DRUG INTERACTIONS 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 amide- containing 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, open- label 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 co- administration 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
Examples
Nitrates/Nitrites Local anesthetics
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 embryo- fetal 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
Pediatric Use
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.
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