion, followed by unconsciousness and respiratory arrest.

Incidence of convulsions is associated with total dose administered and varies with procedure. Local

anesthetics have been associated with localized neurological toxicity, which encompasses numbness,

weakness, and paralysis, and may be slow to resolve or be partially or completely irreversible.

From the clinical trials involving wound infiltration with liposomal bupivacaine, the following neurologic

adverse events were reported with an incidence of at least 1%: dizziness (6.2%), headache (3.8%),

somnolence (2.1%) and lethargy (1.3%)1.

Cardiovascular System Reactions: Toxic blood concentrations depress cardiac conductivity and

excitability leading to atrioventricular block, ventricular arrhythmias, cardiac arrest, and fatalities. Myocardial

contractility is depressed and peripheral vasodilation, decreased cardiac output, and decreased arterial blood

pressure can result.

An analysis, involving a number of clinical trials, was conducted to determine if wound infiltration with

liposomal bupivacaine led to clinically important electrocardiogram (ECG) changes or cardiac related

adverse events. In the analysis, no cardiac safety issues were identified22. In all the wound infiltration studies

involving liposomal bupivacaine, adverse cardiac events reported with an incidence of at least 1% were as

follows: tachycardia (3.9%) and bradycardia (1.6%)1.

Cardiovascular disease: Use with caution in patients with cardiovascular disease including patients with

hypotension or heart block since they may be less capable of compensating for functional changes

associated with prolongation of AV conduction.

Hepatic impairment: Use with caution in hepatic impairment since bupivacaine is hepatically metabolized.

Patients with severe hepatic impairment are at a greater risk of developing toxic plasma concentrations.

Multiple doses: Injections of multiple doses of bupivacaine liposomal injectable suspension may cause

significant increases in plasma concentration due to slow accumulation or slow metabolic degradation.

Hypersensitivity: Systemic hypersensitivity reactions have been reported. These reactions are rare, and

may include urticaria, pruritus, angioneurotic edema, tachycardia, sneezing, and possibly anaphylactoid-like

symptoms.

Accidental intravascular injection: Avoid accidental intravascular injection. Convulsions and cardiac arrest

have been reported with intravascular injection of bupivacaine.

Other local anesthetics: Wait 96 hours after administration of bupivacaine liposomal injectable suspension

before administering other bupivacaine products. Use of bupivacaine liposomal injectable suspension and

other bupivacaine containing products has not been studied. Wait at least 20 minutes after administration of

local lidocaine to administer bupivacaine liposomal injectable suspension

Pre-incisional or pre-procedural anesthetic techniques: Bupivacaine liposomal injectable suspension is

not indicated for pre-incisional or pre-procedural loco-regional anesthetic techniques that require deep and

complete sensory block in the area of administration.

Administration: Epidural, intrathecal, regional nerve block and intravascular or intra-articular routes of

administration or types of analgesia have not been evaluated for liposomal bupivacaine and therefore are not

recommended.

Chondrolysis: Intra-articular infusions of local anesthetics have been described in post marketing reports,

and have resulted in chondrolysis. There have been case reports of chondrolysis from local, single-dose use

of bupivacaine dating back to 1979 due to intra-articular administration. Intra-articular use of liposomal

bupivacaine has not been evaluated and is not recommended.

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15

Special Populations

Safety and effectiveness of liposomal bupivacaine has not been evaluated in patients below the age of 18

years old, pregnant patients, or patients who are nursing1.

Pregnancy: Category C. Bupivacaine liposomal injectable suspension has not been studied in adequate,

well-controlled studies in pregnant women of the effect on the developing fetus. Only consider bupivacaine

liposomal injectable suspension during pregnancy if potential benefits justify the risk to the fetus.

Bupivacaine HCl was administered subcutaneously to rats during fetal organogenesis and no embryo-fetal

effects were observed in rats at high doses. Administration during pregnancy and lactation resulted in

decreased offspring survival. Studies in rabbits showed an increase in embryo-fetal deaths at high doses in

the absence of maternal toxicity1-3.

Nursing mothers: Bupivacaine is excreted to some extent during lactation. A theoretical potential exists for

a nursing infant to be exposed to the drug and is therefore, not recommended.

Pediatric: Bupivacaine liposomal injectable suspension safety and effectiveness has not been established in

patients below the age of 18 years old.

Geriatric: In the bupivacaine liposomal injectable suspension wound infiltration clinical studies, no overall

difference was found for safety or effectiveness between patients greater than 65 years of age and younger

patients. A total number of 171 patients of 823 (20.8%) were greater than 65 years old. Although clinical

experience has not identified differences between these populations, greater sensitivity in some older

individuals cannot be ruled out. Bupivacaine liposomal injectable suspension is excreted by the kidneys;

elderly patients are more likely to be at risk of toxicities as they are more likely to have decreased renal

function1.

Hepatic Impairment: Bupivacaine liposomal injectable suspension is metabolized by the liver and should be

used with caution in patients with hepatic impairment. Patients with severe hepatic disease are at greater risk

of toxic plasma concentrations. In patients with moderate hepatic impairment, mean plasma concentrations

were higher than in healthy control volunteers with approximately 1.5 and 1.6 fold increases in mean Cmax

and AUC, respectively. However, there are no dosage adjustments for hepatic impairment provided in the

manufacturer’s labeling.

Table 6. Role of hepatic function on bupivacaine pharmacokinetics after bupivacaine liposomal

injectable suspension administration2

Mean (Standard

Deviation)

Moderate hepatic

impairment (n=9)

Normal hepatic function

(n=9)

Cmax (ng/mL)

149.1 (42.6)

102.8 (37.7)

Tmax (h)

42.7 (28.2)

54.7 (28.8)

AUCl0-last) (h • ng/mL)

17,177.8 (2349.3)

10,682.7 (4392.6)

AUCl0-∞) (h • ng/mL)

17,975.5 (2447.0) 11,050.7 (4498.8)

Half-life (h)

46.5 (26.3)

37.6 (9.8)

Cl/F (L/h)

17.0 (2.2)

31.2 (11.5)

Vd/F (L)

1131.6 (624.4)

1742.1 (861.9)

Renal Impairment: Bupivacaine liposomal injectable suspension is excreted by the kidneys. Caution should

be used in patients with impaired renal function due to the potential risk of toxic concentrations. No dosage

adjustment is provided in the manufacturer’s labeling for patients with renal impairment. However, the

manufacturer indicates that care should be taken in proper dose selection in these patients. There are no

studies examining the use of bupivacaine liposomal injectable suspension in patients on dialysis.

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

16

Sentinel Events

There are no sentinel events that have been reported in association with bupivacaine liposomal injectable

suspension.

Look-alike / Sound-alike (LA / SA) Error Risk Potential

As part of the Joint Commission standards, LA/SA names are assessed during the formulary selection of

drugs. Based on clinical judgment and an evaluation of LA/SA information from three data sources (Lexi-

Comp, First Databank, and ISMP Confused Drug Name List), the following drug names may cause LASA

confusion:

LA/SA for generic name bupivacaine liposome injectable suspension2:

 Mepivacaine

 Ropivacaine

 Non-liposomal bupivacaine (bupivacaine HCl)

 Buprenorphine

 Benzocaine

Bupivacaine liposomal may be confused with propofol due to similar white, milky appearance. Of

note: This is on the ISMP high alert list of drug classes which have a heightened risk of causing

significant patient harm when used in error.31

Accidental administration of Bupivacaine liposomal injectable suspension intravenously may result in

atrioventricular block, ventricular arrhythmias, and cardiac arrest. No errors had been reported to the FDA by

the manufacturer as of March 2012, however, it is recommended that prepared syringes be properly labeled,

vials separated, and directions for managing bupivacaine toxicity be available3.

LA/SA for trade name Exparel

 Eldepryl

 Extavia

 Enalapril

 Estriol

 Enbrel

 Exterol

 Isuprel

Drug Interactions

Drug-Drug Interactions

 If diluting, only dilute using sterile, preservative-free normal (0.9%) saline for injection. DO NOT

dilute with water or other hypotonic agents as these may disrupt the liposomal structure.

 Do not mix with other drugs prior to administration due to possible free drug rapid release from

liposomes with direct contact.

 Do not admix bupivacaine liposomal injectable suspension with any other product in the same

syringe.

 If concurrently using with locally administered drugs or antiseptics, allow site to dry completely before

administration.

Lidocaine and Other Non-Bupivacaine-Based Local Anesthetics

If administered together locally, non-bupivacaine based local anesthetics (i.e. lidocaine, ropivacaine,

mepivacaine) may cause an immediate displacement of the bupivacaine from the multivesicular liposomes,

potentially affecting the efficacy and safety of the product. This displacement is the result of increased affinity

of non-bupivacaine based local anesthetics to the liposomes.

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

17

Local administration of bupivacaine liposomal injectable suspension and lidocaine should be separated by at

least 20 minutes to negate any displacement and avoid an interaction. Bupivacaine liposomal injectable

suspension can be administered in the same area at least 20 minutes after local administration of lidocaine.

If the time between lidocaine and bupivacaine liposomal injectable suspension is 5 minutes, 10 minutes, 20

minutes; then the plasma bupivacaine Cmax increases by 100%, 67%, or 0%, respectively.

Bupivacaine HCl

Other formulations of bupivacaine should not be administered within 96 hours following administration of

bupivacaine liposomal.

Topical Antiseptics

Because of the surfactant properties of topical antiseptics (e.g., povidone iodine or chlorhexidine), skin

surface should be allowed to dry completely prior to administration of bupivacaine liposomal injectable

suspension.

Coadministration2

The following medications have shown minor to no interaction with Bupivacaine liposomal injectable

suspension and can be co-administered at the same infiltration area: corticosteroids, gentamicin, bacitracin,

cefazolin, ketorolac, and opioids.

Acquisition Cost

Refer to VA pricing sources for updated information.

Pharmacoeconomic Analysis

There are a number of trials that are planned or underway to determine the economic advantage of

bupivacaine liposomal and can be viewed on the clinicaltrials.gov website. However, there is one published

economic trial in adult patients having open colectomy. This trial is a single-center, open-label,

nonrandomized trial in 39 patients. Patients were sequentially assigned to the first cohort of patient controlled

analgesia (PCA) with opioids until the patient was discharged or able to tolerate oral medication (then

received oxycodone alone or combined with acetaminophen) (n=18). The second cohort was enrolled once

the first cohort was fully enrolled. In the second cohort, patients received “multimodal therapy” which

included receipt of a single dose of liposomal bupivacaine 266 mg administered into the surgical site prior to

wound closure (n=21). This cohort also received ketorolac 30 mg (or other NSAID) at the end of surgery

followed by 1000 mg of acetaminophen and ibuprofen 600 mg every 6 hours for 72 hours after surgery;

starting once patients were able to take oral medications. Both groups were offered rescue analgesia with IV

opioids or oxycodone 5 mg/acetaminophen 325 mg every 6 hours if needed until discharge. There were

three primary outcome measures including total mg amount of morphine equivalents post surgery through

discharge; total hospitalization cost; and length of hospital stay. Although there was a difference in total mg

amount of opioid consumed (57 mg vs. 115 mg) in favor of liposomal bupivacaine (Cohort 2), there were too

many variables since the groups did not receive the same standard baseline pain regimen post-op. Cohort 1

received an opioid-based PCA as their analgesic regimen while Cohort 2 received IV ketorolac 30 mg post-

op and scheduled dosing of maximum daily doses of acetaminophen and ibuprofen as their analgesic

regimen. The study design does not allow for concluding that the difference in mg amount of opioid was due

to use of liposomal bupivacaine. Costs and length of stay were also different in favor of liposomal

bupivacaine but since the post-op analgesia regimens were not matched, and Cohort 1 involved the use of

PCA, the cost difference of using a PCA pump vs. oral medications could account for the difference. There

were no differences in hospital readmission, unplanned visits or contact to medical provider, or health

problems after discharge. The primary limitation of the study was in its design. It was a single-center, open-

label, nonrandomized study with a small sample size and included too many variables to draw any

conclusions about the findings27.

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

18

Conclusions

Bupivacaine liposomal injectable suspension (Exparel) is an amide-type local anesthetic in an

encapsulated liposomal formulation developed with the goal of providing a longer duration of anesthesia

compared with its non-liposomal counterpart, bupivacaine hydrochloride or other local anesthetics. The

product utilizes the DepoFoam drug delivery system consisting of an aqueous suspension of multivesicular

liposomes containing bupivacaine in a honeycomb-like structure that allows for a more gradual release. The

FDA approved it in October 2011 for single-dose infiltration into the surgical site for postoperative analgesia.

To date, there have been a limited number of published clinical trials evaluating the safety and efficacy of

liposomal bupivacaine. Three were phase 3 pivotal trials reviewed by the FDA for final approval, two of them

comparing liposomal bupivacaine to placebo and one comparing liposomal bupivacaine to unencapsulated

bupivacaine HCl/epinephrine (unpublished). In each of the trials, the primary endpoint was pain intensity and

duration using the numeric pain rating score through a predetermined period of time postoperatively (24, 72

and 96 hrs). In the placebo-controlled trials (1-bunionectomy, 1-hemorrhoidectomy) liposomal bupivacaine

was associated with statistically less intense pain through the stated time period compared to placebo. In

addition, opioid consumption was statistically less in favor of liposomal bupivacaine versus placebo, but the

clinical relevance of the difference is unknown (Golf-3.8 vs. 4.7 tabs of oxycodone 5 mg/APAP 325 mg

tablets at 24 hrs, p=0.008 and Gorfine-22.3 mg vs. 29.1 mg morphine equivalents at 72 hrs, p=0.0006). In an

unpublished study, liposomal bupivacaine was not statistically different from unencapsulated bupivacaine

HCl/epinephrine in reducing pain intensity through the specified time points or other secondary outcome

measures in patients following hemorrhoidectomy. The FDA reviewer highlighted some important points

regarding the results of these three trials as follows:

 In the two pivotal, placebo controlled trials, liposomal bupivacaine provided postoperative analgesia for up to 24

hours in patients having bunionectormy or hemorrhoidectomy surgery. In these studies, pain intensity was

significantly reduced in patients receiving liposomal bupivacaine compared to placebo for the initial 12 hours after

infiltration, but diminished over the subsequent 12 hours resulting in no clinical meaningful difference in pain

between groups beyond 24 hrs.

 Unpublished, active comparison: Based upon the results, investigators failed to show any statistically or clinically

meaningful advantage of liposomal bupivacaine over bupivacaine HCl when used after hemorrhoidectomy, despite

examining over 60 different efficacy endpoints. Both agents were equally well tolerated.

 The manufacturer did request a priority review. However, that request was denied since the manufacturer was

unable to demonstrate that the use of liposomal bupivacaine reduces the use of opioids or their associated adverse

events or has shown relevant benefit in reduced time to discharge or return to usual activities.

 Since different doses and manner of administration were used in the two studies, extrapolation of dosing and

effectiveness to other surgical interventions is not possible. Additional studies are needed to answer the question of

appropriate dose and manner of administration for use in other surgeries.

 Original recommendation was for the labeling to specifically include postoperative use following bunionectomy or

hemorrhoidectomy. The final labeling was less specific.

 Labeling should contain a strong caution against use of liposomal bupivacaine by other administration routes (other

than single-dose, postoperative wound infiltration) that are commonly used with other local anesthetics in clinical

practice but may be unsafe for this product.

As for other studies, there have been two published phase 2 trials (1-hemorrhoidectomy9, 1-total knee

arthroplasty10) and two phase 3 trials (1-total knee arthroplasty11, 1-breast augmentation18) comparing the

cumulative pain scores between liposomal bupivacaine and unencapsulated bupivacaine HCl (0.25% with

epinephrine 1:200,000). In the phase-2 studies, the primary endpoint of cumulative pain intensity was met in

favor of the liposomal product9,10 but not in the phase-3 studies18. However, since the analysis of pain

intensity was determined over the entire planned study length (through 72 hrs or 4 days), the differences at

the various time points were not entirely consistent between studies to determine the actual length of time

the differences between groups existed or if the differences were clinically important. For example in the

pivotal trials, the primary endpoint was reportedly met through 72 hrs but when the FDA reviewer reported

their findings, the statistical difference from placebo was present only through 24 hours, but not beyond. In

each of the studies, sample sizes were small, multiple comparisons between groups at a number of time

points were made with some showing statistical benefit of the liposomal product and others not, and post-hoc

changes were made to the analysis of one of the studies, thereby limiting the strength of the evidence9. In

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

19

three of the studies, there was no statistical or clinically important difference in total consumption of opioids,

discharge readiness, proportion of patients who were opioid free or who were able to return to work or

resume normal daily activities.

With regard to safety, liposomal bupivacaine was well tolerated and adverse events were not significantly

different than bupivacaine HCl/epinephrine or placebo when administered as a single-dose infiltrated into the

surgical site after bunionectomy or hemorrhoidectomy. The most common adverse events reported with

bupivacaine liposomal injectable suspension were constipation, nausea, and vomiting. Similar to other local

anesthetics, there is a potential for neurologic or cardiovascular adverse events and is related to the total

dose administered. However, other factors may increase the incidence and include the specific anesthetic

used, the route of administration and the patient’s health status. Early signs of central nervous system

toxicity include restlessness, anxiety, incoherent speech, lightheadedness, numbness, tingling of the mouth

and lips, metallic taste, tinnitus, dizziness, blurred vision, twitching, tremors, depression, or drowsiness.

Since liposomal bupivacaine has not been studied or data are limited in patients undergoing other types of

surgery (aside from bunionectomy or hemorrhoidectomy), the safety, efficacy and appropriate doses of

liposomal bupivacaine are not known and therefore, use after other surgeries is not recommended.

Furthermore, other routes of administration or types of analgesia have not been studied and therefore, use is

not recommended (e.g., epidural, intrathecal, regional nerve block or intravascular or intra-articular use).

Although liposomal bupivacaine statistically reduced pain intensity in patients undergoing bunionectomy or

hemorrhoidectomy when compared to placebo, there was no difference in the primary outcome or secondary

outcomes when compared to traditional unencapsulated bupivacaine HCl in an unpublished phase 3 pivotal

trial in patients undergoing hemorrhoidectomy. In two phase 2, dose-ranging studies, liposomal bupivacaine

was associated with improved cumulative pain scores compared to bupivacaine HCl but differences in total

consumption of opioids, readiness for discharge, proportion of patients who were opioid free or who were

able to return to work or resume normal activities were not different between the two bupivacaine products.

Since the safety and efficacy of liposomal bupivacaine has been evaluated primarily in patients undergoing

hemorrhoidectomy or bunionectomy (using a single-dose infiltrated into the surgical site), the safety and

efficacy when used after other surgeries; by other routes of administration; or use for other types of

analgesia are unknown and therefore, use is not recommended in these settings. Based on the existing

evidence, there are no clear or substantive advantages of the liposomal bupivacaine product over

bupivacaine HCl. To date, there are no clinical trials comparing liposomal bupivacaine to other local

anesthetic agents and therefore any clinically important advantages or disadvantages of the liposomal

product are unknown.

References

1. Product Information: BUPIVACAINE LIPOSOME (EXPAREL)™ injection suspension, bupivacaine

liposome injection suspension. Pacira Pharmaceuticals, Inc. (per Manufacturer), San Diego, CA,

2011.

2. BUPIVACAINE LIPOSOME (EXPAREL) (bupivacine liposome injectable suspension). AMCP

Dossier. Pacira. June 6, 2012.

3. Lexi-Comp, Inc. (Lexi-DrugsTM). Lexi-Comp, Inc.; May 4, 2012.

4. Golf M, Daniels SE, Onel E. A phase 3, randomized, placebo-controlled trial of DepoFoam

bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther. Sep

2011;28(9):776-788.

5. Gorfine SR, Onel E, Patou G, Krivokapic ZV. Bupivacaine extended release liposome injection for

prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: A multicenter,

randomized, double-blind, placebo-controlled trial. Dis Colon Rectum. Dec 2011;54(12):1552-1559.

6. Bergese S, Smoot JD, Williams HT. Bupivacaine liposome (Exparel) (bupivacaine extended-release

liposome injection), an investigational analgesic, provides postsurgical pain relief and decreased

opioid use as demonstrated by integrated analysis. 26th Annual Meeting of the Society for

Ambulatory Anesthesia. San Antonio, TX; 2011.

7. Minkowitz H, Onel E, Patronella C, Smoot JD. A 2-year observational study assessing the safety of

DepoFoam bupivacaine after augmentation mammoplasty. Aesthet Surg J 2012; 32:186-193.

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

20

8. Pacira Pharmaceuticals Inc. Clinical trial no. SKY0402-C-203. A phase 2, multicenter, randomized,

double-blind, dose-escalating/de-escalating study to evaluate the safety, efficacy, and

pharmacokinetics of sustained-release encapsulated bupivacaine (SKY0402) administered as a

nerve block in the management of postoperative pain in subjects undergoing bunionectomy. Data on

file.

9. Haas E, Onel E, Miller H, Ragupathi M, White PF. A double-blind, randomized, active controlled

study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local

analgesic formulation. American Surgeon 2012;78:574-581.

10. Bramlett K, Onel E, Viscusi ER, Jones K. A randomized, double-blind, dose-ranging study comparing

wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to

bupivacaine HCl for postsurgical analgesia in total knee arthroplasty. The Knee 2012;19:530-536.

11. Pacira Pharmaceuticals Inc. Clinical trial SIMPLE TKA 311. A phase 3, multicenter, randomized,

double-blind, parallel-group, active-control study to evaluate the safety and efficacy of a single

intraoperative administration of SKY0402 for prolonged postoperative analgesia in subjects

undergoing total knee arthroplasty (TKA) Data on file.

12. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national

survey suggest postoperative pain continues to be undermanaged. Anesth Analg. Aug

2003;97(2):534-540, table of contents.

13. Warfield CA, Kahn CH. Acute pain management. Programs in U.S. hospitals and experiences and

attitudes among U.S. adults. Anesthesiology. Nov 1995;83(5):1090-1094.

14. Beauregard L, Pomp A, Choiniere M. Severity and impact of pain after day surgery. Can J Anaesth.

Apr 1998;45(4):304-311.

15. Gramke HF, de Rijke JM, van Kleef M, et al. The prevalence of postoperative pain in a

crosssectional group of patients after day-case surgery in a university hospital. Clin J Pain. Jul-Aug

2007;23(6):543-548.

16. Lynch EP, Lazor MA, Gellis JE, Orav J, Goldman L, Marcantonio ER. Patient experience of pain

after elective noncardiac surgery. Anesth Analg. Jul 1997;85(1):117-123.

17. Ashburn MA, Caplan RA, Carr DB, et al. Practice guidelines for acute pain management in the

perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on

Acute Pain Management. Anesthesiology. Jun 2004;100(6):1573-1581.

18. Smoot JD, Bergese SD, Onel E, Williams HT, Hedden W. The efficacy and safety of DepoFoam

bupivacaine in patients undergoing bilateral, cosmetic, submuscular augmentation mammaplasty: A

randomized, double blind, active control study. Aesthet Surg J. Jan 1 2012;32(1):69-76.

19. Clinical Trials.gov: A service of the U.S. National Institutes of Health. A Health Economic Trial in

Adult Patients Undergoing Ileostomy Reversal. Last update Feb 2012.

20. Clinical Trials.gov: A service of the U.S. National Institutes of Health. A Phase 3b Health Economic

Trial in Adult Patients Undergoing Laparoscopic Colectomy. Last update Apr 2012.

21. Clinical Trials.gov: A service of the U.S. National Institutes of Health. Evaluation of the Safety and

Efficacy of EXPAREL When Administered by Infiltration Into the Transversus Abdominis Plane (TAP)

for Prolonged Postsurgical Analgesia in Subjects Undergoing Robot-assisted Laparoscopic

Prostatectomy. Last updated My 2013.

22. Bergese SD, Onel E, Morren M, Morganroth J Bupivacaine extended-release liposome injection

exhibits a favorable cardiac safety profile.. Department of Anesthesiology, Ohio State University,

Columbus, OH 43210, USA. Reg Anesth Pain Med. 2012 Mar;37(2):145-51.

23. Davidson EM, Barenholz Y, Cohen R, Haroutiunian S, Kagan L, Ginosar Y. High-Dose Bupivacaine

Remotely Loaded into Multivesicular Liposomes Demonstrates Slow Drug Release Without Systemic

Toxic Plasma Concentrations After Subcutaneous Administration in Humans. Anesth Analg. 2010

Apr 1;110(4):1018-23.

24. Viscusi ER, Candiotti KA, Onel E, Morren M, Ludbrook GL The pharmacokinetics and

pharmacodynamics of liposome bupivacaine administered via a single epidural injection to healthy

volunteers.. Reg Anesth Pain Med. 2012 Nov-Dec;37(6):616-22.

25. Naseem A, Harada T, Wang D et al. Bupivacaine extended release liposome injection does not

prolong QTc interval in a thorough QT/QTc study in healthy volunteers. J Clin Pharmacol 2011.

26. Bergese S, Ramamoorthy S, Patou G, et al. Efficacy profile of liposome bupivacaine, a novel

formulation of bupivacaine for postsurgical analgesia. J Pain Res 2012;5:107–116.

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

21

27. Cohen, SM et al. Extended pain relief trial utilizing infiltration of Exparel, a long acting formulation of

bupivacaine: a Phase IV health economic trial in adult patients undergoing open colectomy. J Pain

Res 2012; 11:567-572.

28. Simone, A. Clinical Review of Exparel (bupivacaine). Available at:

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022496Orig1s000MedR.pdf

29. Viscusi ER, Sinatra R, Onel E, Ramamoorthy SL. The Safety of Liposome Bupivacaine, A Novel

Local Analgesic Formulation. Clin J Pain 2013;Feb 26. Epub ahead of print.

30. Dasta J, Ramamoorthy S, Patou G, Sinatra R. Bupivacaine Liposome Injectable Suspension

Compared with Bupivacaine HCl for the Reduction of Opioid Burden in the Postsurgical Setting. Curr

Med Res Opin 2012;28:1609-1615.

31.

Ex parel Alert

PDF.pdf

Prepared by Kim Schnacky, Pharm.D. And Cathy Kelley, Pharm.D. Catherine.kelley@va.gov

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

21

27. Cohen, SM et al. Extended pain relief trial utilizing infiltration of Exparel, a long acting formulation of

bupivacaine: a Phase IV health economic trial in adult patients undergoing open colectomy. J Pain

Res 2012; 11:567-572.

28. Simone, A. Clinical Review of Exparel (bupivacaine). Available at:

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022496Orig1s000MedR.pdf

29. Viscusi ER, Sinatra R, Onel E, Ramamoorthy SL. The Safety of Liposome Bupivacaine, A Novel

Local Analgesic Formulation. Clin J Pain 2013;Feb 26. Epub ahead of print.

30. Dasta J, Ramamoorthy S, Patou G, Sinatra R. Bupivacaine Liposome Injectable Suspension

Compared with Bupivacaine HCl for the Reduction of Opioid Burden in the Postsurgical Setting. Curr

Med Res Opin 2012;28:1609-1615.

31.

Ex parel Alert

PDF.pdf

Prepared by Kim Schnacky, Pharm.D. And Cathy Kelley, Pharm.D. Catherine.kelley@va.gov

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

22

Appendix 1.

A literature search using PubMed/Medline and Google Scholar was conducted using the following search terms: “bupivacaine”, “sustained release encapsulate

bupivacaine”, “liposome bupivacaine,” “bupivacaine liposomal injectable suspension,” “post-surgical analgesia”, “local anesthetic and pain relief”, “liposome

anesthetic” and “Exparel”. Reference lists of selected articles related to bupivacaine and the product dossier were also used to identify additional sources of

data. Published clinical trials examining the efficacy and/or safety of bupivacaine in humans and for approved indications were included. Included studies were

limited to English language. All randomized controlled trials were published in the manufacturer’s New Drug Application to the FDA.

Clinical Trials (Phase-2 and Off-Label) Evidence Summary Table

Ref. and Evidence

Grade

Drug

Regimens

N

Time

Demographics

Design*

End Points/Results/Comments

Bupivacaine ER Liposome

Injection Exhibits a Favorable

Cardiac Safety Profile.

Bergese SD, et al. 22

A. Exparel® 532

mg SC

B. Exparel® 655

mg SC

16

---

---

· R

· OL

· Seq

· No change from baseline in QtcI of >60 msec with any dose of EXPAREL

High-Dose Bupivacaine Remotely

Loaded into Multivesicular

Liposomes Demonstrates Slow

Drug Release Without Systemic

Toxic Plasma Concentrations After

Subcutaneous Administration in

Humans.

Davidson EM, et al.

23

A. Exparel® 400

mg

B. Bupivacaine HCl

200 mg

8

8 days

· Adults (age 18-45

years)

· Within 20% of IBW

·

No medications in past

week

· OL

· CO

· Peak plasma bupivacaine concentrations were similar in the two groups, despite a 4-

fold increase in total bupivacaine dose administered with the novel liposomal

preparation

· Administration of 0.5%, 1%, &

2% LMVV bupivacaine provided 19, 38, & 48 hours of

analgesia, respectively, compared to 1 hour for the standard 0.5% bupivacaine control

The Pharmacokinetics and

Pharmacodynamics of Liposome

Bupivacaine Administered via a

Single Epidural Injection.

Viscusi ER, et al.34

A. Exparel® 89 mg

B. Exparel® 155

mg

C. Exparel® 266

mg

D. Bupivacaine HCl

50 mg

30

96 hours

· Adults (age 18-49

years)

· BMI <35 kg/m2

· 100% male

· 100% white

· R

· DB

· AC

· Seq

· All doses of Exparel® exhibited significantly greater AUC

0-

t

last

and AUC

0-[infinity]

than

bupivacaine HCl and a longer Tmax

· P<0.001

· Mean Cmax values in the Exparel® 89 mg & 155 mg groups were statistically

significantly lower than the Cmax values for bupivacaine HCl

· P<0.001

· Mean Cmax after administration of Exparel® 266 mg was not statistically significantly

different from bupivacaine HCl 50 mg

· Half-life was similar across the Exparel® groups (14.0-19.3 hours) & ~3x longer than

bupivacaine HCl (5.7 hours)

A 2 Year Observational Study

Assessing the Safety of DepoFoam

Bupivacaine after Augmentation

Study 1:

A. Exparel® 133

mg or 266 mg in

94

Mean 15-

21 months

· Adults (mean age 31.5

y)

· MC

· O

· Long‐term safety follow‐up: Most (>90%) subjects had no change in breast size or

shape or changes in skin or nipple. When noted, such changes were most commonly

attributed to scar contracture.

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

23

Mammoplasty.

Minkowitz H, et al.7

one

breast pocket

B. Bupivacaine HCl

75 mg in the

contralateral side

Study 2:

A. Exparel® 266

mg in each side

(total

dose 532 mg)

B. Bupivacaine HCl

100 mg in each

side (total dose

200 mg)

· Underwent bilateral

cosmetic, submuscular

breast augmentation

· Participated in

previous studies (Smoot

2012, Minkowitz 2012)

· 87.2% white

· In study 1, the incidence of uneven appearance of breasts was low (16.1% for

EXPAREL and 6.3% for bupivacaine HCl; mean time to appearance 7.18 and 14.19

months, respectively), and the difference between the groups was not likely to be

clinically significant.

· In study 2, one bupivacaine HCl recipient had uneven appearance of breasts at

approximately 12 months. There were no reports of palpable hard knots or swelling, and

one report of signs of irritation or implant leakage. There was no clear evidence that

either EXPAREL or bupivacaine HCl was associated with changes in sensation or any

other abnormal finding.

A Phase 2, Multicenter,

Randomized, Double-Blind, Dose-

Escalating/De-Escalating Study to

Evaluate the Safety, Efficacy, and

Pharmacokinetics of Sustained-

Release Encapsulated Bupivacaine

Administered as a Nerve Block in

the Management of Postoperative

Pain in Subjects Undergoing

Bunionectomy.

Pacira Pharmaceuticals, Inc: Data on

File8

A. Exparel® 155

mg

B. Exparel® 200

mg

C. Exparel® 244

mg

D. Exparel® 279

mg

E. Exparel® 310

mg

F. Bupivacaine HCl

125 mg

58

96 hours

· Adults (mean age 52-

59 years)

· Undergoing

a unilateral first

metatarsal

bunionectomy repair

· Under general

Anesthesia

· >90% white

· 57-92% female

· MC

· R

· DB

· PG

· AC

· Primary: Median time to first use of supplemental postsurgical pain medication

(opioid or nonopioid) significantly longer for bupivacaine HCl vs EXPAREL 200 mg

(9.42 vs 1.24 h); no significant difference vs EXPAREL 155 mg (1.94 h) and 310 mg

(2.43 h)

· P<0.001; P>0.05

· Secondary: Median time to first supplemental

postsurgical opioid medication was 96 hours for all treatment groups except EXPAREL

200 mg (7.3 h)

· P>0.05

· Secondary: 33.3% to 64.3% of EXPAREL recipients and 55% of bupivacaine HCl

recipients did not take supplemental opioid medication

· P>0.05

· Secondary: The quantity of supplemental opioid

medication used postsurgically was similar for

EXPAREL 310 mg vs bupivacaine HCl, with an adjusted mean ratio of 0.86 (95% CI

0.25, 3.00). Adjusted mean ratios for EXPAREL 155 mg and 200 mg vs bupivacaine

HCl were 1.37 (95% CI 0.37, 5.37) and 2.56 (95% CI 0.69, 9.49), respectively.

· Secondary: VAS‐A and VAS‐R scores higher in all

EXPAREL groups vs bupivacaine HCl for the first 12 h, but generally lower with

EXPAREL 310 mg vs bupivacaine HCl from 24 to 96 h

· P>0.05

· Secondary: Integrated assessment of VAS scores and total opioid usage showed a

lower effect for EXPAREL 155 mg and 200 mg vs bupivacaine HCl throughout the 96‐h

assessment period, and a better effect for EXPAREL 310 mg vs bupivacaine HCl after

12 h; integrated assessment AUC0‐96 for EXPAREL 310 mg was better (> 4‐fold

greater) than bupivacaine HCl at rest and slightly worse (25% lower AUC) with activity,

but no significant differences between the 2 treatment groups at any time point.

· P>0.05

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

24

A Double-Blind Randomized,

Active Controlled Study for Post-

Hemorrhoidectomy pain

Management with DepoFoam

Bupivacaine, a Liposomal Local

Analgesic.

Haas E, et al.9

A. Exparel® 67 mg

B. Exparel® 200

mg

C. Exparel® 266

mg

D. Bupivacaine HCl

75

mg

100

96 hours

· Adults (mean age 43

y)

· Undergoing

hemorrhoidectomy

· Under general

anesthesia

· 94% white

· MC

· R

· DB

· PG

· AC

· Primary endpoint: EXPAREL 266 mg contained greatest number of subjects receiving

no supplemental opioid pain medication

· P>0.05

· Secondary: Significantly less opioid pain medication consumed by subjects in the

EXPAREL 266 mg at 24, 36, 48, 72, 84, and 96 h

· P≤0.035

· Secondary: AUC of NRS‐R scores significantly reduced

in all EXPAREL treatment groups compared with bupivacaine HCl through 12, 24, 36

(75 mg group was

not significant), 48 (75 mg group was not significant), 60 (75 mg group was not

significant), 72, 84, and 96 h

· P<0.05

· Secondary: Significant improvements in integrated analysis of AUC NRS‐R scores and

supplemental opioid pain medication usage observed in the EXPAREL 200 mg and 266

mg groups over 12, 24, 36, 48, 60, 84 and 96 h, and in the EXPAREL 75‐mg group over

72 and 96 h vs bupivacaine HCl

· P<0.05

·

Secondary: Significant improvements in subject QOL (VAS score) observed at 48 h in

the 266 mg EXPAREL treatment group, at 72 h in the 67, 200, and 266 mg EXPAREL

treatment groups, and at 96 h in the 266 mg EXPAREL treatment group, compared with

bupivacaine HCl group

· P≤0.029

·

Secondary: Over the first 3 postsurgical days, EXPAREL 266 mg significantly reduced

pain intensity by 47%, opioid use by 66%, and opioid‐related side effects by 89%,

relative to bupivacaine HCl 75 mg

· P<0.05 for all

A Randomized, Double-Blind,

Dose-Ranging Study Comparing

Wound Infiltration of DepoFoam

Bupivacaine to Bupivacaine HCl

for Postsurgical Analgesia in Total

Knee Arthroplasty.

Bramlett KW, et al.10

A. Exparel® 133

mg

B. Exparel® 266

mg

C. Exparel® 399

mg

D. Exparel® 532

mg

E. Bupivacaine HCl

150 mg

138

5 days

· Adults (mean age 62

y)

· Undergoing TKA

· Under general

anesthesia

· 62% female

· 92% white

· MC

· R

· DB

· PG

· AC

· Primary: Comparable pain intensity during activity (NRS‐A AUC0‐4d) in each group

· P>0.05

·

Secondary: Comparable proportion of subjects in each group required no supplemental

opioid medication post-

surgically, and the total postsurgical opioid consumption did not

differ between groups

· P>0.05

· Secondary: Significantly lower cumulative pain intensity at rest (AUC NRS‐R) with

EXPAREL 532 mg vs bupivacaine HCl through Day 2, 3, 4 and 5

· P≤0.015

· Secondary: Bupivacaine HCl more effective than EXPAREL 133 mg in integrated

analysis of cumulative pain intensity during activity or rest + supplemental opioid use

· P<0.05

· Secondary: EXPAREL 266 mg or 399 mg significantly delayed time to first opioid

medication vs bupivacaine HCl

· P≤0.005

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

25

·

Secondary: EXPAREL 266 mg or 399 mg significantly delayed time to first occurrence

of PONV vs bupivacaine HCl

· P<0.05

The Efficacy and Safety of

DepoFoam Bupivacaine in Patients

Undergoing Bilateral, Cosmetic,

Submuscular Augmentation

Mammoplasty.

Smoot JD, et al.18

A. Exparel® 266

mg in each side

(total

dose 532 mg)

B. Bupivacaine HCl

100 mg in each

side (total dose

200 mg)

136

96 hours

· Adults (mean age 31

y)

· Undergoing bilateral

cosmetic, submuscular

breast augmentation

· Under general

anesthesia

· MC

· R

· DB

· PG

· AC

· Primary: NRS‐A AUC0‐72 similar (441.0 for EXPAREL and 467.2 with bupivacaine

HCl); study terminated early so not powered to detect a difference in primary endpoint

· P>0.05

· Secondary: NRS‐A and NRS‐R AUCs similar among treatment groups at all post‐dose

assessments (12, 24, 36, 48, 60, 72, 84, 96 h)

· P>0.05

· Secondary: NRS‐A scores significantly lower for

EXPAREL vs bupivacaine HCl at 8 h and 12 h, and NRSR significantly lower at 8 h

· P<0.05

· Secondary: Postsurgical opioid consumption

significantly lower for EXPAREL vs bupivacaine HCl at 24 h (9.73 vs 13.68 mg

morphine equivalents) and 48 h (18.44 vs 55.69 mg)

· P<0.05

· Secondary: No significant difference in median time to first opioid analgesia (2.9 vs

2.5 h for EXPAREL vs bupivacaine HCl)

· P>0.05

· Secondary: Integrated assessment of NRS‐A scores and opioid usage significantly

favored EXPAREL at 12 and 48 h, as did integrated assessment of NRS‐A AUC and

opioid usage between 12 and 72 h and at 96 h

· P<0.05

· Secondary: Integrated assessment of NRS‐R scores and opioid usage significantly

favored EXPAREL at 12, 48, and 60 h, as did integrated assessment of NRS‐R AUC and

opioid usage assessment at 72 and 96 h

· P<0.05

Efficacy Profile of Liposome

Bupivacaine, a Novel Formulation

of Bupivacaine for Postsurgical

Analgesia.

Bergese S, et al.26

A. Exparel® 532

mg

B. Bupivacaine HCl

200 mg

218

96 hours

· Adults (mean 66 y)

· Undergoing TKA

· Under general or

spinal anesthesia,

· 64% female

· 84% white

· MC

· R

· DB

· PG

· Primary: Comparable pain intensity during activity (NRS‐A AUC0‐96) in each group

· P=0.1266

· Secondary: Higher mean NRS‐A score with EXPAREL vs bupivacaine HCl at 48 h

· P=0.363

· Secondary: Comparable total postsurgical opioid consumption in both groups

· P>0.05

· Secondary: Comparable pain scores (NRS‐1 or NRS‐R) at all time points and AUCs of

pain scores in both

groups

· P>0.05

· Secondary: Comparable QOL scores (EQ‐5D) in both groups

Bupivacaine Liposome Injectable Suspension Monograph

Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov

26

· P>0.05

· Secondary: Comparable time to physical recovery and return to daily activities in both

groups

· P>0.05

Bupivacaine ER Liposome

Injection does not Prolong QTc

Interval in a Thorough QT/QTc

Study in Healthy Volunteers.

Naseem A, et al.25

A. Exparel® 300

mg

B. Exparel® 450

mg

C. Exparel® 600

mg

D. Exparel® 750

mg

E. Moxifloxacin

400 mg

Part 1:

49

Part 2:

16

96 hours

· Adults (mean age 26

years)

· No history of CV

disease

· No abnormal ECGs

· Nonsmoking

Part 1:

· R

· DB

· AC

· CO

Part 2:

· OL

· Seq

· The 300 mg & 450 mg Exparel® produced mean QTc shortening of −2.24 ms & −2.45

ms, respectively

· Upper limit of 2-sided 95% CI <10 ms

· Mean QTc prolongation of −3.6 ms (600 mg) & −7.67 ms (750 mg) was identified

· Upper limit of 2-sided 95% CI <10 ms

· All four doses of Exparel® produced a slight shortening of the QTc interval, but only

in the 600 mg dose was statistical significance not reached

· Findings suggest that al

l tested doses of Exparel® do not have any clinically significant

effect on QTc

Extended pain relief trial utilizing

infiltration of Exparel®, a long-

acting multivesicular liposome

formulation of bupivacaine: a

Phase IV health economic trial in

adult patients undergoing open

colectomy

Cohen SM.27

A. Exparel® 266mg

+ IV NSAIDs

followed by PO

NSAIDs

B. PCA with IV

morphine or

hydromorphone

39

10 days

· Adults (mean age 54

years)

· Undergoing colectomy

procedure

· No history of

alcohol/drug abuse

· OL

· Seq

· AC

· Both treatment arms were offered rescue analgesia with IV opioids and/or

oxycodone/APAP 5/325mg q 6h prn until discharge

· Exparel® group was associated with a 50%reduction in average amount of opioids

used s/p surgery, a 59% shorter hospital stay, and 26% lower total average hospital costs

compared with the opioid based regimen.

· p= 0.025, p= 0.004, p= 0.027, respectively

· Mean QTc prolongation of −3.6 ms (600 mg) & −7.67 ms (750 mg) was identified

· Upper limit of 2-sided 95% CI <10 ms

· Open-label study design weakens generalizability of results and increase risk for bias.

Small sample size and use of rescue opioids in both groups also weakens the study.

MC=multicenter; R=randomized; DB=double‐blind; PC=placebo‐controlled; AC=active-controlled, PG=parallel group; CO =crossover; NRS‐R=pain intensity score at rest;

NRS‐A=pain intensity score during activity; NRS AUC=cumulative pain intensity score; QOL=quality of life; Seq=sequential; VAS=visual analog scale; h=hours.