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A Review of the Compatibility of Liposome
Bupivacaine With Other Drug Products and
Commonly Used Implant Materials
Vladimir Kharitonov, PhD
Vice President, Research and Process
Development, Pacira Pharmaceuticals,
Inc., San Diego, CA
Correspondence:
Vladimir Kharitonov, PhD,
Research and Process Development,
Pacira Pharmaceuticals, Inc.,
10450 Science Center Drive,
San Diego, CA 92121.
Tel: 858-625-2424
Fax: 858-625-2439
E-mail: VladimirKharitonov@pacira.com
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C L I N I C A L F E AT U R E S
DOI: 10.3810/pgm.2014.01.2733
Abstract: The compatibility of a medication with other drugs and implanted materials is an
important factor impacting drug safety and efficacy. The liposomal formulation of the local
anesthetic bupivacaine is designed to provide prolonged postsurgical analgesia. Its compatibility
with other drugs and materials depends on the compatibility of the drug itself, along with the
integrity of liposome and liposomal components. A series of studies was conducted to evaluate
the compatibility of liposome bupivacaine with diluents, implanted materials, and other drugs
likely to be encountered in the surgical settings in which it is used. Liposome bupivacaine
demonstrated compatibility with diluents (normal saline, lactated Ringer’s solution) and with
implanted materials (silicone, stainless steel, titanium, polypropylene, expanded polytetrafluoro-
ethylene), with little or no change in percent of free bupivacaine, packed particle volume, or
particle size distribution; liposome bupivacaine exhibited little or no change in the properties of
the test materials. Liposome bupivacaine had clinically meaningful interactions with other local
anesthetics, including lidocaine, ropivacaine, mepivacaine, or bupivacaine HCl (at liposome
bupivacaine to bupivacaine HCl ratios , 2:1), which resulted in substantial displacement and
release of free bupivacaine from liposomes. Liposome bupivacaine may be locally administered
after $ 20 minutes following local administration of lidocaine, ropivacaine, or mepivacaine.
Co-administration of liposome bupivacaine and bupivacaine HCl into the same site should be
at ratios $ 2:1. Interactions between liposome bupivacaine and epinephrine, corticosteroids,
antibiotics, non-steroidal anti-inflammatory drugs, tranexamic acid, and opioid analgesics were
not clinically meaningful; liposome bupivacaine may be safely co-administered with these
agents. No adverse synergistic effects on liposome bupivacaine were observed in evaluations
involving multiple medications compared with each drug’s individual effects.
Keywords: analgesia; liposome bupivacaine; drug compatibility; postoperative pain
Introduction
Infused or injected medications must be compatible, non-reactive, or minimally ­reactive
with co-administered drugs and implanted materials. The physical and ­chemical
properties of the drug in question should not be altered by other medications and
materials; conversely, the medication should not alter the physicochemical properties
of other drugs and materials. To a significant extent, compatibility rests on the acid/
base properties of the medication in question.1
A liposomal formulation of the short-acting local anesthetic bupivacaine (Exparel),
which extends the duration of analgesia for # 72 hours via prolonged release of bupi-
vacaine over time,2,3 was approved by the US Food and Drug Administration (FDA) in
2011 for administration into the surgical site during surgery to reduce the incidence and
severity of postsurgical pain.3 The pharmacodynamics and pharmacokinetics of this
formulation have been extensively studied in both nonclinical and clinical s­ tudies across
Vladimir Kharitonov
numerous surgical models.4–24 The compatibility of liposome
bupivacaine and other substances depends not only on potential
interactions with bupivacaine itself, but also on maintaining
the structure and properties of the DepoFoam drug delivery
system that allows gradual release of the active drug.
This article reviews the results from a number of ­studies
that were conducted to examine the compatibility of liposome
bupivacaine with other drugs and materials in the surgical
­setting. This paper will help clinicians use liposome bupi-
vacaine safely and effectively and gain useful knowledge
regarding compatibility issues. Liposome bupivacaine has
demonstrated a favorable tolerability profile in clinical stud-
ies, with a low incidence of treatment-related adverse events
(AEs) and study discontinuations.25–29 Because liposome
bupivacaine is typically administered as part of a multimodal
analgesic regimen involving $ 1 other analgesic medication,
the results of the compatibility studies of liposome bupi-
vacaine are encouraging.25 Similarly, the low incidence of
AEs associated with liposome bupivacaine that was reported
in studies involving surgeries with implanted materials
(eg, breast augmentation, total knee arthroplasty) suggests
a compatibility of liposome bupivacaine with s­ ilicone and
metallic implants.25,29
Materials and Methods
Data were compiled and reviewed from published5,29 and
unpublished studies (Pacira Pharmaceuticals, Inc., unpublished
data, 2009) conducted to systematically evaluate the compat-
ibility of liposome bupivacaine with diluents, other drugs,
and implantable materials frequently used or encountered
during surgical procedures. The results of the compatibility
studies performed to date are described in this report. In these
studies, an increase # 15% in free bupivacaine levels was
considered not clinically relevant; if released during a period
of 72 hours, this difference would constitute # 13 mg of free
bupivacaine per day. Total bupivacaine, free bupivacaine, lyso-
dierucoylphosphatidylcholine (lyso-DEPC), and erucic acid
levels were measured by reversed-phase high-performance
liquid chromatography. Laser light scattering was used to
measure particle size and pH was measured by glass electrode.
All experiments were in vitro tests unless otherwise stated.
Results
Compatibility With Diluents
Normal Saline
The milligram dose of liposome bupivacaine is expressed
as the free base (ie, 266 mg of bupivacaine base is chemi-
cally equivalent to 300 mg of bupivacaine HCl).2 ­Liposome
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b­ upivacaine is supplied in 20-mL vials at a free-base
­bupivacaine concentration of 13.3  mg/mL (1.3%).3 With
typical usage, liposome bupivacaine is emptied from the
vial in which it is supplied and either injected as is or diluted
with preservative-free normal sterile saline (0.9% NaCl)
prior to injection. Possible drivers of incompatibility during
withdrawal, dilution, and injection of liposome bupivacaine
include the dilution factor, storage time and temperature
within the syringe, needle gauge, and rate of ejection through
the needle. These factors might conceivably affect the
concentration of free bupivacaine, as well as the liposome
particle size distribution.
Volume expansion with normal saline-to-liposome bupi-
vacaine factors # 15:1 were evaluated; however, the greatest
dilution recommended to be used clinically in product label-
ing is 14:1 to support a safety margin in the event of over-
expansion of volume beyond 14:1. Results from the volume
expansion study are summarized in Table 1. The change in the
proportion of free bupivacaine was negligible for a dilution
range from no dilution to 15:1; even at a dilution of 15:1, the
percentage of free bupivacaine only increased by 3% (from
3.0% to 6.0%), which is not clinically relevant.
Lactated Ringer’s Solution
Diluent evaluations were also conducted with lactated
Ringer’s solution using various dilution factors and incuba-
tion times/temperatures; these evaluations used liposome
bupivacaine diluted in normal saline as controls. Results
are summarized in Table 2. No clinically meaningful differ-
ences were observed in the proportion of free bupivacaine,
whether it was diluted in normal saline or in lactated Ringer’s
solution.
Compatibility With Tubing/Implant Materials
Polypropylene and Expanded Polytetrafluoro-ethylene
Polypropylene (PP) and expanded polytetrafluoro-ethylene
(ePTFE) mesh implants are frequently employed to reinforce
Table 1.  Effects of Dilution With NSa on Free Bupivacaine Levels
Dilution Factor Total Bupivacaine Free Bupivacaine, %
Concentration, mg/mL
1 (no dilution) 13.4 3.0
2x 6.8 3.6
5x 2.8 3.9
10x 1.4 4.8
15xb 0.9 6.0
a
0.9% NaCl solution.
A dilution factor of 14 is the highest dilution factor expected to be used in clinical
b
settings.
Abbreviation: NS, normal saline.
 Review of Liposome Bupivacaine Compatibility Studies

Table 2.  Comparative Effects of Dilution With Lactated Ringer’s
Solution and NS on Free Bupivacaine Levelsa
Temperature/ NS Lactated Ringer’s
Time Point Solution
DF 2 DF 10 DF 50 DF 2
25°C/5 min 5.1% 5.5% 8.7% 5.0%
25°C/2 h 5.6% 6.1% 9.3% 5.5%
37°C/2 h 5.7% 7.0% 14.1% 5.7%
a
Percentages shown are proportions of free bupivacaine.
Abbreviations: DF, dilution factor; NS, normal saline.
surgical hernia repair and abdominal wall reconstruction.
Polypropylene and ePTFE mesh samples were incubated
in either undiluted liposome bupivacaine (13.3  mg/mL3)
or a normal saline control for 96 hours at 37°C. Following
incubation, the mechanical properties of the mesh samples
were evaluated using a ball burst force test, which measures
the force required to rupture the mesh, and a suture reten-
tion strength test, which measures the resistance of a mesh
during removal of sutures. Key attributes of the liposome
bupivacaine solution were also assessed, including percent
free bupivacaine, percent packed particle volume (PPV),
pH, and particle size.
Incubation of PP and ePTFE mesh in liposome bupiva-
caine had no clinically relevant effect on mesh strength by
either the ball burst force test or the suture retention strength
test. There was a slight reduction in mean ball burst force after
incubation in liposome bupivacaine compared with normal
saline for both mesh types (mean kg force ± SD for saline
control vs liposome bupivacaine; PP: 58.1 ± 3.3 vs 56.8 ± 4.8;
ePTFE: 24.1 ± 0.8 vs 22.8 ± 1.7). However, this reduction
was substantially lower than the ± 15% normal variability
in strength for unexposed mesh reported by vendors of both
mesh types.
Table 3 summarizes key liposome bupivacaine parameters
following incubation with PP and ePTFE mesh samples.
Comparing the PP and ePTFE results with the “no mesh
sample” control reveals that incubation with PP and ePTFE
mesh had no clinically meaningful effect on the key proper-
ties of liposome bupivacaine, including percent free bupiva-
caine, PPV, and particle size distribution.
DF 10 DF 50
5.8% 10.4%
Silicone
6.1% 10.3%
7.2% 13.6%
Silicone tubing is used during the manufacture of liposome
bupivacaine, especially during filling and product potency
adjustment. Silicone is also used extensively in breast
implants, nearly all of which have an outer surface of silicone
elastomer. Samples of smooth-type and textured-type silicone
breast implant material were incubated with liposome bupi-
vacaine (full strength) or with normal saline as a control for
7 days at 37°C, and were subsequently evaluated with respect
to tensile strength and tensile set. For tensile strength, the per-
cent elongation of the samples was determined as a function
of the tensile stress. For tensile set, the samples were stretched
to a certain percent of the initial length and then allowed to
relax. The initial and final dimensions of the samples were
measured and tensile set was calculated as the percent differ-
ence between the initial and final values. Smooth and textured
implant materials had similar tensile strength and tensile set
after incubation with liposome bupivacaine or normal saline;
test results are summarized in Table 4.
To further characterize possible interactions between
silicone and liposome bupivacaine, key attributes of lipo-
some bupivacaine were evaluated following a “worst-case
scenario” of exposure at 37°C to smooth and textured silicone
implant material. The results were compared with a control
incubated at 37°C without silicone and a liposome bupi-
vacaine control stored at 2–8°C (Table 5). Incubation with
silicone had no effect on total bupivacaine, free bupivacaine
percent, or on PPV percent. Particulate matter remained
within product specifications (# 6000/vial for particles
$ 10 µm; # 600/vial for particles $ 25 µm). An increase in
particle size was observed for the samples incubated at 37°C.

Table 3.  Properties of Liposome Bupivacaine 13.3 mg/mL3 Following Incubation With PP and ePTFE Mesh Material
Sample Free Bupivacaine, % PPV, % pH Particle Size (volume weighted diameter, μm)a
d10 d50 d90
ePTFE mesh b
3.9 33.3 5.9 16.5 63.8 265.4
PP meshb 4.9 32.9 5.8 17.1 61.2 227.5
No mesh controlc 5.8 31.4 5.8 17.6 93.0 307.0
Vial controld 1.9 36.4 6.0 16.5 44.9 325.3
a
Particle size distribution listed as volume weighted diameter; d10, d50, and d90 represent particle diameters at the 10th, 50th, and 90th volume percentiles, respectively, of the
particle size distribution.
b
ePTFE and PP mesh samples were incubated with liposome bupivacaine at 37°C for 96 hours.
c
No mesh controls included liposome bupivacaine incubated at 37°C for 96 hours with no mesh sample.
d
Vial control samples were incubated at ambient temperature for 96 hours with no mesh sample.
Abbreviations: ePTFE, expanded polytetrafluoro-ethylene; PP, polypropylene; PPV, packed particle volume.

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Vladimir Kharitonov

Table 4.  Tensile Strength and Tensile Set of Smooth- and Textured-Type Silicone Breast Implant Material Following Incubation With
Liposome Bupivacaine
Tensile Strength
Parameter Saline Control Liposome Bupivacaine
Smooth Implant
Mean tensile strength at break, psi (SD) 1683 (110) 1690 (120)
Mean percent elongation at break, % (SD) 733 (15) 707 (32)
Textured Implant
Mean tensile strength at break, psi (SD) 1193 (15) 1217 (96)
Mean percent elongation at break, % (SD) 713 (35) 683 (45)
Tensile Set
Parameter Saline Control Liposome Bupivacaine
Smooth Implant
Initial distance between marks, in 1.003 1.001
Distance between marks after exposure, in 1.05 1.02
Mean tensile set, % (SD) 4.7 (0.9) 1.8 (0.5)
Textured Implant
Initial distance between marks, in 1.002 1.002
Distance between marks after exposure, in 1.027 1.012
Mean tensile set, % (SD) 2.4 (1.2) 1.0 (0.6)
Abbreviation: SD, standard deviation.

However, this is typical for liposome bupivacaine at elevated
temperatures and the increase was less for silicone-incubated
liposome bupivacaine than for liposome bupivacaine alone.
As anticipated, incubation at 37°C increased the level of
lipid breakdown products lyso-DEPC and erucic acid;30 the
increase in lyso-DEPC with silicone incubation is likely due
to a pH change caused by the silicone implants.
The lack of observable effects of co-incubation at
37°C on either the mechanical properties of silicone or
the ­characteristics of liposome bupivacaine demonstrates
that liposome bupivacaine is compatible with both smooth
and textured silicone. Additional assurance for the lack of
clinically relevant interaction between liposome bupivacaine
and silicone is provided by 2-year observational studies of
women (N  = 94) undergoing breast augmentation using
silicone implants. In 1 study, women received liposome
bupivacaine in 1 breast and bupivacaine HCl in the other;
in the other study, women were randomized to liposome

Table 5.  Liposome Bupivacaine Attributes Following Exposure to Smooth- and Textured-Type Silicone Implant Material
Attribute Liposome Bupivacaine Liposome Bupivacaine Liposome Bupivacaine Liposome Bupivacaine
Exposed to Textured Exposed to Smooth Incubated at 37°C Incubated at 2–8°C
Silicone Implant Silicone Implant for 7 Days (Control) for 7 Days (Control)
Incubated at 37°C Incubated at 37°C
for 7 Days for 7 Days
Total bupivacaine, mg/mL 14.0 13.8 13.7 13.9
Free bupivacaine, % 1.2 1.3 1.6 0.6
Packed particle volume, % 36.8 36.8 35.3 39.1
Particulates $ 10 μm 2338 4751 NA NA
Particulates $ 25 μm 118 279 NA NA
Particle size distribution,a μm
 d10 15.2 14.8 15.6 15.0
 d50 27.9 27.4 32.9 25.4
 d90 75.1 71.4 103.9 49.3
Lyso-DEPC,b μg/mL 149.4 143.5 101.6 68.3
Erucic acid,b μg/mL 167.8 167.2 156.3 138.7
Total bupivacaine-related ND ND ND ND
substances
Particle size distribution listed as volume weighted diameter; d10, d50, and d90 represent particle diameters at the 10th, 50th, and 90th volume percentiles, respectively, of the
a

particle size distribution.

b
Lyso-DEPC and erucic acid are lipid breakdown products.
Abbreviations: Lyso-DEPC, lyso-diethyl pyrocarbonate; NA, not assayed; ND, not detectable.

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 Review of Liposome Bupivacaine Compatibility Studies

bupivacaine or to bupivacaine HCl for treatment in both Other Local Anesthetics

breasts.29 There were no differences attributable to study
drugs between liposome bupivacaine–treated and bupiva-
caine HCl–treated breasts with respect to subject-reported
outcomes (eg, pain, tingling, numbness, unusual sensations)
or to physical examination findings,29 suggesting that the
use of liposome bupivacaine is compatible with silicone
breast augmentation.
Stainless Steel and Titanium
Both stainless steel and titanium are used in certain types
of surgical implants and liposome bupivacaine is also
manufactured in equipment constructed of 316L stainless
steel. To evaluate the effects of liposome bupivacaine on
these metal alloys and vice versa, samples of stainless steel
(316L, 72 cm2) and titanium (high strength: grade 5, 6 Al-4V,
57 cm2) were incubated in liposome bupivacaine or saline
for 7 days at 37°C.
There were no observable changes (damage or discolor-
ation) to the stainless steel or to the titanium alloy samples.
Attributes of liposome bupivacaine following incubation with
metal alloys and a control sample are shown in Table 6; there
were no clinically meaningful changes in these characteristics
relative to the control sample. The relative increase in particle
size distribution when particle diameters are at 90 percent of
volume distribution is typical of liposome bupivacaine upon
exposure to 37°C for 7 days.
Compatibility With Drugs
The principal focus when assessing the compatibility of
liposome bupivacaine with other drugs was on the impact
of exposure on the fraction of unencapsulated, or free, bupi-
vacaine and on particle size.
Bupivacaine HCl
The compatibility of liposome bupivacaine with bupi-
vacaine HCl was assessed using relative liposome
bupivacaine:bupivacaine HCl dilution ratios that ranged
from 24:1 to 1:12. Assessments were made immediately after
mixing and again after 24  hours. Results of these assess-
ments (Table 7) show that the extended-release properties
of liposome bupivacaine may be compromised at liposome
bupivacaine:bupivacaine HCl ratios # 1:12 because of the
excessive release of free bupivacaine (∼50% at the 1:12
ratio); however, release of free bupivacaine at liposome
bupivacaine:bupivacaine HCl ratios $ 2:1 was approxi-
mately equal to 5% or less. Therefore, liposome bupivacaine
may be co-administered into the same surgical site with
bupivacaine HCl formulations (eg, Marcaine, Sensorcaine)
at liposome bupivacaine:bupivacaine HCl ratios $ 2:1.
Lidocaine, Ropivacaine, and Mepivacaine
The compatibility of the local anesthetics lidocaine, ropi-
vacaine, and mepivacaine with liposome bupivacaine was
evaluated by co-incubation assays in various dilution ratios,
which were assessed immediately after mixing and after 1 and
24 hours. As summarized in Table 8, non–bupivacaine-based
local anesthetics have a strong interaction with liposome bupi-
vacaine and result in the rapid release of free bupivacaine from
liposomal vesicles at higher ratios of local anesthetic:liposome
bupivacaine. Co-incubation of non-bupivacaine local anes-
thetics with liposome bupivacaine at the same dilution ratios
changed the size distribution of liposome particles very little,
which shows that the release of free bupivacaine is not the
result of liposome particle disruption. Therefore, the exten-
sive release of bupivacaine from the ­liposome matrix upon

Table 6.  Liposome Bupivacaine Attributes Following Incubation With Stainless Steel and Titanium
Attribute Liposome Bupivacaine Incubated With Liposome Bupivacaine Incubated With Controla
Stainless Steel (316L) at 37°C for 7 Days Titanium (6AL-4V) at 37°C for 7 Days
Total bupivacaine, mg/mL 14.1 14.1 14.2
Free bupivacaine, % 5.6 5.7 5.7
Packed particle volume, % 35.7 36.4 36.4
Particle size distribution,b μm
 d10 14.6 14.6 14.3
 d50 43.0 45.9 39.9
 d90 251.3 240.7 186.8
Erucic acid,c μg/mL 42.8 43.3 42.1
Lyso-DEPC,c μg/mL 33.6 34.1 33.0
a
Control was liposome bupivacaine incubated with no metals for 7 days at 37°C.
b
Particle size distribution listed as volume weighted diameter; d10, d50, and d90 represent particle diameters at the 10th, 50th, and 90th volume percentiles, respectively, of the
particle size distribution.
c
Lyso-DEPC and erucic acid are lipid breakdown products.
Abbreviation: Lyso-DEPC, lyso-diethyl pyrocarbonate.

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Vladimir Kharitonov

Table 7.  Percentage of Encapsulated Bupivacaine Remaining in Liposome Bupivacaine Following Incubation With Bupivacaine HCl
Dose Ratio Liposome Bupivacaine HCl, mg Encapsulated Bupivacaine
(liposome bupivacaine: Bupivacaine, mg After Mixing, %
bupivacaine HCl) Immediately After 24 h
at RT at RT
24:1 266 12.5 99 98
5.2:1 155 33 NM 94
3.5:1 155 50 98 99
2:1 133 75 94 99
1:12 11 150 48 52
Abbreviations: NM, not measured; RT, room temperature.

co-incubation with other local anesthetics appears to result
from the stronger affinity for the matrix shown by the non-
bupivacaine local anesthetics, which leads to displacement
of bupivacaine from the matrix.
The in vivo interactions between liposome bupivacaine
and lidocaine were investigated in mini-pigs by administra-
tion of liposome bupivacaine at various time intervals and in
various dose ratios (1:2, 1:1, and 2:1) after administration at
the same site. A pig model was chosen for this study because
pig skin morphology and physiology closely resemble that of
humans.5 Blood samples were collected prior to administra-
tion of the study drug at 5, 10, 15, and 30 minutes, as well
as at 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 hours after study
drug administration. Maximum bupivacaine plasma levels
were elevated compared with liposome bupivacaine alone
when liposome bupivacaine was administered premixed
with lidocaine, or when the drug was administered at 1, 5, or
10 minutes following lidocaine administration, which indi-
cated an increase in free bupivacaine release in the presence
of lidocaine. However, the maximum bupivacaine plasma
level was reduced with increased time between administra-
tions and there was no evidence of an increased release of free
bupivacaine when liposome bupivacaine was administered
20 or 40 minutes after lidocaine administration.5
Overall, these results show that the release of free bupi-
vacaine from liposome bupivacaine is similar between lido-
caine, ropivacaine, or mepivacaine. Therefore, $ 20 minutes
should elapse between infiltration of any of these anesthetics
and liposome bupivacaine into the same surgical site.
Epinephrine
Compatibility of liposome bupivacaine with epinephrine was
evaluated at low, high, and clinically relevant epinephrine
concentrations, assessed immediately after mixing and after
24 hours. As summarized in Table 9, co-incubation of lipo-
some bupivacaine with epinephrine at high concentration, but
not at low concentration, led to a slight increase in the release
of free bupivacaine; however, particle size was not affected.
When co-incubated at concentrations approximating clini-
cally relevant levels (20 mL liposome bupivacaine [266 mg
bupivacaine] plus 0.6 mg epinephrine diluted to 80 mL), there
was only a small increase in free bupivacaine levels (13.8%
vs 10.6% for liposome bupivacaine control).
These results suggest that there is only a minor physi-
cochemical interaction between liposome bupivacaine
and epinephrine; therefore, epinephrine solutions may
be co-­a dministered in the same location as liposome
bupivacaine.

Table 8.  Percentage of Free Bupivacaine in Mixtures of Liposome Bupivacaine With Selected Local Anesthetics
Liposome Liposome Bupivacaine Drug Amount Free Bupivacaine, %
Bupivacaine: Concentration, Volume, Concentration, Volume, Initial 1h 24 h
Drug Ratio, w/w mg/mL mL mg/mL mLa RT RT
12:1 13.3 20 Lidocaine 5 5 9.4 9.1 8.1
1:32 2.2 5 20 20 89.0 89.0 89.0
12:1 13.3 20 Mepivacaine 5 5 14.5 14.2 12.0
1:32 2.2 5 20 20 101.9 101.7 101.6
30:1 13.3 20 Ropivacaine 2 5 7.1 7.5 7.5
1:16 2.2 5 10 20 75.0 84.4 85.4
N/A 13.3 1 Saline (control) N/A 1 2.3 2.7 2.9
N/A 13.3 1 N/A 30 8.7 11.1 12.5
a
As product labeling for liposome bupivacaine recommends a maximum liposome bupivacaine:diluent dilution factor of 1:14 for clinical use.
Abbreviations: N/A, not applicable; RT, room temperature; w/w, weight/weight.

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Table 9.  Percentage of Free Bupivacaine Following Incubation of Liposome Bupivacaine With Epinephrine
Liposome Bupivacaine Epinephrine
Concentration Volume Concentration
(mg/mL) (mL) (mg/mL)
13.3 20 1 0.025
2.2 5 1
Liposome bupivacaine control N/A
(diluted with saline to 2.5 mg/mL)
Abbreviations: N/A, not applicable; RT, room temperature.
Corticosteroids: Triamcinolone and
Methylprednisolone
The compatibility of liposome bupivacaine in ­combination
with the commonly used corticosteroids triamcinolone
acetonide and methylprednisolone was assessed using a
bracketing approach, which involved the co-incubation of
low and high concentrations of liposome bupivacaine with
each corticosteroid for 24 hours at room temperature. When
liposome bupivacaine at high concentration was incubated
with triamcinolone or methylprednisolone at low concen-
tration, there was no clinically meaningful effect on free
bupivacaine release, but there was an increase in particle
size. Because the corticosteroid suspensions have par-
ticle size distributions similar to liposome bupivacaine and
because the addition of liposome bupivacaine may have
reduced the  anti-aggregation effect of polysorbate 80  in
the corticosteroid suspensions, it is unclear whether the
change in particle size distribution represents the aggregation
of corticosteroid particles, liposome bupivacaine particles,
or a combination of both. When liposome bupivacaine at
low concentration was incubated with each corticosteroid at
high concentration, there was an increase in free bupivacaine
­levels approximately equal to 20% to 30% after 24 hours, but
there was no effect on particle size. There was no increase
in free bupivacaine levels with co-incubation at a clinically
relevant dose ratio of 3.75:1 (266 mg liposome bupivacaine:
80 mg methylprednisolone).
Based on these results, liposome bupivacaine may be
co-administered at the same location as methylpredniso-
lone or triamcinolone as long as the drugs are not premixed
beforehand.
Anti-infective Drugs
Bacitracin, Gentamicin, and Cefazolin
The compatibility of liposome bupivacaine with the antibiot-
ics bacitracin, gentamicin, and cefazolin was evaluated by
incubating 15 mL of liposome bupivacaine (200 mg bupiva-
caine) with 20 mL of a saline solution containing a mixture
of the 3 antibiotics (2000 units bacitracin, 3.2 mg ­gentamicin,
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Review of Liposome Bupivacaine Compatibility Studies
Free Bupivacaine (%)
Volume Initial 1h 24 h
(mL) RT RT
4.7 6.6 5.2
0.125 12.3 16.8 16.1
N/A 8.5 10.7 12.3
48 mg cefazolin) at 37°C for 24 hours. Co-incubation resulted
in only a very small increase in particle size distribution and
free bupivacaine levels. These antibiotics, which are com-
monly used to prevent postsurgical infection, may therefore
be co-administered with liposome bupivacaine.
Cefuroxime
The antibiotic cefuroxime is commonly used in knee surgery.
The compatibility of liposome bupivacaine with cefuroxime
was assessed by incubating 20 mL of liposome bupivacaine
(266 mg bupivacaine) with 1.5 g/16 mL of cefuroxime or saline
alone (control) at room temperature or at 37°C for 24 hours.
At room temperature, percent free bupivacaine increased to
6.3% immediately after mixing (percent free bupivacaine
was 5.4% in the control solution) and further increased to
8.3% after 4 hours and to 15.4% after 24 hours. At 37°C,
percent free bupivacaine increased dramatically to 90%.
Observation revealed that liposome bupivacaine particle
size decreased by a few microns at 24 hours. Based on the
observation of minimal changes after 4 hours of incubation
at room temperature, cefuroxime can be co-administered at
the same site with liposome bupivacaine.
Povidone Iodine
The compatibility of liposome bupivacaine with the ­topical
antiseptic povidone iodine, which is commonly used to
disinfect skin prior to surgical incisions, was assessed by
co-incubation of 15  mL liposome bupivacaine with 3  mL
povidone iodine for 24 hours at 37°C. Co-incubation resulted
in substantial and clinically meaningful changes in both
particle size and free bupivacaine levels; however, because
povidone iodine and similar disinfecting solutions are applied
topically and allowed to dry prior to surgical or needle pen-
etration, there is little possibility of contact with liposome
bupivacaine under normal use. Therefore, topical antiseptics
may be used in preparation for surgical procedures in which
liposome bupivacaine is administered as long as there is no
direct mixing between the 2 compounds. Notably, this also
means that if these compounds are used for the irrigation
Vladimir Kharitonov
of a wound, the wound should ideally be rinsed until clear
prior to the infiltration of liposome bupivacaine; in any case,
instillation of the liquid liposome bupivacaine into a cavity
where one of the disinfecting solutions is resting in liquid
form should be avoided.
Non-Steroidal Anti-inflammatory Drugs and Opioids
Evaluation of the compatibility of liposome bupivacaine
with the non-steroidal anti-inflammatory drugs ketorolac or
morphine was performed by co-incubating 266 mg liposome
bupivacaine in 80  mL saline with either 30  mg ketorolac
tromethamine or 10 mg morphine sulfate for 24 hours
at 37°C. The results of co-incubation are summarized in
Table 10 and show that there were minimal increases in free
bupivacaine levels; therefore, ketorolac or morphine may be
co-administered at the same site as liposome bupivacaine.
Anti-hypertensive and Anti-hemorrhagic Drugs
Clonidine
The compatibility of liposome bupivacaine with cloni-
dine was assessed by the co-incubation of 20 mL of lipo-
some bupivacaine (266 mg bupivacaine) with clonidine
0.08  mg/0.8  mL, clonidine 0.8  mg/8  mL, or saline alone
(control) at room temperature or at 37°C for 24 hours. Percent
free bupivacaine increased to 4.5% immediately after mixing
with clonidine 0.08 mg and to 5.1% with clonidine 0.8 mg
(percent free bupivacaine was 4.4% and 4.8% in the control
solutions, respectively) and remained essentially unchanged
after 24 hours of incubation at room temperature and at 37°C.
There was no change in liposome bupivacaine particle size
after 24 hours at room temperature and a slight increase in
particle size after 24 hours at 37°C. Based on these results,
liposome bupivacaine can be co-administered at the same
site with clonidine.
Tranexamic Acid
The compatibility of liposome bupivacaine with tranexamic
acid was assessed by co-incubation of 20 mL of liposome
bupivacaine (266 mg bupivacaine) with tranexamic acid
0.2 g/5 mL, tranexamic acid 2.0 g/50 mL, or saline alone
Table 10.  Percentage of Free Bupivacaine Following Incubation of Liposome Bupivacaine With Ketorolac and Morphine
Co-Incubated Druga
Control alone (liposome bupivacaine 266 mg)
Ketorolac tromethamine 30 mg + liposome bupivacaine 266 mg
Morphine sulfate 10 mg + liposome bupivacaine 266 mg
Test samples were diluted with NS to a total volume of 80 mL and incubated at 37°C for 24 hours.
a
Abbreviation: NS, normal saline.
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(control) at room temperature or at 37°C for 24 hours. In the
high-dilution tranexamic acid mixture (2.0 g/20 mL), percent
free bupivacaine increased to 5.7% immediately after mix-
ing (percent free bupivacaine was 6.1% in the saline control
solution). Percent free bupivacaine increased to 7.7% and
10.9% after 24 hours of incubation at room temperature and
at 37°C, respectively. There was no change in particle size
after 24 hours at room temperature, but there was a slight
increase in particle size after 24 hours at 37°C. These results
indicate that liposome bupivacaine can be co-administered
at the same site with tranexamic acid.
Compatibility With Other Potentially
Co-Administered Drugs Used in Total
Knee Arthroplasty
Because liposome bupivacaine is designed for use in surgical
settings that typically involve co-administration of multiple
other drugs, liposome bupivacaine was co-incubated with a
range of other medications according to the matrix summarized
in Table 11. The drugs listed in Table 11 were mixed with lipo-
some bupivacaine and then diluted to a total volume of 80 mL
with normal saline; all mixtures were incubated at ambient
temperature or at 37°C for 24 hours. The co-incubated drugs
included epinephrine, ketorolac, ropivacaine, methylpredni-
solone, morphine sulfate, and bupivacaine HCl.
Results of the co-incubation combination studies were
consistent with observed results from individual compat-
ibility studies. For example, the combination that included
the local anesthetic ropivacaine demonstrated immediate
release of encapsulated bupivacaine and an increase in par-
ticle size; therefore, combinations of liposome bupivacaine
and ropivacaine should be avoided. In contrast, the combi-
nation containing bupivacaine HCl showed no effect on the
amount of free bupivacaine, consistent with results observed
at liposome bupivacaine:bupivacaine HCl ratios $ 2:1. In
general, there was no evidence of synergism between the
tested drugs with respect to effects on liposome bupivacaine;
co-administration of liposome bupivacaine with various drug
combinations should be guided by results from individual
drug compatibility evaluations.
Initial Free Bupivacaine, % Final Free Bupivacaine, %
(24 h at 37°C)
10.6 14.2
5.8 8.3
6.5 9.8

Table 11.  Co-Incubation Matrix for Liposome Bupivacaine Compatibility Evaluation With Drugs Used in Knee Arthroplasty
Liposome Epinephrine Ketorolac Ropivacaine Methylprednisolone Morphine Sulfate Morphine Sulfate Bupivacaine
Bupivacaine 1 mg/mL Tromethamine 10 mg/mL 80 mg/mL
13.3 mg/mL 30 mg/mL
20 mL 0.5 mL 1 mL 30 mL
0.6 mL 1 mL
0.3 mL
0.5 mL
0.3 mL
0.3 mL
Discussion
When combined with existing knowledge of the physico-
chemical properties of liposome bupivacaine, the results of
the compatibility studies described here led to a number of
recommendations regarding the administration of liposome
bupivacaine. First, per package labeling, liposome bupiva-
caine should not be admixed with substances or drugs other
than normal saline prior to injection into surgical sites.
Second, non–bupivacaine-based local anesthetics, includ-
ing lidocaine, ropivacaine, and mepivacaine, may induce an
immediate release of bupivacaine from liposome bupivacaine
via displacement of bupivacaine if administered together
locally; therefore, administration of liposome bupivacaine
may follow the administration of these non–bupivacaine-
based local anesthetics after a delay $ 20 minutes. Third,
bupivacaine HCl may impact the pharmacokinetic and/or
physicochemical properties of liposome bupivacaine when
the milligram dose of bupivacaine HCl is . 50% of the
liposome bupivacaine dose. Liposome bupivacaine may
be co-administered into the same site immediately follow-
ing administration of bupivacaine HCl if the dose ratio of
­liposome bupivacaine to bupivacaine HCl is $  2:1. Co-­
administration of both drug forms will increase overall expo-
sure to bupivacaine. Fourth, when a topical antiseptic such as
povidone iodine is applied for disinfection prior to surgical
incision or needle insertion, the site should be allowed to
dry completely before liposome bupivacaine is administered
into the surgical site. If antiseptics are used for irrigation of
a wound, the wound should be rinsed until clear prior to the
infiltration of liposome bupivacaine. Fifth, in recognition that
physicians may choose to use liposome bupivacaine along
with other implantable materials and other agents, several
studies have been conducted to test such combinations.
Implantable materials, including polypropylene, ePTFE,
silicone, stainless steel, and titanium, are not affected by the
presence of liposome bupivacaine any more than they are by
saline. Likewise, these implantable materials do not affect the
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Review of Liposome Bupivacaine Compatibility Studies
Injection Pentahydrate HCl
1 mg/mL 10 mg/mL 5 mg/mL
1 mL 10 mL 24 mL
1 mL 10 mL
1 mL 1 mL
1 mL
properties of liposome bupivacaine; liposome bupivacaine
may be safely administered in the presence of these materials.
Sixth, liposome bupivacaine may be administered undiluted
(13.3 mg/mL3)or diluted in preservative-free normal saline
(0.9%) for injection or lactated Ringer’s solution in a maxi-
mum volume # 280 mL (ie, 1:14 dilution by volume). Per
product labeling, liposome bupivacaine must not be diluted
with water or other hypotonic agents, which will disrupt the
liposomal particle structure. Seventh, epinephrine may be
used locally in the same area in which liposome bupivacaine
has been administered.
Conclusion
This article reviews studies conducted to assess the compati-
bility of liposome bupivacaine with other drugs and materials.
Importantly, aside from normal saline, liposome bupivacaine
should not be admixed with other substances or drugs prior
to administration and appropriate precautions should be
taken when liposome bupivacaine is co-administered in the
same surgical area as other local anesthetics. The data and
recommendations outlined in this paper will help clinicians
maximize the safety and efficacy of liposome bupivacaine
and reduce the risk of AEs and/or compromised efficacy aris-
ing from compatibility issues with liposome bupivacaine.
Acknowledgments
The author would like to thank the Research and Develop-
ment personnel at Pacira Pharmaceuticals, Inc. for the work
performed to complete the compatibility studies.
Conflict of Interest Statement
Vladimir Kharitonov, PhD, is employed by Pacira Pharma-
ceuticals, Inc.
This study was funded by Pacira Pharmaceuticals, Inc.
Editorial assistance was provided by Peloton Advantage,
LLC, and supported by Pacira Pharmaceuticals, Inc. The
author was fully responsible for the content, editorial
Vladimir Kharitonov
d­ ecisions, and opinions expressed in the current article, and
did not receive an honorarium related to the development
of this manuscript.
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