BUPIVACAINE: 11,356 Adverse Event Reports & Safety Profile

SENSORCAINE-MPF / SENSORCAINE-MPF WITH EPINEPHRINE injections contains bupivacaine hydrochloride, a local anesthetic agent with and without epinephrine (as bitartrate) 1:200,000. The route of administration for SENSORCAINE-MPF / SENSORCAINE-MPF WITH EPINEPHRINE is parenterally by injection, for infiltration, perineural, caudal, epidural, or retrobulbar use. SENSORCAINE-MPF / SENSORCAINE-MPF WITH EPINEPHRINE injections are Methyl Paraben Free (MPF). SENSORCAINE/SENSORCAINE WITH EPINEPHRINE injections contains bupivacaine hydrochloride, a local anesthetic agent with and without epinephrine (as bitartrate) 1:200,000. The route of administration for SENSORCAINE / SENSORCAINE WITH EPINEPHRINE is parenterally by injection, for infiltration and perineural use. Bupivacaine hydrochloride is a white or almost white, crystalline powder or colorless crystals, soluble in water, freely soluble in alcohol. Bupivacaine is related chemically and pharmacologically to the aminoacyl local anesthetics. It is a homologue of mepivacaine and is chemically related to lidocaine. All three of these anesthetics contain an amide linkage between the aromatic nucleus and the amino, or piperidine group. They differ in this respect from the procaine-type local anesthetics, which have an ester linkage. Bupivacaine hydrochloride chemical name is 2-piperidinecarboxamide, 1-butyl- N -(2,6-dimethylphenyl)-, monohydrochloride, monohydrate. The molecular formula is C 18 H 28 N 2 O·HCl·H 2 O, with a molecular weight of 342.9 g/mol. Bupivacaine hydrochloride monohydrate has the following chemical structure: The pK a of bupivacaine (8.1) is similar to that of lidocaine (7.86). However, bupivacaine possesses a greater degree of lipid solubility and is protein bound to a greater extent than lidocaine. Epinephrine bitartrate is a white to greyish white or light brownish-grey, odorless, crystalline powder, freely soluble in water, slightly soluble in 96% ethanol and methanol, practically insoluble in chloroform, methylene chloride and ether. Epinephrine bitartrate chemical name is (-)-3,4-Dihydroxy- α [(methylamino)methyl] benzyl alcohol (+) tartrate (1:1) salt. The molecular formula is C 9 H 13 NO 3 ·C 4 H 6 O 6 , with a molecular weight of 333.29 g/mol. Epinephrine bitartrate has the following chemical structure: Bupivacaine Hydrochloride Monohydrate Chemical Structure Epinephrine Bitartrate Chemical Structure SENSORCAINE-MPF in single dose vials is a sterile, isotonic, clear, colorless, and preservative-free solution. Each mL contains 2.64 mg, 5.27 mg, or 7.92 mg of bupivacaine hydrochloride monohydrate (equivalent to 2.22 mg, 4.44 mg or 6.66 mg of bupivacaine, and also equivalent to 2.5 mg, 5.0 mg, or 7.5 mg of bupivacaine hydrochloride anhydrous; respectively), 8.0 mg sodium chloride for isotonicity, and sodium hydroxide and/or hydrochloric acid as pH adjusters. The pH of these solutions is adjusted to between 4.0 and 6.5. SENSORCAINE-MPF WITH EPINEPHRINE 1:200,000 (as bitartrate) in single dose vials is a sterile, isotonic, clear, colorless to slightly yellow and preservative-free solution. Each mL contains 2.64 mg, 5.27 mg, or 7.92 mg of bupivacaine hydrochloride monohydrate (equivalent to 2.22 mg, 4.44 mg or 6.66 mg of bupivacaine, and also equivalent to 2.5 mg, 5.0 mg or 7.5 mg bupivacaine hydrochloride anhydrous; respectively), 0.0091 mg or 9.09 mcg of epinephrine bitartrate (equivalent to 0.005 mg of epinephrine base), 0.5 mg sodium metabisulfite as an antioxidant, 0.2 mg citric acid (anhydrous) as a stabilizer, 8.0 mg sodium chloride for isotonicity, and sodium hydroxide and/or hydrochloric acid as pH adjusters. The pH of these solutions is adjusted to between 3.3 to 5.5. SENSORCAINE in multiple dose vials is a sterile, isotonic, clear, colorless solution. Each mL contains 2.64 mg, or 5.27 mg, of bupivacaine hydrochloride monohydrate (equivalent to 2.22 mg, or 4.44 mg of bupivacaine, and also equivalent to 2.5 mg and 5.0 mg of bupivacaine hydrochloride anhydrous; respectively), 8.0 g sodium chloride for isotonicity, 1 mg of methyl paraben as an antiseptic preservative and sodium hydroxide and/or hydrochloric acid as pH adjusters. The pH of these solutions is adjusted to between 4.0 and 6.5. SENSORCAINE WITH EPINEPHRINE 1:200,000 (as bitartrate) in multiple dose vials is a sterile, isotonic, clear, colorless to slightly yellow solution. Each mL contains 2.64 mg, or 5.27 mg, of bupivacaine hydrochloride monohydrate (equivalent to 2.22 mg, or 4.44 mg of bupivacaine, and also equivalent to 2.5 mg and 5.0 mg of bupivacaine hydrochloride anhydrous; respectively), 8.0 mg sodium chloride for isotonicity, 0.0091 mg or 9.09 mcg of epinephrine bitartrate (equivalent to 0.005 mg of epinephrine base), 1 mg methylparaben as an antiseptic preservative, 0.5 mg sodium metabisulfite as an antioxidant, 0.2 mg citric acid (anhydrous) as a stabilizer, and sodium hydroxide and/or hydrochloric acid as pH adjusters. The pH of these solutions is adjusted to between 3.3 to 5.5.

AND USAGE Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection are recommended for each type of block indicated to produce local or regional anesthesia or analgesia [see Dosage and Administration (2.2) ].

Bupivacaine Hydrochloride

Injection contains bupivacaine, an amide local anesthetic, and Bupivacaine Hydrochloride and Epinephrine Injection is a combination of bupivacaine, an amide local anesthetic, and epinephrine, an alpha and beta-adrenergic agonist.

Bupivacaine Hydrochloride Injection/Bupivacaine

Hydrochloride and Epinephrine Injection is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. For each type of block indicated to produce local or regional anesthesia or analgesia, specific concentrations and presentations are recommended. ( 1 , 2.2 ) Limitations of Use Not all blocks are indicated for use with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection given clinically significant risks associated with use. ( 1 , 2.2 , 4 , 5.1 , 5.4 , 5.5 , 5.7 , 5.9 ) Limitations of Use Not all blocks are indicated for use with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection given clinically significant risks associated with use [see Dosage and Administration (2.2) , Contraindications (4) , Warnings and Precautions (5.1 , 5.4 , 5.5 , 5.7 , 5.9) ] .

AND ADMINISTRATION

• Not for intrathecal use. ( 2.1 )
• Avoid use of solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia. ( 2.1 , 5.4 )
• Three mL of Bupivacaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) is recommended for use as a test dose prior to caudal and lumbar epidural blocks when clinical conditions permit. ( 2.4 )
• See full prescribing information for: o Recommended concentrations and dosages of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection according to type of block. ( 2.2 ) o Additional dosage and administration information pertaining to use in epidural anesthesia, test dose for caudal and lumbar epidural blocks, use in dentistry, and use in ophthalmic surgery. ( 2.3 , 2.4 , 2.5 , 2.6 )

2.1 Important Dosage and Administration Information

• Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is not for intrathecal use.
• Avoid use of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia [see Warnings and Precautions (5.4) ] .
• Discard unused portions of solution not containing preservatives, i.e., those supplied in single-dose vials, following initial use.
• Visually inspect this product for particulate matter and discoloration prior to administration whenever solution and container permit.

Bupivacaine Hydrochloride Injection/Bupivacaine

Hydrochloride and Epinephrine Injection are clear, colorless solutions. Do not administer solutions which are discolored or contain particulate matter.

• Mixing or the prior or intercurrent use of any other local anesthetic with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is not recommended because of insufficient data on the clinical use of such mixtures.

Administration

Precautions

• Bupivacaine Hydrochloride Injection Injection/Bupivacaine Hydrochloride and Epinephrine Injection are to be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed.
• Use Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection only if the following are immediately available: oxygen, cardiopulmonary resuscitative equipment and drugs, and the personnel resources needed for proper management of toxic reactions and related emergencies [see Warnings and Precautions (5.2) , Adverse Reactions (6) , Overdosage (10) ] .
• The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects related to local anesthetic systemic toxicity when additional local anesthetics are administered with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection [see Warnings and Precautions (5.2) , Drug Interactions (7.1) , Overdosage (10) ] .
• Aspirate for blood or cerebrospinal fluid (where applicable) prior to injecting Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, both the initial dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, a negative aspiration for blood or cerebrospinal fluid does not ensure against an intravascular or intrathecal injection [see Warnings and Precautions (5.9) ] .
• Avoid rapid injection of a large volume of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection and use fractional (incremental) doses when feasible.
• During major regional nerve blocks, such as those of the brachial plexus or lower extremity, the patient should have an indwelling intravenous catheter to assure adequate intravenous access. The lowest dosage of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection that results in effective anesthesia should be used to avoid high plasma levels and serious adverse reactions.
• Perform careful and constant monitoring of cardiovascular and respiratory (adequacy of oxygenation and ventilation) vital signs and the patient's level of consciousness after each local anesthetic injection.
• Use Bupivacaine Hydrochloride and Epinephrine Injection in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, or penis [see Warnings and Precautions (5.12) ] .

2.2 Recommended Concentrations and Dosages of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection The dosage of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient. Administer the smallest dosage and concentration required to produce the desired result. The types of block and recommended Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection concentrations are shown in Table 1.

Table

1. Types of Block and Recommended Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection Concentrations ✓= indicated use [see Warnings and Precautions (5.1) ]. Type of Block Bupivacaine Hydrochloride Bupivacaine Hydrochloride and Epinephrine 0.25% (2.5 mg/mL) 0.5% (5 mg/mL) 0.75% (7.5 mg/mL)

Bupivacaine Hydrochloride Injection

0.75% (7.5 mg/mL) is not recommended for nonobstetrical surgical procedures in pregnant patients. 0.25% (2.5 mg/mL) 0.5% (5 mg/mL) Local infiltration ✓ ✓ Peripheral nerve block ✓ ✓ ✓ ✓ Retrobulbar block ✓ Sympathetic block ✓ Caudal block Avoid use of multiple-dose vials of Bupivacaine Hydrochloride Injection and Bupivacaine Hydrochloride and Epinephrine Injection for caudal or epidural anesthesia [see Warnings and Precautions (5.4) ] . ✓ ✓ ✓ ✓ Lumbar epidural block ✓ ✓ ✓ (not for obstetrical anesthesia) ✓ ✓ Epidural test dose ✓ Dental block ✓ At recommended dosages, Bupivacaine Hydrochloride/Bupivacaine Hydrochloride and Epinephrine produces complete sensory block, but the effect on motor function differs among the three concentrations.

Table

2 provides information on the expected effect on motor function for the three concentrations.

Table

2. Types of Block and Recommended Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection Concentrations Bupivacaine Hydrochloride Injection Concentration Motor Function 0.25% (2.5 mg/mL) These products include Bupivacaine Hydrochloride Injection and Bupivacaine Hydrochloride and Epinephrine Injection [the epinephrine concentration (1:200,000) is not included in the table]. When used for caudal, epidural, or peripheral nerve block, produces incomplete motor block. Should be used for operations in which muscle relaxation is not important, or when another means of providing muscle relaxation is used concurrently. Onset of action may be slower than with the 0.5% (5 mg/mL) or 0.75% (7.5 mg/mL) solutions. 0.5% (5 mg/mL) Provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is essential. 0.75% (7.5 mg/mL) These are only Bupivacaine Hydrochloride Injection products [there is no 0.75% (7.5 mg/mL) concentration for Bupivacaine Hydrochloride and Epinephrine Injection]. Produces complete motor block. Most useful for epidural block in abdominal operations requiring complete muscle relaxation, and for retrobulbar anesthesia. Not for obstetrical anesthesia. The duration of anesthesia with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is such that for most indications, a single dose is sufficient. The maximum dosage limit within the recommended dosage range must be individualized in each case after evaluating the size and physical status of the patient, as well as the anticipated rate of systemic absorption from a particular injection site. The dosages in Table 3 are recommended as a guide for use in the average adult. These doses may be repeated once every three hours. Do not exceed a total daily dosage of 400 mg in 24 hours. The duration of anesthetic effect may be prolonged by the addition of epinephrine.

Table

3.

Recommended

Concentrations and Doses of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in Adults Type of Block Concentration of Bupivacaine Hydrochloride Injection Each Dose Motor Block With continuous (intermittent) techniques, repeat doses increase the degree of motor block. The first repeat dose of 0.5% (5 mg/mL) may produce complete motor block. Intercostal nerve block with 0.25% (2.5 mg/mL) also may produce complete motor block for intra-thoracic and upper intra-abdominal surgery. mL mg of Bupivacaine Hydrochloride Injection Local infiltration 0.25% (2.5 mg/mL) Solutions with or without epinephrine (i.e., applies to Bupivacaine Hydrochloride Injection and Bupivacaine Hydrochloride and Epinephrine Injection).

The Bupivacaine

Hydrochloride and Epinephrine Injection products include epinephrine (1:200,000). Up to 70 (without epinephrine) Up to 175 (without epinephrine) ― Up to 90 (with epinephrine) Up to 225 (with epinephrine) Peripheral nerve block 0.5% (5 mg/mL) 5–35 (without epinephrine) 25–175 (without epinephrine) moderate to complete 5–45 (with epinephrine) 25–225 (with epinephrine) 0.25% (2.5 mg/mL) 5–70 (without epinephrine) 12.5–175 (without epinephrine) moderate to complete 5–90 (with epinephrine) 12.5–225 (with epinephrine) Retrobulbar block [see Dosage and Administration (2.6) ] 0.75% (7.5 mg/mL) 2–4 15–30 complete Sympathetic block 0.25% (2.5 mg/mL) 20–50 50–125 ― Caudal block [see Dosage and Administration (2.4) ] 0.5% (5 mg/mL) 15–30 75–150 moderate to complete 0.25% (2.5 mg/mL) 15–30 37.5–75 moderate Lumbar epidural block [see Dosage and Administration (2.3) ] 0.75% (7.5 mg/mL) For single-dose use; not for intermittent epidural technique. Not for obstetrical anesthesia. 10–20 75–150 complete 0.5% (5 mg/mL) 10–20 50–100 moderate to complete 0.25% (2.5 mg/mL) 10–20 25–50 partial to moderate Epidural test dose [see Dosage and Administration (2.4) ] 0.5% (5 mg/mL) with epinephrine 2–3 10–15 (10–15 micrograms epinephrine) ― Dental [see Dosage and Administration (2.5) ] 0.5% (5 mg/mL) with epinephrine 1.8–3.6 per site 9–18 per site ―

2.3 Use in Epidural Anesthesia During the administration of epidural anesthesia, it is recommended that a test dose of Bupivacaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) be administered initially and the effects monitored before the full dose is given. When using a &quot;continuous&quot; catheter technique, test doses should be given prior to both the initial and all supplemental doses, because a catheter in the epidural space can migrate into a blood vessel or through the dura <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . During epidural administration, administer Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, 0.5% (5 mg/mL) and Bupivacaine Hydrochloride Injection 0.75% (7.5 mg/mL) solutions in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Administer injections slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Perform syringe aspirations before and during each supplemental injection in continuous (intermittent) catheter techniques. In obstetrics, use ONLY the 0.5% (5 mg/mL) and 0.25% (2.5 mg/mL) concentrations of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>; incremental doses of 3 mL to 5 mL of the 0.5% (5 mg/mL) solution not exceeding 50 mg to 100 mg at any dosing interval are recommended. Repeat doses should be preceded by a test dose containing epinephrine if not clinically contraindicated. Use only the single-dose vials for caudal or epidural anesthesia; avoid use of the multiple-dose vials for these procedures, which contain a preservative <span class="opacity-50 text-xs">[see Dosage and Administration (2.1 , 2.4) , Warnings and Precautions (5.4 , 5.9) ]</span> .

2.4 Test Dose for Caudal and Lumbar Epidural Blocks Three mL of Bupivacaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) is recommended for use as a test dose prior to caudal and lumbar epidural blocks when clinical conditions permit. This test dose may serve as a warning of unintended intravascular or intrathecal injection. Closely monitor for early clinical signs of toxicity following each test dose <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9) ]</span> . Allot adequate time for onset of spinal block to detect possible intrathecal injection. An intravascular or intrathecal injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal, or cardiovascular effects from the epinephrine <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2 , 5.9) , Overdosage (10) ]</span>.

2.5 Use in Dentistry Bupivacaine Hydrochloride and Epinephrine Injection 0.5% (5 mg/mL) is recommended for infiltration and block injection in the maxillary and mandibular area when a longer duration of local anesthesia is desired, such as for procedures generally associated with significant postoperative pain. The average dose of 1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg) may be used if necessary to produce adequate anesthesia after allowing 2 to 10 minutes for block onset <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span>. Use the lowest effective dose and allow time between injections; it is recommended that the total dose for all injection sites, spread out over a single dental sitting, not exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of 0.5% (5 mg/mL)

Bupivacaine

Hydrochloride and Epinephrine Injection). Inject slowly and with frequent aspirations.

2.6 Use in Ophthalmic Surgery When Bupivacaine Hydrochloride Injection 0.75% (7.5 mg/mL) is used for retrobulbar block, complete corneal anesthesia usually precedes onset of clinically acceptable external ocular muscle akinesia. Therefore, presence of akinesia rather than anesthesia alone should determine readiness of the patient for surgery <span class="opacity-50 text-xs">[see Warnings and Precautions (5.15) ]</span> .

ZYNRELEF is contraindicated in: Patients with a known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to any local anesthetic agent of the amide-type, NSAIDs, or to any of the other components of ZYNRELEF [see Warnings and Precautions (5.9 , 5.14) ] . Patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.9) ] . Patients undergoing obstetrical paracervical block anesthesia. The use of bupivacaine in this technique has resulted in fetal bradycardia and death [see Use in Specific Populations (8.1) ] . Patients undergoing coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1) ] . ZYNRELEF is contraindicated for: Patients with a known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to any local anesthetic agent of the amide-type, NSAIDs, or to any of the other components of ZYNRELEF ( 4 ) Patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients ( 4 ) Patients undergoing obstetrical paracervical block anesthesia ( 4 ) Patients undergoing coronary artery bypass graft (CABG) surgery ( 4 )

REACTIONS The following serious adverse reactions have been associated with bupivacaine hydrochloride in clinical trials and are described in greater detail in other sections of the labeling: Central Nervous System Reactions [see Warnings and Precautions (5.1) ]

Cardiovascular System

Reactions [see Warnings and Precautions (5.1) ]

Allergic

Reactions [see Warnings and Precautions (5.1) ] Chondrolysis [see Warnings and Precautions (5.1) ] Methemoglobinemia [see Warnings and Precautions (5.1) ] Accidental intravascular injection [see Warnings and Precautions (5.2) ] Adverse reactions reported with an incidence greater than or equal to 10% following EXPAREL administration via: Infiltration in adults were nausea, constipation, and vomiting ( 6.1 ). Nerve block in adults were nausea, pyrexia, headache, and constipation ( 6.1 ). Infiltration in pediatric patients six to less than 17 years of age were nausea, vomiting, constipation, hypotension, anemia, muscle twitching, blurred vision, pruritus, and tachycardia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Pacira Pharmaceuticals, Inc. at 1-855-RX-EXPAREL (1-855-793-9727) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adverse Reactions

Reported in All Local Infiltration Clinical Studies in Adults The safety of EXPAREL (local administration into the surgical site) was evaluated in 10 randomized, double-blind, clinical studies (including Studies 1 and 2 [see Clinical Studies (14.2) ] ) that included 823 adult patients who had various surgical procedures. Patients were administered an EXPAREL dose ranging from 66 to 532 mg (two times the maximum recommended dose of 266 mg). In these studies, following EXPAREL administration, the: Most common adverse reactions (incidence greater than or equal to 10%) were nausea, constipation, and vomiting. Common adverse reactions (incidence greater than or equal to 2% to less than 10%) were pyrexia, dizziness, peripheral edema, anemia, hypotension, pruritus, tachycardia, headache, insomnia, postoperative anemia, muscle spasms, hemorrhagic anemia, back pain, somnolence, and procedural pain. Less common adverse reactions (incidence less than 2%) were chills, erythema, bradycardia, anxiety, urinary retention, pain, edema, tremor, postural dizziness, paresthesia, syncope, incision site edema, procedural hypertension, procedural hypotension, procedural nausea, muscular weakness, neck pain, generalized pruritus, pruritic rash, hyperhidrosis, cold sweat, urticaria, palpitations, sinus bradycardia, supraventricular extrasystoles, ventricular extrasystoles, ventricular tachycardia, hypertension, pallor, anxiety, confusional state, depression, agitation, restlessness, hypoxia, laryngospasm, apnea, respiratory depression, respiratory failure, increased body temperature, increased blood pressure (BP), decreased BP, decreased oxygen saturation, urinary incontinence, blurred vision, tinnitus, drug hypersensitivity, and hypersensitivity. Neurological and Cardiac Adverse Reactions In the EXPAREL surgical site infiltration studies, following EXPAREL administration adverse reactions with an incidence greater than or equal to 1% in the: Nervous System Disorders system organ class were dizziness (6.2%), headache (3.8%), somnolence (2.1%), hypoesthesia (1.5%), and lethargy (1.3%).

Cardiac

Disorders system organ class were tachycardia (3.9%) and bradycardia (1.6%).

Adverse Reactions

Reported in All Local Infiltration Placebo-Controlled Trials in Adults Adverse reactions with an incidence greater than or equal to 2% reported by adult patients in clinical studies who underwent a bunionectomy (Study 1) or hemorrhoidectomy (Study 2) [see Clinical Studies (14.2) ] that compared 106 mg of EXPAREL (8 mL) to placebo and 266 mg of EXPAREL (20 mL) to placebo are shown in Table 1.

Table

1: Treatment-Emergent Adverse Reactions with an Incidence Greater than or Equal to 2%: Local Infiltration Placebo-Controlled Studies in Adults (Studies 1 and 2)

System Organ Class Preferred Term

Study 1 Study 1: Bunionectomy; Study 2 Study 2: Hemorrhoidectomy; EXPAREL Placebo EXPAREL Placebo 106 mg (N=97) n (%) (N=96) n (%) 266 mg (N=95) n (%) (N=94) n (%) TEAE = treatment-emergent adverse event. At each level of summation (overall, system organ class, preferred term), patients are only counted once. Preferred terms are included where at least 2% of patients reported the event in any treatment group. Any TEAE 53 (54.6) 59 (61.5) 10 (10.5) 17 (18.1)

Gastrointestinal Disorders

41 (42.3) 38 (39.6) 7 (7.4) 13 (13.8)

Nausea

39 (40.2) 36 (37.5) 2 (2.1) 1 (1.1)

Vomiting

27 (27.8) 17 (17.7) 2 (2.1) 4 (4.3)

Constipation

2 (2.1) 1 (1.0) 2 (2.1) 2 (2.1)

Anal Hemorrhage

0 (0.0) 0 (0.0) 3 (3.2) 4 (4.3)

Painful Defecation

0 (0.0) 0 (0.0) 2 (2.1) 5 (5.3)

Rectal Discharge

0 (0.0) 0 (0.0) 1 (1.1) 3 (3.2)

Nervous System Disorders

20 (20.6) 30 (31.3) 0 (0.0) 0 (0.0)

Dizziness

11 (11.3) 25 (26.0) 0 (0.0) 0 (0.0)

Headache

5 (5.2) 8 (8.3) 0 (0.0) 0 (0.0)

Somnolence

5 (5.2) 1 (1.0) 0 (0.0) 0 (0.0)

Syncope

2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)

Skin And Subcutaneous Tissue Disorders

8 (8.2) 7 (7.3) 0 (0.0) 0 (0.0)

Generalized Pruritus

5 (5.2) 6 (6.3) 0 (0.0) 0 (0.0)

Pruritus

3 (3.1) 1 (1.0) 0 (0.0) 0 (0.0)

Investigations

5 (5.2) 3 (3.1) 4 (4.2) 3 (3.2)

Increased Alanine Aminotransferase

3 (3.1) 3 (3.1) 1 (1.1) 0 (0.0)

Increased Aspartate Aminotransferase

3 (3.1) 2 (2.1) 0 (0.0) 0 (0.0)

Increased Blood Creatinine

2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)

Increased Body Temperature

0 (0.0) 0 (0.0) 3 (3.2) 3 (3.2)

General Disorders And Administration Site

Conditions 4 (4.1) 0 (0.0) 1 (1.1) 1 (1.1)

Feeling Hot

2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)

Pyrexia

2 (2.1) 0 (0.0) 1 (1.1) 1 (1.1)

Infections And Infestations

2 (2.1) 1 (1.0) 0 (0.0) 0 (0.0)

Fungal Infection

2 (2.1) 1 (1.0) 0 (0.0) 0 (0.0) Injury, Poisoning And Procedural Complications 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)

Post Procedural Swelling

2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)

Metabolism And Nutrition Disorders

2 (2.1) 2 (2.1) 0 (0.0) 0 (0.0)

Decreased Appetite

2 (2.1) 2 (2.1) 0 (0.0) 0 (0.0)

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 who had spine or cardiac surgical procedures was evaluated in one randomized, open-label, clinical study in which EXPAREL was administered by infiltration into the surgical site (Study Peds-1) and one single-arm, open-label study in which EXPAREL was administered by infiltration into the surgical site (Study Peds-2) [see Use in Specific Populations (8.4) ]. 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, following EXPAREL administration the: Most common adverse reactions (incidence greater than or equal to 10%) were nausea, vomiting, constipation, hypotension, anemia, muscle twitching, blurred vision, pruritus, and tachycardia. Common adverse reactions (incidence greater than or equal to 2% to less than 10%) were bradycardia, muscle spasms, tachypnea, oral hypoesthesia, postoperative anemia, dizziness, pyrexia, diarrhea, hypoacusis, hypoesthesia, back pain, hematuria, incontinence, muscular weakness, and visual impairment. Less common adverse reactions (incidence less than 2%) were flatulence, abdominal pain, dyspepsia, lip swelling, pain in extremity, musculoskeletal pain, flank pain, musculoskeletal chest pain, hypertension, sinus tachycardia, ventricular extrasystoles, dysgeusia, paresthesia, burning sensation, syncope, diplopia, eye swelling, dyspnea, atelectasis, hypopnea, hypoxia, chest pain, face edema, gait disturbance, generalized pruritus, rash, delayed recovery from anesthesia, fall, incision site hemorrhage, joint dislocation, seroma, hypomagnesemia, acidosis, hyperglycemia, metabolic acidosis, ear discomfort, decreased urine output, increased heart rate (HR), anxiety, panic attack, ear infection, and fungal wound infection. Neurological and Cardiac Adverse Reactions in Pediatric Patients Aged 6 to Less than 17 Years Old In the EXPAREL infiltration studies in pediatric patients aged 6 to less than 17 years old (Studies Peds-1 and Peds-2), following EXPAREL administration adverse reactions with an incidence greater than or equal to 1% in the: Nervous System Disorders system organ class were dizziness (6.3%, n=5), and dysgeusia (1.3%, n=1).

Cardiac

Disorders system organ class were tachycardia (11.3%, n=9), bradycardia (8.8%, n=7), sinus tachycardia (1.3%, n=1), and ventricular extrasystoles (1.3%, n=1).

Adverse Reactions

Reported in All Local Infiltration Trials in Pediatric Patients Aged 6 to Less than 17 Years Old Adverse reactions with an incidence greater than or equal to 2% reported by patients in clinical studies (Studies Peds-1 and Peds-2) studying 4 mg/kg EXPAREL are shown in Table 2.

Table

2: Treatment-Emergent Adverse Reactions (TEAE) with an Incidence Greater than or Equal to 2%: Local Infiltration Studies in Pediatric Patients Aged 6 to Less than 17 Years Old (Study Peds-1 and Peds-2)

System Organ Class Preferred Term

Study Peds-1 Study 1: Includes spine surgery patients aged 6 to less than 17 years old, and cardiac surgery patients aged 6 to less than 12 years old.

Study

Peds-2 Study 2: Includes spine surgery patients aged 12 to less than 17 years old.

Spine

Surgery EXPAREL 4 mg/kg Patients received EXPAREL 4 mg/kg, not to exceed 266 mg. (N=36) n (%)

Cardiac

Surgery EXPAREL 4 mg/kg (N=29) n (%)

Spine

Surgery EXPAREL 4 mg/kg (N=15) n (%) At each level of summation (overall, system organ class, preferred term), patients are only counted once. Preferred terms are included where at least 2% of patients reported the event in any treatment group. TEAE = treatment-emergent adverse event. Patients with at least one TEAE 24 (66.7) 9 (31.0) 15 (100.0) Blood and lymphatic system disorders 0 0 15 (100)

Anemia

0 0 15 (100) Cardiac disorders 3 (8.3) 1 (3.4) 12 (80.0)

Bradycardia

2 (5.6) 0 5 (33.3) Sinus tachycardia 0 1 (3.4) 0 Tachycardia 1 (2.8) 0 8 (53.3) Ventricular extrasystoles 0 0 1 (6.7) Ear and labyrinth disorders 2 (5.6) 0 2 (13.3) Ear discomfort 0 0 1 (6.7)

Hypoacusis

2 (5.6) 0 1 (6.7) Eye disorders 10 (27.8) 1 (3.4) 4 (26.7)

Diplopia

1 (2.8) 0 0 Eye swelling 0 0 1 (6.7)

Increased Lacrimation

0 0 0 Blurred Vision 7 (19.4) 1 (3.4) 3 (20.0) Visual impairment 2 (5.6) 0 0 Gastrointestinal disorders 18 (50.0) 7 (24.1) 14 (93.3)

Abdominal Pain

0 0 1 (6.7)

Constipation

9 (25.0) 4 (13.8) 7 (46.7)

Nausea

11 (30.6) 2 (6.9) 9 (60.0)

Diarrhea

3 (8.3) 0 0 Dyspepsia 1 (2.8) 0 0 Flatulence 0 0 1 (6.7)

Oral Hypoesthesia

4 (11.1) 0 2 (13.3)

Lip Swelling

0 0 1 (6.7)

Vomiting

10 (27.8) 4 (13.8) 8 (53.3) General disorders and administration site conditions 0 1 (3.4) 3 (20.0) Chest pain 1 (2.8) 0 0 Face edema 0 1 (3.4) 0 Gait disturbance 0 0 1 (6.7) Generalized edema 0 0 0 Pyrexia 0 0 3 (20.0) Infections and infestations 1 (2.8) 1 (3.4) 0 Ear infection 1 (2.8) 0 0 Fungal wound infection 0 1 (3.4) 0 Injury, poisoning and procedural complications 8 (22.2) 0 1 (6.7)

Postoperative Anemia

5 (13.9) 0 0 Delayed recovery from anesthesia 1 (2.8) 0 0 Fall 0 0 1 (6.7) Incision site hemorrhage 1 (2.8) 0 0 Joint dislocation 1 (2.8) 0 0 Procedural hemorrhage 0 0 0 Seroma 1 (2.8) 0 0 Metabolism and nutrition disorders 0 3 (10.3) 0 Acidosis 0 1 (3.4) 0 Hyperglycemia 0 1 (3.4) 0 Hypomagnesaemia 0 1 (3.4) 0 Metabolic acidosis 0 1 (3.4) 0 Musculoskeletal and connective tissue disorders 8 (22.2) 1 (3.4) 12 (80.0) Back pain 0 0 2 (13.3) Flank pain 0 0 1 (6.7) Muscle twitching 3 (8.3) 1 (3.4) 9 (60.0) Muscle spasms 4 (11.1) 0 3 (20.0) Muscular weakness 0 0 2 (13.3) Musculoskeletal pain 1 (2.8) 0 0 Musculoskeletal chest pain 0 0 1 (6.7) Pain in extremity 0 0 1 (6.7) Nervous system disorders 3 (8.3) 0 7 (46.7) Burning sensation 0 0 1 (6.7)

Dizziness

2 (5.6) 0 3 (20.0)

Dysgeusia

1 (2.8) 0 0 Headache 0 0 0 Hypoesthesia 0 0 3 (20.0)

Paresthesia

0 0 1 (6.7)

Syncope

1 (2.8) 0 0 Psychiatric disorders 0 2 (13.3)

Anxiety

0 0 1 (6.7) Panic attack 0 0 1 (6.7) Renal and urinary disorders 0 0 2 (13.3)

Hematuria

0 0 2 (13.3) Respiratory, thoracic and mediastinal disorders 3 (8.3) 1 (3.4) 7 (46.7)

Atelectasis

0 0 1 (6.7)

Bradypnea

0 0 0 Dyspnea 0 1 (3.4) 0 Hypopnea 1 (2.8) 0 0 Hypoxia 1 (2.8) 0 0 Pleural effusion 0 0 0 Tachypnea 1 (2.8) 0 6 (40.0) Skin and subcutaneous tissue disorders 4 (11.1) 0 6 (40.0)

Pruritus

3 (8.3) 0 6 (40.0)

Generalized Pruritus

1 (2.8) 0 0 Rash 0 0 1 (6.7) Vascular disorders 4 (11.1) 1 (3.4) 14 (93.3) Hot flush 0 0 0 Hypotension 4 (11.1) 0 14 (93.3)

Hypertension

0 1 (3.4) 0 Systolic hypertension 0 0 0 Adverse Reactions Reported in Placebo-Controlled Nerve Block Clinical Studies in Adults The safety of EXPAREL was evaluated in four randomized, double-blind, placebo-controlled nerve block clinical studies (Studies 3, 6, 7, 8) [see Clinical Studies (14.3 , 14.4) ] involving 469 EXPAREL-treated adult patients and 357 placebo-treated patients who had various surgical procedures. Patients were administered placebo or an EXPAREL dose of either 133 or 266 mg (two times the maximum recommended dose for these nerve blocks). In these studies, following EXPAREL administration via nerve block (perineural use) the: Most common adverse reactions (incidence greater than or equal to 10%) were nausea, pyrexia, and constipation. Common adverse reactions (incidence greater than or equal to 2% to less than 10%) were muscle twitching, dysgeusia, urinary retention, fatigue, headache, confusional state, hypotension, hypertension, oral hypoesthesia, generalized pruritus, hyperhidrosis, tachycardia, sinus tachycardia, anxiety, fall, increased body temperature, peripheral edema, sensory loss, increased hepatic enzyme, hiccups, hypoxia, and post-procedural hematoma. Less common adverse reactions (incidence less than 2%) were arrhythmia, atrial fibrillation, first degree atrioventricular block, bradycardia, left bundle branch block, right bundle branch block, cardiac arrest, impaired hearing, blurred vision, visual impairment, asthenia, chills, hyperthermia, cellulitis, lung infection, pneumonia, procedural nausea, wound dehiscence, wound secretion, electrocardiogram QT prolonged, white blood cell count increased, arthralgia, back pain, joint swelling, decreased mobility, muscle spasms, muscular weakness, musculoskeletal pain, paraesthesia, presyncope, sedation, somnolence, syncope, delirium, dysuria, urinary incontinence, atelectasis, cough, dyspnea, lung infiltration, blister, drug eruption, erythema, rash, urticaria, deep vein thrombosis, hematoma, and orthostatic hypotension. The most common and common adverse reactions for the four randomized, double-blind, placebo-controlled nerve block clinical studies (Studies 3, 6, 7, 8) are shown in Table 3. Neurological and Cardiac Adverse Reactions In the EXPAREL nerve block placebo-controlled studies, following EXPAREL administration adverse reactions with an incidence greater than or equal to 1% in the: Nervous System Disorders system organ class were motor dysfunction (14.9%), dysgeusia (7.2%), headache (5.1%), hypoesthesia (2.3%), and sensory loss (2.3%).

Cardiac

Disorders system organ class were tachycardia (3%), sinus tachycardia (2.3%), and bradycardia (1.3%).

Table

3: Treatment-Emergent Adverse Reactions with an Incidence Greater than or Equal to 2%: Nerve Block Placebo-Controlled Studies (Studies 3, 6, 7, and 8)

System Organ Class

Preferred Term EXPAREL 133 mg (N=168) n (%) EXPAREL 266 mg (N=301) n (%) Placebo (N=357) n (%) At each level of summation (overall, system organ class, preferred term), patients are only counted once. Preferred terms are included where at least 2% of patients reported the event in any treatment group. TEAE = treatment-emergent adverse event. Number of Patients with at Least One TEAE 152 (90.5) 260 (86.4) 299 (83.8) Blood and Lymphatic System Disorders 2 (1.2) 22 (7.3) 15 (4.2)

Anemia

2 (1.2) 18 (6.0) 13 (3.6)

Cardiac Disorders

13 (7.7) 34 (11.3) 38 (10.6)

Atrial Fibrillation

1 (0.6) 4 (1.3) 8 (2.2)

Sinus Tachycardia

3 (1.8) 8 (2.7) 4 (1.1)

Tachycardia

3 (1.8) 11 (3.7) 10 (2.8)

Gastrointestinal Disorders

84 (50.0) 154 (51.2) 184 (51.5)

Constipation

29 (17.3) 66 (21.9) 68 (19.0)

Dyspepsia

3 (1.8) 7 (2.3) 7 (2.0)

Oral Hypoesthesia

6 (3.6) 8 (2.7) 7 (2.0)

Nausea

62 (36.9) 111 (36.9) 133 (37.3)

Vomiting

17 (10.1) 55 (18.3) 73 (20.4)

General Disorders And Administration Site

Conditions 52 (31.0) 102 (33.9) 91 (25.5)

Fatigue

7 (4.2) 15 (5.0) 15 (4.2)

Feeling Cold

0 10 (3.3) 8 (2.2)

Peripheral Edema

4 (2.4) 6 (2.0) 8 (2.2)

Peripheral Swelling

3 (1.8) 8 (2.7) 4 (1.1)

Pyrexia

36 (21.4) 70 (23.3) 64 (17.9) Injury, Poisoning And Procedural Complications 18 (10.7) 44 (14.6) 32 (9.0)

Postoperative Anemia

0 8 (2.7) 10 (2.8)

Contusion

4 (2.4) 1 (0.3) 0 Fall 4 (2.4) 8 (2.7) 1 (0.3)

Post Procedural Hematoma

4 (2.4) 1 (0.3) 0 Procedural Hypotension 2 (1.2) 13 (4.3) 7 (2.0)

Investigations

18 (10.7) 31 (10.3) 31 (8.7)

Increased Body Temperature

1 (0.6) 10 (3.3) 4 (1.1)

Increased Hepatic Enzyme

7 (4.2) 1 (0.3) 3 (0.8) Metabolism and Nutrition Disorders 13 (7.7) 18 (6.0) 25 (7.0)

Hypokalemia

7 (4.2) 9 (3.0) 14 (3.9)

Musculoskeletal And Connective Tissue Disorders

22 (13.1) 47 (15.6) 41 (11.5)

Decreased Mobility

0 6 (2.0) 5 (1.4)

Muscle Twitching

14 (8.3) 21 (7.0) 25 (7.0)

Nervous System Disorders

72 (42.9) 101 (33.6) 112 (31.4)

Dizziness

8 (4.8) 28 (9.3) 40 (11.2)

Dysgeusia

12 (7.1) 22 (7.3) 21 (5.9)

Headache

14 ( 8.3) 10 (3.3) 10 (2.8)

Hypoesthesia

6 (3.6) 5 (1.7) 2 (0.6)

Motor Dysfunction

35 (20.8) 35 (11.6) 37 (10.4)

Sensory Loss

4 (2.4) 7 (2.3) 1 (0.3)

Psychiatric Disorders

10 (6.0) 33 (11.0) 44 (12.3)

Anxiety

3 (1.8) 9 (3.0) 6 (1.7)

Confusional State

3 (1.8) 15 (5.0) 14 (3.9)

Insomnia

5 (3.0) 10 (3.3) 19 (5.3)

Renal And Urinary Disorders

9 (5.4) 31 (10.3) 31 (8.7)

Urinary Retention

5 (3.0) 23 (7.6) 22 (6.2) Respiratory, Thoracic And Mediastinal Disorders 18 (10.7) 30 (10.0) 31 (8.7)

Dyspnea

2 (1.2) 4 (1.3) 8 (2.2)

Hiccups

4 (2.4) 4 (1.3) 1 (0.3)

Hypoxia

4 (2.4) 3 (1.0) 3 (0.8)

Skin And Subcutaneous Tissue Disorders

24 (14.3) 63 (20.9) 84 (23.5)

Hyperhidrosis

1 (0.6) 14 (4.7) 15 (4.2)

Pruritus

10 (6.0) 45 (15.0) 55 (15.4)

Generalized Pruritus

6 (3.6) 7 (2.3) 14 (3.9)

Vascular Disorders

16 (9.5) 30 (10.0) 44 (12.3)

Hypertension

3 (1.8) 15 (5.0) 21 (5.9)

Hypotension

11 (6.5) 8 (2.7) 19 (5.3)

Adverse Reactions

Reported in Active-Controlled Nerve Block Clinical Studies in Approved Populations The safety of EXPAREL was evaluated in two randomized, double-blind, active-controlled nerve block clinical studies in 189 adult patients who had a bunionectomy or a total knee arthroplasty (Studies 4 and 5) [see Clinical Studies (14.3) ] . Via nerve block, patients received 133 mg of EXPAREL, 266 mg of EXPAREL (two times the maximum recommended EXPAREL dose) [see Dosage and Administration (2.3) ] or 133 mg of EXPAREL admixed with 50 mg of bupivacaine HCl. In both of these studies the active comparator was 50 mg of bupivacaine HCl. The most common adverse reactions (incidence greater than or equal to 10%) in Studies 4 and 5 following: EXPAREL administration as a nerve block were nausea and constipation. Administration of EXPAREL admixed with bupivacaine as a nerve block were nausea, constipation, muscle spasms, and headache. The common adverse reactions (incidence greater than or equal to 2% to less than 10%) in Studies 4 and 5 following: EXPAREL administration as a nerve block were pruritus, vomiting, dyspepsia, headache, peroneal nerve palsy, rash and hypertension. Administration of EXPAREL admixed with bupivacaine as a nerve block were vomiting, dyspepsia, heart rate increased, hypokalaemia, hyponatraemia, back pain, disorientation, oropharyngeal pain, hypoaesthesia, pruritus, dizziness, insomnia, hypertension, hypoxia, hypotension, pyrexia, and tachycardia. The less common adverse reactions (incidence less than 2%) in Studies 4 and 5 following: EXPAREL administration as a nerve block were increased BP, pyrexia, arthralgia, insomnia, muscle spasms, asthenia, increased systolic BP, diarrhea, facial pain, migraine, muscle twitching, throat irritation, post procedural erythema, post procedural edema, dizziness, hypoesthesia, rhinorrhea, and paresthesia. Administration of EXPAREL admixed with bupivacaine as a nerve block were increased BP, procedural pain, rash, pruritic rash, anemia, anxiety, arthralgia, atrial fibrillation, decreased blood potassium, decreased BP, increased systolic BP, increased body temperature, bradycardia, confusional state, decreased appetite, diarrhea, dysarthria, fall, feeling cold, decreased HR, hot flush, joint swelling, leukocytosis, mental status changes, neuralgia, orthostatic hypotension, decreased oxygen saturation, pneumonia, post procedural hematoma, post procedural inflammation, post procedural swelling, pruritic rash, positive staphylococcus test, syncope, and urinary tract infection . The most common and common adverse reactions in adult patients in the active-controlled clinical studies are shown in Table 4.

Table

4: Treatment-Emergent Adverse Reactions with an Incidence Greater than or Equal to 2%: Nerve Block Active-Controlled Studies (Studies 4 and 5)

System Organ Class

Preferred Term EXPAREL 133 mg (N=81) n (%) EXPAREL 266 mg (N=22) n (%) EXPAREL 133 mg + Bupi (N = 86) n (%) Bupi (N=162) n (%) At each level of summation (overall, system organ class, preferred term), patients were only counted once. Preferred terms are included where at least 2% of patients reported the event in any treatment group. TEAE = treatment-emergent adverse event. Number of Patients with at Least One TEAE 42 (51.9) 13 (59.1) 77 (89.5) 116 (71.6)

Cardiac Disorders Tachycardia

0 0 4 (4.7) 5 (3.1)

Gastrointestinal Disorders Constipation

10 (12.3) 3 (13.6) 30 (34.9) 47 (29.0)

Dyspepsia

2 (2.5) 1 (4.5) 2 (2.3) 2 (1.2)

Nausea

13 (16) 9 (40.9) 34 (39.5) 49 (30.2)

Vomiting

4 (4.9) 5 (22.7) 5 (5.8) 13 (8.0)

General Disorders And Administration Site

Conditions Pyrexia 0 1 (4.5) 3 (3.5) 3 (1.9)

Investigations Increased

Heart rate 0 0 3 (3.5) 3 (1.9) Metabolism and Nutrition Disorders Hypokalemia 0 0 2 (2.3) 2 (1.2)

Hyponatremia

0 0 2 (2.3) 2 (1.2)

Musculoskeletal And Connective Tissue Disorders

Back pain 0 0 2 (2.3) 3 (1.9)

Muscle Spasms

2 (2.5) 0 11 (12.8) 10 (6.2)

Nervous System Disorders Dizziness

2 (2.5) 0 4 (4.7) 4 (2.5)

Headache

8 (9.9) 1 (4.5) 13 (15.1) 6 (3.7)

Hypoaesthesia

0 9 (12.7) 2 (2.1) 0 Peroneal Nerve Palsy 3 (3.7) 0 0 0 Psychiatric Disorders Disorientation 0 0 2 (2.3) 0 Insomnia 2 (2.5) 0 5 (5.8) 14 (8.6) Respiratory, Thoracic And Mediastinal Disorders Hypoxia 0 0 4 (4.7) 4 (2.5)

Oropharyngeal Pain

0 0 2 (2.3) 0 Skin And Subcutaneous Tissue Disorders Pruritus 6 (7.4) 1 (4.5) 6 (7.0) 9 (5.6)

Rash

4 (4.9) 1 (4.5) 1 (1.2) 1 (0.6)

Vascular Disorders Hypertension

3 (3.7) 1 (4.5) 5 (5.8) 7 (4.3)

Hypotension

0 0 3 (3.5) 9 (5.6)

Notable Adverse

Reactions from Active-Controlled Studies in Unapproved Populations The safety of EXPAREL was evaluated in a multicenter, randomized, double-blind, active-controlled trial in 119 patients undergoing foot and ankle procedures (Study 9) [see Clinical Studies (14.3) ] . Patients were administered a dose of either 266 mg EXPAREL, 266 mg EXPAREL admixed with 50 mg bupivacaine HCl, or 100 mg bupivacaine HCl. The following adverse reactions were observed following administration of EXPAREL or EXPAREL admixed with bupivacaine in Study 9 that either were not observed in Studies 4 and 5, or were observed at a higher frequency than was observed in Studies 4 and 5. These include: The most common adverse reactions (incidence greater than 10%) observed in Study 9 at higher frequencies than Studies 4 and 5: hypoesthesia (21% vs. 1% and 0%, respectively), paresthesia (10% vs. 1% and 0%, respectively). The common adverse reactions (incidence greater than or equal to 2% to less than 10%) observed in Study 9 but not in Studies 4 and 5: epistaxis, motor dysfunction, pain in extremity, skin abrasion, infusion site pain, muscular weakness.

6.2 Postmarketing Experience Because adverse reactions reported during postmarketing are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions are consistent with those observed in clinical studies and most commonly involve the following system organ classes: 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).

AND PRECAUTIONS Dose-Related Toxicity : Monitor cardiovascular and respiratory vital signs and patient's state of consciousness after application of ZYNRELEF ( 5.3 ). When using ZYNRELEF with other local anesthetics, overall local anesthetic exposure must be considered through 72 hours ( 5.3 ). Hepatotoxicity : If abnormal liver tests persist or worsen, perform a clinical evaluation of the patient ( 5.5 ). Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.6 , 7 ).

Heart

Failure and Edema : Avoid use of ZYNRELEF in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.7 ).

Renal

Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ZYNRELEF in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function ( 5.8 ).

Anaphylactic

Reactions : Seek emergency help if an anaphylactic reaction occurs ( 5.9 ). Risk of Joint Cartilage Necrosis and Degeneration with Unapproved Intra-articular Use : Animal studies evaluating the effects of ZYNRELEF following intra-articular administration in the knee joint demonstrated cartilage necrosis and degeneration ( 5.10 , 13.2 ). Chondrolysis : Limit exposure to articular cartilage due to the potential risk of chondrolysis ( 5.11 ). Methemoglobinemia : Cases of methemoglobinemia have been reported in association with local anesthetic use ( 5.12 ).

Serious Skin

Reactions : NSAIDs, including meloxicam, can cause serious skin adverse reactions. If symptoms present, evaluate clinically ( 5.14 ).

Drug

Reaction with Eosinophilia and Systemic Symptoms (DRESS) : If symptoms are present, evaluate clinically ( 5.15 ).

Fetal

Toxicity : Limit use of NSAIDs, including ZYNRELEF, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the ductus arteriosus ( 5.16 , 8.1 ).

Hematologic

Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.17 ).

5.1 Cardiovascular (CV)

Thrombotic

Events with NSAID Use Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. The risk of these events following single-dose local application of ZYNRELEF is uncertain. To minimize the potential risk for an adverse CV event in NSAID-treated patients, do not exceed the recommended dose. Physicians and patients should remain alert for the development of such events following treatment with ZYNRELEF, even in the absence of previous CV symptoms. Inform patients about the signs and symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as meloxicam, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2) ] .

Coronary Artery Bypass

Graft (CABG)

Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. ZYNRELEF is contraindicated in the setting of CABG [see Contraindications (4) ] . Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of ZYNRELEF in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ZYNRELEF is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. The risk of these events following single-dose local application of ZYNRELEF is uncertain.

5.2 Gastrointestinal Bleeding, Ulceration, and Perforation with NSAID Use NSAIDs, including meloxicam in ZYNRELEF, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Risk

Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most post marketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated Patients Use the recommended dose for each indicated surgical procedure. Avoid administration of analgesic doses of more than one NSAID at a time. If additional NSAID medication is indicated in the postoperative period, monitor patients for signs and symptoms of NSAID-related GI adverse reactions. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert for signs and symptoms of GI ulceration and bleeding following treatment with ZYNRELEF. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7) ] .

5.3 Dose-Related Toxicity The safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. The toxic effects of local anesthetics are additive. Avoid additional local anesthetic administration within 96 hours following ZYNRELEF instillation. If additional local anesthetic administration with ZYNRELEF cannot be avoided based on clinical need, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient&apos;s state of consciousness should be performed after administration of ZYNRELEF. Possible early warning signs of central nervous system (CNS) toxicity are restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, CNS depression, or drowsiness. Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death.

5.4 Risk of Use in Patients with Impaired Cardiovascular Function Patients with impaired cardiovascular function (e.g., hypotension, heart block) may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by ZYNRELEF. Monitor patients closely for blood pressure, heart rate, and ECG changes.

5.5 Hepatotoxicity Local Anesthetics, Including Bupivacaine 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. NSAIDs Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including meloxicam. The risk of these events following single-dose local application of ZYNRELEF is uncertain. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and &quot;flu-like&quot; symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), perform a clinical evaluation of the patient <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]</span> .

5.6 Hypertension NSAIDs, including meloxicam in ZYNRELEF, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> . Monitor blood pressure (BP) after administration of ZYNRELEF.

5.7 Heart Failure and Edema The Coxib and traditional NSAID Trialists&apos; Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of meloxicam may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> . The risk of these events following single-dose local application of ZYNRELEF is uncertain. Avoid the use of ZYNRELEF in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ZYNRELEF is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

5.8 Renal Toxicity and Hyperkalemia Renal Toxicity ZYNRELEF is a single-use product that contains an NSAID. Long-term administration of NSAIDs has resulted in renal papillary necrosis, renal insufficiency, acute renal failure, and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. The renal effects of meloxicam may hasten the progression of renal dysfunction in patients with preexisting renal disease. Because some meloxicam metabolites are excreted by the kidney, monitor patients for signs of worsening renal function. Correct volume status in dehydrated or hypovolemic patients prior to initiating ZYNRELEF. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of ZYNRELEF <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> . Avoid the use of ZYNRELEF in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If ZYNRELEF is used in patients with advanced renal disease, monitor patients for signs of worsening renal function <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

5.9 Anaphylactic Reactions NSAIDs Meloxicam, contained in ZYNRELEF, has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . Seek emergency help if an anaphylactic reaction occurs.

5.10 Risk of Joint Cartilage Necrosis with Unapproved Intra-articular Use The safety and effectiveness of intra-articular use of ZYNRELEF in orthopedic surgical procedures other than for foot and ankle procedures have not been established, and ZYNRELEF is not approved for use via other intra-articular administration routes. Animal studies evaluating the effects of ZYNRELEF following intra-articular administration in the knee joint demonstrated cartilage necrosis and degeneration <span class="opacity-50 text-xs">[see Nonclinical Toxicology (13.2) ]</span> .

5.11 Chondrolysis Limit exposure to articular cartilage due to the potential risk of chondrolysis. Intra-articular infusions of local anesthetics, following arthroscopic and other surgical procedures is an unapproved use, and there have been post marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of glenohumeral chondrolysis have been described in pediatric patients and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are associated with chondrolysis. The time of onset of symptoms, such as joint pain, stiffness, and loss of motion can be variable, but may begin as early as the 2 nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who have experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

5.12 Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue any oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

5.13 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma, which may include: chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, NSAIDs are contraindicated in patients with this form of aspirin sensitivity <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . When ZYNRELEF is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for exacerbation of asthma symptoms.

5.14 Serious Skin Reactions NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions. ZYNRELEF is contraindicated in patients with previous serious skin reactions to NSAIDs <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.15 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug

Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ZYNRELEF. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, evaluate the patient immediately and treat as clinically indicated.

5.16 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including ZYNRELEF, in pregnant women at about 30 weeks gestation and later. NSAIDs, including ZYNRELEF, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal

Renal Impairment Use of NSAIDs, including ZYNRELEF, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ZYNRELEF use to the lowest effective dose. Because meloxicam can be detected in plasma beyond 48 hours after administration of ZYNRELEF, consider ultrasound monitoring for oligohydramnios. If oligohydramnios occurs, follow up according to clinical practice [see Use in Specific Populations (8.1) ] .

5.17 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with ZYNRELEF has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including meloxicam, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> .

5.18 Masking of Inflammation and Fever The pharmacological activity of ZYNRELEF in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

PRECAUTIONS General: The safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use (See WARNINGS , ADVERSE REACTIONS , and OVERDOSAGE ). During major regional nerve blocks, the patient should have intravenous fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible.

Epidural

Anesthesia: During epidural administration of Bupivacaine Hydrochloride, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Injections should be made slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and the effects monitored before the full dose is given. When using a "continuous" catheter technique, test doses should be given prior to both the original and all reinforcing doses, because plastic tubing in the epidural space can migrate into a blood vessel or through the dura. When clinical conditions permit, the test dose should contain epinephrine (10 mcg to 15 mcg has been suggested) to serve as a warning of unintended intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient "epinephrine response" within 45 seconds, consisting of an increase in heart rate and/or systolic blood pressure, circumoral pallor, palpitations, and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart rate should be monitored for a heart rate increase. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a transient rise in systolic blood pressure. The test dose should also contain 10 mg to 15 mg of Bupivacaine Hydrochloride or an equivalent amount of another local anesthetic to detect an unintended intrathecal administration. This will be evidenced within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk).

The Test

Dose formulation of Bupivacaine Hydrochloride contains 15 mg of bupivacaine and 15 mcg of epinephrine in a volume of 3 mL. An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects. Injection of repeated doses of local anesthetics may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical status. Local anesthetics should also be used with caution in patients with hypotension or heartblock. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of CNS toxicity. Local anesthetic solutions containing a vasoconstrictor should be used cautiously and in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, or penis. Patients with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. Because amide-local anesthetics such as Bupivacaine Hydrochloride are metabolized by the liver, these drugs, especially repeat doses, 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. Local anesthetics should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by these drugs. Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are employed in patients during or following the administration of potent inhalation anesthetics. In deciding whether to use these products concurrently in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Because it is not known whether amide-type local anesthetics may trigger this reaction and because the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and prompt institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene (Consult dantrolene sodium intravenous package insert before using). Use in Head and Neck Area: Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental, and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anesthetic along the subdural space to the midbrain. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded (See DOSAGE AND ADMINISTRATION ). Use in Ophthalmic Surgery: Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block, as with all other regional procedures, the immediate availability of equipment, drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be assured (see also WARNINGS and Use In Head and Neck Area , above). As with other anesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions, which may occur following relatively low total doses. A concentration of 0.75% bupivacaine is indicated for retrobulbar block; however, this concentration is not indicated for any other peripheral nerve block, including the facial nerve, and not indicated for local infiltration, including the conjunctiva (see INDICATIONS AND USAGE and PRECAUTIONS , General ).

Mixing Bupivacaine

Hydrochloride with other local anesthetics is not recommended because of insufficient data on the clinical use of such mixtures.

When Bupivacaine Hydrochloride

0.75% is used for retrobulbar block, complete corneal anesthesia usually precedes onset of clinically acceptable external ocular muscle akinesia. Therefore, presence of akinesia rather than anesthesia alone should determine readiness of the patient for surgery. Use in Dentistry: Because of the long duration of anesthesia, when Bupivacaine Hydrochloride 0.5% with epinephrine is used for dental injections, patients should be cautioned about the possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advised not to chew solid foods or test the anesthetized area by biting or probing. Information for Patients: When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the package insert of Bupivacaine Hydrochloride. Patients receiving dental injections of Bupivacaine Hydrochloride should be cautioned not to chew solid foods or test the anesthetized area by biting or probing until anesthesia has worn off (up to 7 hours). Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

Clinically Significant Drug

Interactions: The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential. Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Patients who are administered local anesthetics are 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 nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine hydrochloride have not been conducted. The mutagenic potential and the effect on fertility of bupivacaine hydrochloride have not been determined. Pregnancy: There are no adequate and well-controlled studies in pregnant women.

Bupivacaine

Hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses. This does not exclude the use of Bupivacaine at term for obstetrical anesthesia or analgesia (See Labor and Delivery ). Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closure of the hard palate). The high doses are comparable to the daily maximum recommended human dose (MRHD) of 400 mg/day on a mg/m 2 body surface area (BSA) basis. No embryo-fetal effects were observed in rats at the high dose which caused increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level representing approximately 1/5th the MRHD on a BSA basis. In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, & 40 mg/kg/day, decreased pup survival was observed at the high dose. The high dose is comparable to the daily MRHD of 400 mg/day on a BSA basis. Labor and Delivery: SEE BOXED WARNING REGARDING OBSTETRlCAL USE OF 0.75% BUPIVACAINE HYDROCHLORIDE.

Bupivacaine

Hydrochloride is contraindicated for obstetrical paracervical block anesthesia. Local anesthetics rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity (See CLINICAL PHARMACOLOGY , Pharmacokinetics ). 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 CNS, peripheral vascular tone, and cardiac function. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient's legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable. Epidural, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Epidural anesthesia has been reported to prolong the second stage of labor by removing the parturient's reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. This has not been reported with bupivacaine. It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and gravid uterus displaced to the left.

Nursing

Mothers: Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. Because of the potential for serious adverse reactions in nursing infants from bupivacaine, a decision should be made whether to discontinue nursing or not administer bupivacaine, taking into account the importance of the drug to the mother.

Pediatric

Use: Until further experience is gained in pediatric patients younger than 12 years, administration of Bupivacaine Hydrochloride in this age group is not recommended. Continuous infusions of bupivacaine in children have been reported to result in high systemic levels of bupivacaine and seizures; high plasma levels may also be associated with cardiovascular abnormalities (See WARNINGS , PRECAUTIONS , and OVERDOSAGE ).

Geriatric

Use: Patients over 65 years, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with Bupivacaine Hydrochloride (See ADVERSE REACTIONS ). Elderly patients may require lower doses of Bupivacaine Hydrochloride (See PRECAUTIONS , Epidural Anesthesia and DOSAGE AND ADMINISTRATION ). In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger patients (See CLINICAL PHARMACOLOGY ). This product 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. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (See CLINICAL PHARMACOLOGY ).

INTERACTIONS Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs) : Monitor patients for bleeding who are concomitantly taking ZYNRELEF with drugs that interfere with hemostasis ( 7.2 ).

Ace

Inhibitors, Angiotensin Receptor Blockers (ARBs), or Beta-Blockers : Concomitant use with ZYNRELEF may diminish the antihypertensive effect of these drugs. Monitor blood pressure ( 7.2 ).

Ace

Inhibitors and ARBs : Concomitant use with ZYNRELEF in elderly, volume-depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function ( 7.2 ). Diuretics : NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effect ( 7.2 ).

7.1 Bupivacaine Drug Interactions In clinical studies, other local anesthetics (including ropivacaine and lidocaine) have been administered before, during, or after application of ZYNRELEF without evidence of local anesthetic systemic toxicity. Administration of ZYNRELEF with other formulations of local anesthetics, including bupivacaine liposome injectable suspension, has not been studied <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> . The toxic effects of local anesthetics are additive. Avoid additional use of local anesthetics within 96 hours following administration of ZYNRELEF. If co-administration cannot be avoided, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) , Warnings and Precautions (5.1) and Overdosage (10) ]</span> . 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 (Table 5).

Table

5. Examples of Drugs Associated with Methemoglobinemia Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine

7.2 Meloxicam Drug Interactions See Table 6 for clinically significant drug interactions with meloxicam.

Table

6.

Clinically Significant Drug

Interactions with Meloxicam Drugs that Interfere with Hemostasis Clinical Impact: Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of ZYNRELEF with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.17)] .

Aspirin Clinical

Impact: In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ] . Intervention: If aspirin is indicated in the postoperative period, monitor patients for signs and symptoms of GI bleeding [see Clinical Pharmacology (12.3) ] .

Ace

Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of ZYNRELEF and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of ZYNRELEF and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ] . When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Diuretics Clinical

Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs have reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Intervention: During concomitant use of ZYNRELEF with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects.

Digoxin Clinical

Impact: The concomitant use of NSAIDS with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of ZYNRELEF and digoxin, monitor serum digoxin levels.

Lithium Clinical

Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3) ] . Intervention: Monitor patients on lithium for signs of lithium toxicity.

Methotrexate Clinical

Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of ZYNRELEF and methotrexate, monitor patients for methotrexate toxicity.

Cyclosporine Clinical

Impact: Concomitant use of NSAIDs and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of ZYNRELEF and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity [see Warnings and Precautions (5.2) ] . Intervention: If additional NSAID or salicylate medication is indicated in the postoperative period, monitor patients for signs and symptoms of GI toxicity [see Clinical Pharmacology (12.3) ] .

Pemetrexed Clinical

Impact: Concomitant use of NSAIDs and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of ZYNRELEF and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.