(For full prescribing information refer to package insert)
INDICATIONS AND USAGE
EXPAREL is indicated for administration into the surgical site to
produce postsurgical analgesia.
EXPAREL has not been studied for use in patients younger than 18 years
EXPAREL is contraindicated in obstetrical paracervical block anesthesia.
While EXPAREL has not been tested with this technique, the use of
bupivacaine HCl with this technique has resulted in fetal bradycardia
WARNINGS AND PRECAU TIONS
Warnings and Precautions Specifc for EXPAREL
As there is a potential risk of severe life-threatening adverse effects
associated with the administration of bupivacaine, EXPAREL should be
administered in a setting where trained personnel and equipment are
available to promptly treat patients who show evidence of neurological
or cardiac toxicity.
Caution should be taken to avoid accidental intravascular injection of
EXPAREL. Convulsions and cardiac arrest have occurred following
accidental intravascular injection of bupivacaine and other amide-containing products.
Using EXPAREL followed by other bupivacaine formulations has
not been studied in clinical trials. Formulations of bupivacaine other
than EXPAREL should not be administered within 96 hours following
administration of EXPAREL.
EXPAREL has not been evaluated for the following uses and, therefore,
is not recommended for these types of analgesia or routes of
• regional nerve blocks
• intravascular or intra-articular use
EXPAREL has not been evaluated for use in the following patient
population and, therefore, it is not recommended for administration to
• patients younger than 18 years old
• pregnant patients
The ability of EXPAREL to achieve effective anesthesia has not been
studied. Therefore, EXPAREL 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.
Clinical Trial Experience
The safety of EXPAREL was evaluated in 10 randomized, double-blind,
local administration into the surgical site clinical studies involving
823 patients undergoing various surgical procedures. Patients were
administered a dose ranging from 66 to 532 mg of EXPAREL. In these
studies, the most common adverse reactions (incidence greater than
or equal to 10%) following EXPAREL administration were nausea,
constipation, and vomiting.
The common adverse reactions (incidence greater than or equal
to 2% to less than 10%) following EXPAREL administration were
pyrexia, dizziness, edema peripheral, anemia, hypotension, pruritus,
tachycardia, headache, insomnia, anemia postoperative, muscle spasms,
hemorrhagic anemia, back pain, somnolence, and procedural pain.
EXPAREL can be administered in the ready to use suspension or diluted
to a concentration of up to 0.89 mg/mL (i.e., 1: 14 dilution by volume)
with normal (0.9%) saline or lactated Ringer’s solution. EXPAREL must
not be diluted with water or other hypotonic agents as it will result in
disruption of the liposomal particles.
EXPAREL should not be admixed with local anesthetics other than
bupivacaine. Non-bupivacaine based local anesthetics, including
lidocaine, may cause an immediate release of bupivacaine from
EXPAREL if administered together locally. The administration of
EXPAREL may follow the administration of lidocaine after a delay of
20 minutes or more.
Bupivacaine HCl administered together with EXPAREL may impact the
pharmacokinetic and/or physicochemical properties of EXPAREL, and
this effect is concentration dependent. Therefore, bupivacaine HCl and
EXPAREL may be administered simultaneously in the same syringe,
and bupivacaine HCl may be injected immediately before EXPAREL as
long as the ratio of the milligram dose of bupivacaine HCl solution to
EXPAREL does not exceed 1: 2.
The toxic effects of these drugs are additive and their administration
should be used with caution including monitoring for neurologic and
cardiovascular effects related to toxicity.
Other than bupivacaine as noted above, EXPAREL should not be
admixed with other drugs prior to administration.
USE IN SPECIFIC POPULATIONS
There are no studies conducted with EXPAREL in pregnant women.
In animal reproduction studies, embryo-fetal deaths were observed
with subcutaneous administration of bupivacaine to rabbits during
organogenesis at a dose equivalent to 1.6 times the maximum
recommended human dose (MRHD) of 266 mg. Subcutaneous
administration of bupivacaine to rats from implantation through weaning
produced decreased pup survival at a dose equivalent to 1.5 times the
MRHD [see Data]. Based on animal data, advise pregnant women of the
potential risks to a fetus.
The background risk of major birth defects and miscarriage for the
indicated population is unknown. However, the background risk in the
U. S. general population of major birth defects is 2-4% and of miscarriage
is 15-20% of clinically recognized pregnancies.
Labor or Delivery
Bupivacaine is contraindicated for obstetrical paracervical block
anesthesia. While EXPAREL has not been studied with this technique,
the use of bupivacaine for obstetrical paracervical block anesthesia has
resulted in fetal bradycardia and death.
Bupivacaine can rapidly cross the placenta, and when used for epidural,
caudal, or pudendal block anesthesia, can cause varying degrees of
maternal, fetal, and neonatal toxicity. The incidence and degree of toxicity
depend upon the procedure performed, the type, and amount of drug
used, and the technique of drug administration. Adverse reactions in the
parturient, fetus, and neonate involve alterations of the central nervous
system, peripheral vascular tone, and cardiac function.
Bupivacaine hydrochloride was administered subcutaneously to rats and
rabbits during the period of organogenesis (implantation to closure of
the hard plate). Rat doses were 4. 4, 13. 3, and 40 mg/kg/day (equivalent
to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA
comparisons and a 60 kg human weight) and rabbit doses were 1.3,
5. 8, and 22. 2 mg/kg/day (equivalent to 0.1, 0.4 and 1.6 times the MRHD,
respectively, based on the BSA comparisons and a 60 kg human weight).
No embryo-fetal effects were observed in rats at the doses tested with the
high dose causing increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of
Decreased pup survival was noted at 1.5 times the MRHD in a rat pre- and
post-natal development study when pregnant animals were administered
subcutaneous doses of 4. 4, 13. 3, and 40 mg/kg/day buprenorphine
hydrochloride (equivalent to 0.2, 0.5 and 1.5 times the MRHD,
respectively, based on the BSA comparisons and a 60 kg human weight)
from implantation through weaning (during pregnancy and lactation).
Limited published literature reports that bupivacaine and its’ metabolite,
pipecolylxylidide, are present in human milk at low levels. There is no
available information on effects of the drug in the breastfed infant
or effects of the drug on milk production. The developmental and
health benefts of breastfeeding should be considered along with the
mother’s clinical need for EXPAREL and any potential adverse effects
on the breastfed infant from EXPAREL or from the underlying maternal
Safety and effectiveness in pediatric patients have not been established.
Of the total number of patients in the EXPAREL surgical site infltration
clinical studies (N=823), 171 patients were greater than or equal to
65 years of age and 47 patients were greater than or equal to 75 years
of age. No overall differences in safety or effectiveness were observed
between these patients and younger patients. Clinical experience with
EXPAREL has not identifed differences in effcacy or safety between
elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out.
Because amide-type local anesthetics, such as bupivacaine, are
metabolized by the liver, these drugs should be used cautiously in
patients with hepatic disease. Patients with severe hepatic disease,
because of their inability to metabolize local anesthetics normally, are at
a greater risk of developing toxic plasma concentrations.
Bupivacaine is known to be substantially excreted by the kidney, and
the risk of toxic reactions to this drug may be greater in patients with
impaired renal function. Care should be taken in dose selection of
In the clinical study program, maximum plasma concentration (Cmax)
values of approximately 34,000 ng/mL were reported and likely refected
inadvertent intravascular administration of EXPAREL or systemic
absorption of EXPAREL at the surgical site. The plasma bupivacaine
measurements did not discern between free and liposomal-bound
bupivacaine making the clinical relevance of the reported values
uncertain; however, no discernible adverse events or clinical sequelae
were observed in these patients.
DOSAGE AND ADMINISTRATION
EXPAREL is intended for single-dose administration only.
The recommended dose of EXPAREL is based on the following factors:
• Size of the surgical site
• Volume required to cover the area
• Individual patient factors that may impact the safety of an amide
• Maximum dose of 266 mg ( 20 mL)
As general guidance in selecting the proper dosing for the planned
surgical site, two examples of dosing are provided. One example of
the recommended dose comes from a study in patients undergoing
bunionectomy. A total of 8 mL (106 mg) was administered as 7 mL of
EXPAREL infltrated into the tissues surrounding the osteotomy, and
1 mL infltrated into the subcutaneous tissue.
Another example comes from a study of patients undergoing
hemorrhoidectomy. A total of 20 mL (266 mg) of EXPAREL was diluted
with 10 mL of saline, for a total of 30 mL, divided into six 5 mL aliquots,
injected by visualizing the anal sphincter as a clock face and slowly
infltrating one aliquot to each of the even numbers to produce a feld block.
Admixing EXPAREL with drugs other than bupivacaine HCl prior to
administration is not recommended.
• Non-bupivacaine based local anesthetics, including lidocaine,
may cause an immediate release of bupivacaine from EXPAREL
if administered together locally. The administration of EXPAREL
may follow the administration of lidocaine after a delay of 20
minutes or more.
• Bupivacaine HCl administered together with EXPAREL may impact
the pharmacokinetic and/or physicochemical properties of EXPAREL,
and this effect is concentration dependent. Therefore, bupivacaine
HCl and EXPAREL may be administered simultaneously in the same
syringe, and bupivacaine HCl may be injected immediately before
EXPAREL as long as the ratio of the milligram dose of bupivacaine
HCl solution to EXPAREL does not exceed 1: 2.
The toxic effects of these drugs are additive and their administration
should be used with caution including monitoring for neurologic
and cardiovascular effects related to toxicity.
• When a topical antiseptic such as povidone iodine (e.g.,
Betadine®) is applied, the site should be allowed to dry before
EXPAREL is administered into the surgical site. EXPAREL should
not be allowed to come into contact with antiseptics such as
povidone iodine in solution.
Studies conducted with EXPAREL demonstrated that the most common
implantable materials (polypropylene, PTFE, silicone, stainless steel,
and titanium) are not affected by the presence of EXPAREL any more
than they are by saline. None of the materials studied had an adverse
effect on EXPAREL.
Non-Interchangeability with Other Formulations of Bupivacaine
Different formulations of bupivacaine are not bioequivalent even if the
milligram dosage is the same. Therefore, it is not possible to convert
dosing from any other formulations of bupivacaine to EXPAREL and
Local infltration of EXPAREL results in signifcant systemic plasma
levels of bupivacaine which can persist for 96 hours. Systemic plasma
levels of bupivacaine following administration of EXPAREL are not
correlated with local effcacy.
CLINICAL S TUDIES
The effcacy of EXPAREL was compared to placebo in two multicenter,
randomized, double-blinded clinical trials. One trial evaluated the
treatments in patients undergoing bunionectomy; the other trial evaluated
the treatments in patients undergoing hemorrhoidectomy.
A multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial evaluated the safety and effcacy of 106 mg ( 8 mL)
EXPAREL in 193 patients undergoing bunionectomy. The mean age was
43 years (range 18 to 72).
Study medication was administered directly into the site at the conclusion
of the surgery, prior to closure. There was an infltration of 7 mL of
EXPAREL into the tissues surrounding the osteotomy and 1 mL into the
Pain intensity was rated by the patients on a 0 to 10 numeric rating scale
(NRS) out to 72 hours. Postoperatively, patients were allowed rescue
medication ( 5 mg oxycodone/325 mg acetaminophen orally every 4 to
6 hours as needed) or, if that was insuffcient within the frst 24 hours,
ketorolac ( 15 to 30 mg IV). The primary outcome measure was the area
under the curve (AUC) of the NRS pain intensity scores (cumulative
pain scores) collected over the frst 24 hour period. There was a
signifcant treatment effect for EXPAREL compared to placebo. EXPAREL
demonstrated a signifcant reduction in pain intensity compared to
placebo for up to 24 hours (p<0.001).
A multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial evaluated the safety and effcacy of 266 mg
( 20 mL) EXPAREL in 189 patients undergoing hemorrhoidectomy. The
mean age was 48 years (range 18 to 86).
Study medication was administered directly into the site (greater than
or equal to 3 cm) at the conclusion of the surgery. Dilution of 20 mL of
EXPAREL with 10 mL of saline, for a total of 30 mL, was divided into
six 5 mL aliquots. A feld block was performed by visualizing the anal
sphincter as a clock face and slowly infltrating one aliquot to each of
the even numbers.
Pain intensity was rated by the patients on a 0 to 10 NRS at multiple
time points up to 72 hours. Postoperatively, patients were allowed
rescue medication (morphine sulfate 10 mg intramuscular every 4
hours as needed).
The primary outcome measure was the AUC of the NRS pain intensity
scores (cumulative pain scores) collected over the frst 72 hour period.
There was a signifcant treatment effect for EXPAREL compared to
This resulted in a decrease in opioid consumption, the clinical beneft of
which was not demonstrated.
Twenty-eight percent of patients treated with EXPAREL required no
rescue medication at 72 hours compared to 10% treated with placebo.
For those patients who did require rescue medication, the mean amount
of morphine sulfate intramuscular injections used over 72 hours was
22 mg for patients treated with EXPAREL and 29 mg for patients treated
The median time to rescue analgesic use was for 15 hours for patients
treated with EXPAREL and one hour for patients treated with placebo.
Pacira Pharmaceuticals, Inc.
San Diego, CA 92121 USA