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Bupivacaine Liposome Injectable Suspension Monograph

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the Archive section when the information is deemed to be no longer current.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bupivacaine HCl/epinephrine (unpublished).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
4
postoperatively (24, 72 and 96 hrs). In the placebo-controlled trials (1-bunionectomy , 15
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 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unpublished study, liposomal bupivacaine was not statistically different from unencapsulated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:




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

Bupivacaine Liposome Injectable Suspension Monograph







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.
9

There have been two published phase 2 trials (1-hemorrhoidectomy , 1-total knee arthroplasty )
11
18
and two published phase 3 trials (1-total knee arthroplasty , 1-breast augmentation ) 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
9,10
11,18
but not in the phase-3 studies
. However, since the analysis of pain
liposomal product
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
9
limiting the strength of the evidence.
9,10,11
, there was no statistical or clinically important difference in total
In three of the studies
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

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

Bupivacaine Liposome Injectable Suspension Monograph






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 nonliposomal 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
1
one formulation to another.

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

Bupivacaine Liposome Injectable Suspension Monograph

Table 1. PK Parameters of Bupivacaine Liposomal Injectable Suspension

Bunionectomy 106 mg (8 mL)
(N=26)

Hemorrhoidectomy 266 mg (20 mL)
(N=25)

166(92.7)

867 (353)

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)

Parameters
Mean Cmax
(ng/mL)
Median Tmax
(h)

Table adapted from product information

Table 2. PK parameters of bupivacaine liposomal injectable suspension and bupivacaine HCl
PK Parameter

EXPAREL

2,3

Bupivacaine HCl

Metabolism

Hepatic conjugation with glucuronic acid;
inactive metabolite pipecoloxylidine (PPX)

Elimination

Urine (6% unchanged)

Half-life

24-34 h

2.7 h

Protein binding

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
17
bupivacaine.

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).

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

Bupivacaine Liposome Injectable Suspension Monograph

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

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

Bupivacaine Liposome Injectable Suspension Monograph






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
4-5, 28

Summary of Efficacy Findings
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
4
or
liposomal bupivacaine to placebo in patients undergoing bunionectomy (n=193 patients)
5
hemorrhoidectomy (n=189 patients) . The third, unpublished trial involved a comparison of liposomal
28
bupivacaine with bupivacaine HCl in patients having hemorrhoidectomy . 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.

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

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.

Intervention: LBup 8 mL (120 mg) or
Placebo

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.

Outcome Measures

Patients were d/c after
24 hrs and staff called
patients to get
assessments beyond
24 hrs.

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

Primary: AUC-NRS
score through 24 hrs
(Measured at 2, 4, 8,
12, 24, 26, 48, 60 and
72 hrs post-op)

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

*Sponsored by Pacira
Pharma

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.

Exclusion/Intervention

Total use of rescue opioids (tabs)
through 24 hrs:
LBup: 3.8 tabs vs. 4.7 tabs placebo
(p=0.008)

Time to first opioid:
LBup: 7.2 hrs vs. 4.3 hrs placebo
(p<0.0001)

Pts receiving no opioids:
Statistical difference in favor of LBup
through 24 hrs, after that, no diff.

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)

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)

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)

N=193 randomized, 97 to LBup, 96 to
placebo. 4 pts from each group
withdrew or violated study protocol.
Mean age: 42 years

Results

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

Clinical Trial

FDA Reviewer Conclusion: Superior to placebo
when used with oxycodone, acetaminophen and

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 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.

Adverse Events/Comments

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.

Bupivacaine Liposome Injectable Suspension Monograph

Exclusion: pregnancy, significant
medical conditions believed to
interfere with study results,
etoh/substance abuse within past 2
yrs, uncontrolled psychiatric
disorders, know allergy or

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 46 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.

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.

Secondary:
*Total post-op use of

Primary Endpoint:
AUC-NRS through 96
hrs.

Patients remained at
study site for 72 hrs.

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 postop analgesia.
*ADEs
*Caregiver satisfaction
with wound healing.

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)

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

Unpublished28
Phase 3, R, MC, DB
N=198
Inclusion: Adult men
and women
undergoing 2 or 3

*Sponsored by Pacira
Pharma

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.

Primary endpoint:
AUC-NRS (mean): LBup: 393 vs.
Bupivacaine HCl/epi: 359

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
N=198 randomized, LBup=99 pts,
Bupivacaine HCl/epi=99 pts

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%.

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.

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 comments:
After 24 hrs, there is no difference between
placebo and LBup with regard to the primary
endpoint.

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.
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.

Bupivacaine Liposome Injectable Suspension Monograph

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.

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.

Unclear length of stay
at study site.

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 postop analgesia.
*Blinded care providers
satisfaction with postop analgesia.
*Time to return to work
or normal daily
activities.
ADEs were monitored
through day 8 and
deaths through 30 d.

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.”

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.

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.”

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.

Comments/Limitations:
Unpublished

No significant difference through 96 hrs
(p=0.15).

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

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.

*Sponsored by Pacira
Pharma

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.

Bupivacaine Liposome Injectable Suspension Monograph

Additional Information from FDA Reviewer

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 Gorfine22.3 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
9
10
There have been two published phase 2 trials (1-hemorrhoidectomy , 1-total knee arthroplasty ) and two
11
18
published phase 3 trials (1-total knee arthroplasty , 1-breast augmentation ) 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
9,10
11,18
but not in the phase-3 studies
. However, since the analysis of pain intensity was
liposomal product
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
4-5,28
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
9
were made to the analysis of one of the studies, thereby limiting the strength of the evidence. 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)

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

Bupivacaine Liposome Injectable Suspension Monograph



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



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



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
11
recovery and return to daily activities.



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

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

Bupivacaine Liposome Injectable Suspension Monograph

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
18
unrelated to safety.


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

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 data

1,4-5

Bupivacaine
liposomal injectable
4
suspension (8 mL)

Placebo

42.3%

39.6%

Nausea

40.2%

37.5%

Vomiting

27.8%

17.7%

Constipation

2.1%

Nervous System
Disorders

20.6%

31.3%

Dizziness

11.3%

26%

Headache

5.2%

8.3%

Somnolence

5.2%

Gastrointestinal
Disorders

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

Bupivacaine
liposomal injectable
5
suspension (30 mL)

Placebo

7.4%

13.8%

2.1%

1.1%

2.1%

4.3%

2.1%

Bupivacaine Liposome Injectable Suspension Monograph

Skin Disorders

8.2%

7.3%

Pruitus

3.1%

Other

5.2%

Increased Alanine
Aminotransferase

3.1%

0
--

3.1%

1.1%

Increased Aspartate
Aminotransferase

3.1%

2.1%

Serum Creatinine
Increased

2.1%

Feeling Hot

2.1%

0
Post Procedural
2.1%
0%
Swelling
0
1
Adverse events derived from 2 pivotal studies. Table adapted from product information
4
Study 1: Bunionectomy
5
Study 2: Hemorrhoiddectomy

0
0

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
2,29
mostly assessed as mild or moderate severity . 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
1
and death .

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

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

Bupivacaine Liposome Injectable Suspension Monograph

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%),
1
somnolence (2.1%) and lethargy (1.3%) .
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
22
adverse events. In the analysis, no cardiac safety issues were identified . In all the wound infiltration studies
involving liposomal bupivacaine, adverse cardiac events reported with an incidence of at least 1% were as
1
follows: tachycardia (3.9%) and bradycardia (1.6%) .
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.

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

Bupivacaine Liposome Injectable Suspension Monograph

Special Populations
Safety and effectiveness of liposomal bupivacaine has not been evaluated in patients below the age of 18
1
years old, pregnant patients, or patients who are nursing .
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
1-3
the absence of maternal toxicity .
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
1
function .
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 C max
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
2
injectable suspension administration

Mean (Standard
Deviation)
Cmax (ng/mL)
Tmax (h)
AUCl0-last) (h • ng/mL)
AUCl0-∞) (h • ng/mL)
Half-life (h)
Cl/F (L/h)
Vd/F (L)

Moderate hepatic
impairment (n=9)
149.1 (42.6)
42.7 (28.2)
17,177.8 (2349.3)
17,975.5 (2447.0)
46.5 (26.3)
17.0 (2.2)
1131.6 (624.4)

Normal hepatic function
(n=9)
102.8 (37.7)
54.7 (28.8)
10,682.7 (4392.6)
11,050.7 (4498.8)
37.6 (9.8)
31.2 (11.5)
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.

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

Bupivacaine Liposome Injectable Suspension Monograph

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 (LexiComp, First Databank, and ISMP Confused Drug Name List), the following drug names may cause LASA
confusion:
2

LA/SA for generic name bupivacaine liposome injectable suspension :
 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
31
significant patient harm when used in error.
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,
3
vials separated, and directions for managing bupivacaine toxicity be available .
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.

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

Bupivacaine Liposome Injectable Suspension Monograph

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.
2

Coadministration
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 postop 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, openlabel, nonrandomized study with a small sample size and included too many variables to draw any
27
conclusions about the findings .

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

Bupivacaine Liposome Injectable Suspension Monograph

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.
9

As for other studies, there have been two published phase 2 trials (1-hemorrhoidectomy , 1-total knee
10
11
18
arthroplasty ) and two phase 3 trials (1-total knee arthroplasty , 1-breast augmentation ) 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
9,10
18
but not in the phase-3 studies . However, since the analysis of pain
favor of the liposomal product
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
9
changes were made to the analysis of one of the studies, thereby limiting the strength of the evidence . In

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

Bupivacaine Liposome Injectable Suspension Monograph

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
th
opioid use as demonstrated by integrated analysis. 26 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.

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

Bupivacaine Liposome Injectable Suspension Monograph

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.

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

Bupivacaine Liposome Injectable Suspension Monograph

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.
Exparel Alert
PDF.pdf

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

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

Study 1:
A. Exparel® 133
mg or 266 mg in

D. Bupivacaine HCl
50 mg

C. Exparel® 266
mg

B. Exparel® 155
mg

A. Exparel® 89 mg

B. Bupivacaine HCl
200 mg

A. Exparel® 400
mg

B. Exparel® 655
mg SC

mg SC

Drug
Regimens
A. Exparel®
532

Mean 1521 months

96 hours

8 days

---

Time

· Adults (mean age 31.5
y)

· 100% white

· 100% male

· BMI <35 kg/m2

· Adults (age 18-49
years)

· No medications in past
week

· Within 20% of IBW

· Adults (age 18-45
years)

---

R
DB
AC
Seq

· MC
·O

·
·
·
·

· OL
· CO

·R
· OL
· Seq

Demographics Design*

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

A 2 Year Observational Study
Assessing the Safety of DepoFoam
Bupivacaine after Augmentation

The Pharmacokinetics and
Pharmacodynamics of Liposome
Bupivacaine Administered via a
Single Epidural Injection.
Viscusi ER, et al.34

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

Injection Exhibits a Favorable
Cardiac Safety Profile.
Bergese SD, et al. 22

Ref. and Evidence
Grade
Bupivacaine ER
Liposome

· 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.

· Half-life was similar across the Exparel® groups (14.0-19.3 hours) & ~3x longer than
bupivacaine HCl (5.7 hours)

· Mean Cmax after administration of Exparel® 266 mg was not statistically significantly
different from bupivacaine HCl 50 mg

· 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

· All doses of Exparel® exhibited significantly greater AUC0-tlast and AUC0-[infinity] than
bupivacaine HCl and a longer Tmax
· P<0.001

· 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

· Peak plasma bupivacaine concentrations were similar in the two groups, despite a 4fold increase in total bupivacaine dose administered with the novel liposomal
preparation

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

End Points/Results/Comments

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

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.

Appendix 1.

Bupivacaine Liposome Injectable Suspension Monograph

F. Bupivacaine HCl
125 mg

E. Exparel® 310
mg

D. Exparel® 279
mg

C. Exparel® 244
mg

B. Exparel® 200
mg

A. Exparel® 155
mg

B. Bupivacaine HCl
100 mg in each
side (total dose
200 mg)

Study 2:
A. Exparel® 266
mg in each side
(total
dose 532 mg)

B. Bupivacaine HCl
75 mg in the
contralateral side

one
breast pocket

96 hours

· 57-92% female

· >90% white

· Under general
Anesthesia

· Undergoing
a unilateral first
metatarsal
bunionectomy repair

· Adults (mean age 5259 years)

· 87.2% white

· Participated in
previous studies (Smoot
2012, Minkowitz 2012)

· Underwent bilateral
cosmetic, submuscular
breast augmentation

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

A Phase 2, Multicenter,
Randomized, Double-Blind, DoseEscalating/De-Escalating Study to
Evaluate the Safety, Efficacy, and
Pharmacokinetics of SustainedRelease Encapsulated Bupivacaine
Administered as a Nerve Block in
the Management of Postoperative
Pain in Subjects Undergoing
Bunionectomy.
Pacira Pharmaceuticals, Inc: Data on
File8

Mammoplasty.
Minkowitz H, et al.7

·
·
·
·
·
MC
R
DB
PG
AC

· 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

· 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: 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: 33.3% to 64.3% of EXPAREL recipients and 55% of bupivacaine HCl
recipients did not take supplemental opioid medication
· 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

· 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

· 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.

· 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.

Bupivacaine Liposome Injectable Suspension Monograph

E. Bupivacaine HCl
150 mg

D. Exparel® 532
mg

C. Exparel® 399
mg

B. Exparel® 266
mg

· 92% white

· 62% female

· Under general
anesthesia

· Undergoing TKA

· Adults (mean age 62
y)

· Under general
anesthesia

· Undergoing
hemorrhoidectomy

· Adults (mean age 43
y)

A. Exparel® 133
mg
5 days

96 hours

· 94% white

138

100

D. Bupivacaine HCl
75
mg

C. Exparel® 266
mg

B. Exparel® 200
mg

A. Exparel® 67 mg

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

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 Double-Blind Randomized,
Active Controlled Study for PostHemorrhoidectomy pain
Management with DepoFoam
Bupivacaine, a Liposomal Local
Analgesic.
Haas E, et al.9

·
·
·
·
·

MC
R
DB
PG
AC

· Secondary: EXPAREL 266 mg or 399 mg significantly delayed time to first opioid
medication vs bupivacaine HCl
· P≤0.005

· 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: 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: 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

· Primary: Comparable pain intensity during activity (NRS‐A AUC0‐4d) in each group
· P>0.05

· 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

· 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: 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: 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: 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

· Primary endpoint: EXPAREL 266 mg contained greatest number of subjects receiving
no supplemental opioid pain medication
· P>0.05

Bupivacaine Liposome Injectable Suspension Monograph

B. Bupivacaine HCl
200 mg

A. Exparel® 532
mg

B. Bupivacaine HCl
100 mg in each
side (total dose
200 mg)

A. Exparel® 266
mg in each side
(total
dose 532 mg)

218

136

96 hours

· 84% white

· 64% female

· Under general or
spinal anesthesia,

· Undergoing TKA

· Adults (mean 66 y)

· Under general
anesthesia

· Undergoing bilateral
cosmetic, submuscular
breast augmentation

· Adults (mean age 31
y)

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

Efficacy Profile of Liposome
Bupivacaine, a Novel Formulation
of Bupivacaine for Postsurgical
Analgesia.
Bergese S, et al.26

The Efficacy and Safety of
DepoFoam Bupivacaine in Patients
Undergoing Bilateral, Cosmetic,
Submuscular Augmentation
Mammoplasty.
Smoot JD, et al.18

·
·
·
·

·
·
·
·
·

MC
R
DB
PG

MC
R
DB
PG
AC

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

· 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 total postsurgical opioid consumption in both groups
· P>0.05

· Secondary: Higher mean NRS‐A score with EXPAREL vs bupivacaine HCl at 48 h
· P=0.363

· Primary: Comparable pain intensity during activity (NRS‐A AUC0‐96) in each group
· P=0.1266

· 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

· 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: 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: 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: 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: 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

· 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: EXPAREL 266 mg or 399 mg significantly delayed time to first occurrence
of PONV vs bupivacaine HCl
· P<0.05

Bupivacaine Liposome Injectable Suspension Monograph

B. PCA with IV
morphine or
hydromorphone

A. Exparel® 266mg
+ IV NSAIDs
followed by PO
NSAIDs

E. Moxifloxacin
400 mg

D. Exparel® 750
mg

C. Exparel® 600
mg

B. Exparel® 450
mg

A. Exparel® 300
mg

Part 2:
16

Part 1:
49

10 days

96 hours

· No history of
alcohol/drug abuse

· Undergoing colectomy
procedure

· Adults (mean age 54
years)

· Nonsmoking

· OL
· Seq
· AC

Part 2:
· OL
· Seq

· No abnormal ECGs

· No history of CV
disease

Part 1:
·R
· DB
· AC
· CO

· Adults (mean age 26
years)

· 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.

· 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

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

· 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.

· Both treatment arms were offered rescue analgesia with IV opioids and/or
oxycodone/APAP 5/325mg q 6h prn until discharge

· Findings suggest that all tested doses of Exparel® do not have any clinically significant
effect on QTc

· 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

· 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

· 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

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

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.

Extended pain relief trial utilizing
infiltration of Exparel®, a longacting multivesicular liposome
formulation of bupivacaine: a
Phase IV health economic trial in
adult patients undergoing open
colectomy
Cohen SM.27

Bupivacaine ER Liposome
Injection does not Prolong QTc
Interval in a Thorough QT/QTc
Study in Healthy Volunteers.
Naseem A, et al.25

· Secondary: Comparable time to physical recovery and return to daily activities in both
groups
· P>0.05

· P>0.05

Bupivacaine Liposome Injectable Suspension Monograph

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MK 00649 VA Monograph Exparel Report

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