Children's Hospitals Today - Summer 2022 - 7

DRUG INTERACTIONS
Pediatric Use
Brief Summary
(For full prescribing information refer to package insert)
INDICATIONS AND USAGE
EXPAREL is indicated for single-dose infiltration in patients aged 6 years
and older to produce postsurgical local analgesia and in adults as an
interscalene brachial plexus nerve block to produce postsurgical regional
analgesia.
Limitation of Use: Safety and efficacy has not been established in other
nerve blocks.
CONTRAINDICATIONS
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 and
death.
WARNINGS AND PRECAUTIONS
Warnings and Precautions Specific 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 amidecontaining
products.
Avoid additional use of local anesthetics 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 administration.
* epidural
* intrathecal
* regional nerve blocks other than interscalene brachial plexus nerve
block
* 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 these groups.
* patients younger than 6 years old for infiltration
* patients younger than 18 years old for interscalene brachial plexus
nerve block
* pregnant patients
The potential sensory and/or motor loss with EXPAREL is temporary and
varies in degree and duration depending on the site of injection and dosage
administered and may last for up to 5 days as seen in clinical trials.
ADVERSE REACTIONS
Clinical Trial Experience
Adverse Reactions Reported in Local Infiltration Clinical Studies
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.
Adverse Reactions Reported in All Local Infiltration Clinical Studies in
Pediatric Patients Aged 6 to Less Than 17 Years
The safety of EXPAREL in 110 pediatric patients between the age of 6
and 17 years old undergoing various surgical procedures was evaluated
in one randomized, open-label, clinical study in which EXPAREL was
administered by infiltration into the surgical site and one single-arm, openlabel
study in which EXPAREL was administered by infiltration into the
surgical site. Patients were administered a weight-based dose of EXPAREL
at 4 mg/kg (maximum dose of 266 mg) or bupivacaine HCl 2 mg/kg
(maximum dose of 175 mg). In these studies, the most common adverse
reactions (incidence greater than or equal to 10%) following EXPAREL
administration were nausea, vomiting, constipation, hypotension, anemia,
muscle twitching, vision blurred, pruritus, and tachycardia.
The common adverse reactions (incidence greater than or equal to 2%
to less than 10%) following EXPAREL administration were bradycardia,
muscle spasms, tachypnea, hypoesthesia oral, anemia postoperative,
dizziness, pyrexia, diarrhea, hypoacusis, hypoesthesia, back pain,
hematuria, incontinence, muscular weakness, and visual impairment.
Adverse Reactions Reported in Nerve Block Clinical Studies
The safety of EXPAREL was evaluated in four randomized, double-blind,
placebo-controlled nerve block clinical studies involving 469 patients
undergoing various surgical procedures. Patients were administered a
dose of either 133 or 266 mg of EXPAREL. In these studies, the most
common adverse reactions (incidence greater than or equal to 10%)
following EXPAREL administration were nausea, pyrexia, and constipation.
The common adverse reactions (incidence greater than or equal to 2%
to less than 10%) following EXPAREL administration as a nerve block
were muscle twitching, dysgeusia, urinary retention, fatigue, headache,
confusional state, hypotension, hypertension, hypoesthesia oral, pruritus
generalized, hyperhidrosis, tachycardia, sinus tachycardia, anxiety, fall,
body temperature increased, edema peripheral, sensory loss, hepatic
enzyme increased, hiccups, hypoxia, post-procedural hematoma.
Postmarketing Experience
These adverse reactions are consistent with those observed in clinical
studies and most commonly involve the following system organ classes
(SOCs): Injury, Poisoning, and Procedural Complications (e.g., drug-drug
interaction, procedural pain), Nervous System Disorders (e.g., palsy,
seizure), General Disorders And Administration Site Conditions (e.g., lack
of efficacy, pain), Skin and Subcutaneous Tissue Disorders (e.g., erythema,
rash), and Cardiac Disorders (e.g., bradycardia, cardiac arrest).
The toxic effects of local anesthetics are additive and their coadministration
should be used with caution including monitoring for
neurologic and cardiovascular effects related to local anesthetic systemic
toxicity. Avoid additional use of local anesthetics within 96 hours following
administration of EXPAREL.
Patients who are administered local anesthetics may be at increased risk
of developing methemoglobinemia when concurrently exposed to the
following drugs, which could include other local anesthetics:
Examples of Drugs Associated with Methemoglobinemia:
Class
Nitrates/Nitrites
Local anesthetics
Examples
nitric oxide, nitroglycerin, nitroprusside,
nitrous oxide
articaine, benzocaine, bupivacaine, lidocaine,
mepivacaine, prilocaine, procaine, ropivacaine,
tetracaine
Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea,
ifosfamide, rasburicase
Antibiotics
Antimalarials
Anticonvulsants
Other drugs
Bupivacaine
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.
Non-bupivacaine Local Anesthetics
EXPAREL should not be admixed with local anesthetics other than
bupivacaine. Nonbupivacaine 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. There
are no data to support administration of other local anesthetics prior to
administration of EXPAREL.
Other than bupivacaine as noted above, EXPAREL should not be admixed
with other drugs prior to administration.
Water and Hypotonic Agents
Do not dilute EXPAREL with water or other hypotonic agents, as it will result
in disruption of the liposomal particles
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
There are no studies conducted with EXPAREL in pregnant women.
In animal reproduction studies, embryo-fetal deaths were observed
with subcutaneous administration of bupivacaine to rabbits during
organogenesis at a dose equivalent to 1.6 times the maximum
recommended human dose
(MRHD)
of
266
mg.
Subcutaneous
administration of bupivacaine to rats from implantation through weaning
produced decreased pup survival at a dose equivalent to 1.5 times the
MRHD [see Data]. Based on animal data, advise pregnant women of the
potential risks to a fetus.
The background risk of major birth defects and miscarriage for the
indicated population is unknown. However, the background risk in the U.S.
general population of major birth defects is 2-4% and of miscarriage is
15-20% of clinically recognized pregnancies.
Clinical Considerations
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.
Data
Animal Data
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 embryofetal
deaths was observed in rabbits at the high dose in the absence of
maternal toxicity.
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).
Lactation
Risk Summary
Limited published literature reports that bupivacaine and its metabolite,
pipecoloxylidide, are present in human milk at low levels. There is no
available information on effects of the drug in the breastfed infant or effects
of the drug on milk production. The developmental and health benefits of
breastfeeding should be considered along with the mother's clinical need
for EXPAREL and any potential adverse effects on the breastfed infant from
EXPAREL or from the underlying maternal condition.
dapsone, nitrofurantoin, para-aminosalicylic
acid, sulfonamides
chloroquine, primaquine
Phenobarbital, phenytoin, sodium valproate
acetaminophen, metoclopramide, quinine,
sulfasalazine
The safety and effectiveness of EXPAREL for single-dose infiltration to
produce postsurgical local anesthesia have been established in pediatric
patients aged 6 years and older. Use of EXPAREL for this indication is
supported by evidence from adequate and well-controlled studies in adults
with additional pharmacokinetic and safety data in pediatric patients aged
6 years and older.
Safety and effectiveness have not been established in pediatric patients
aged less than 6 years old for local infiltration or less than 18 years old for
interscalene brachial plexus nerve block.
Geriatric Use
Of the total number of patients in the EXPAREL local infiltration 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. Of the total
number of patients in the EXPAREL nerve block clinical studies (N=531),
241 patients were greater than or equal to 65 years of age and 60 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 identified differences
in efficacy or safety between elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.
Hepatic Impairment
Amide-type local anesthetics, such as bupivacaine, are metabolized by
the liver. Patients with severe hepatic disease, because of their inability to
metabolize local anesthetics normally, are at a greater risk of developing
toxic plasma concentrations, and potentially local anesthetic systemic
toxicity.
Therefore, consider increased monitoring for local anesthetic
systemic toxicity in subjects with moderate to severe hepatic disease.
Renal Impairment
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. This should be considered when performing dose selection
of EXPAREL.
OVERDOSAGE
Clinical Presentation
Acute emergencies from local anesthetics are generally related to high plasma
concentrations encountered during therapeutic use of local anesthetics or to
unintended intravascular injection of local anesthetic solution.
Signs and symptoms of overdose include CNS symptoms (perioral
paresthesia, dizziness, dysarthria, confusion, mental obtundation, sensory
and visual disturbances and eventually convulsions) and cardiovascular
effects (that range from hypertension and tachycardia to myocardial
depression, hypotension, bradycardia and asystole).
Plasma levels of bupivacaine associated with toxicity can vary. Although
concentrations of 2,500 to 4,000 ng/mL have been reported to elicit early
subjective CNS symptoms of bupivacaine toxicity, symptoms of toxicity
have been reported at levels as low as 800 ng/mL.
Management of Local Anesthetic Overdose
At the first sign of change, oxygen should be administered.
The first step in the management of convulsions, as well as underventilation
or apnea, consists of immediate attention to the maintenance of a patent
airway and assisted or controlled ventilation with oxygen and a delivery
system capable of permitting immediate positive airway pressure by
mask. Immediately after the institution of these ventilatory measures,
the adequacy of the circulation should be evaluated, keeping in mind
that drugs used to treat convulsions sometimes depress the circulation
when administered intravenously. Should convulsions persist despite
adequate respiratory support, and if the status of the circulation permits,
small increments of an ultra-short acting barbiturate (such as thiopental
or thiamylal) or a benzodiazepine (such as diazepam) may be administered
intravenously. The clinician should be familiar, prior to the use of
anesthetics, with these anticonvulsant drugs. Supportive treatment of
circulatory depression may require administration of intravenous fluids
and, when appropriate, a vasopressor dictated by the clinical situation
(such as ephedrine to enhance myocardial contractile force).
If not treated immediately, both convulsions and cardiovascular
depression can result in hypoxia, acidosis, bradycardia, arrhythmias and
cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary
resuscitative measures should be instituted.
Endotracheal intubation, employing drugs and techniques familiar to the
clinician, maybe indicated, after initial administration of oxygen by mask,
if difficulty is encountered in the maintenance of a patent airway or if
prolonged ventilatory support (assisted or controlled) is indicated.
DOSAGE AND ADMINISTRATION
Important Dosage and Administration Information
* EXPAREL is intended for single-dose administration only.
* Different formulations of bupivacaine are not bioequivalent even if the
milligram strength is the same. Therefore, it is not possible to convert
dosing from any other formulations of bupivacaine to EXPAREL.
* DO NOT dilute EXPAREL with water or other hypotonic agents, as it
will result in disruption of the liposomal particles.
* Use suspensions of EXPAREL diluted with preservative-free normal
(0.9%) saline for injection or lactated Ringer's solution within 4 hours
of preparation in a syringe.
* Do not administer EXPAREL if it is suspected that the vial has been
frozen or exposed to high temperature (greater than 40°C or 104°F)
for an extended period.
* Inspect EXPAREL visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Do
not administer EXPAREL if the product is discolored.
Recommended Dosing
Local Analgesia via Infiltration Dosing in Adults
The recommended dose of EXPAREL for local infiltration in adults is up to
a maximum dose of 266mg (20 mL), and is based on the following factors:
* Size of the surgical site
* Volume required to cover the area
* Individual patient factors that may impact the safety of an amide local
anesthetic
As general guidance in selecting the proper dosing, two examples of
infiltration dosing are provided:
* In patients undergoing bunionectomy, a total of 106 mg (8 mL)
of EXPAREL was administered with 7 mL infiltrated into the
tissues surrounding the osteotomy, and 1 mL infiltrated into the
subcutaneous tissue.

Children's Hospitals Today - Summer 2022

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