APMA News - November/December 2021 - 71

ZYNRELEF™ (bupivacaine and meloxicam)
extended-release solution, for soft tissue or periarticular
instillation use
BRIEF SUMMARY OF PRESCRIBING INFORMATION
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
* Nonsteroidal anti-infl ammatory drugs (NSAIDs) cause an
increased risk of serious cardiovascular thrombotic events,
including myocardial infarction and stroke, which can be fatal.
This risk may occur early in treatment and may increase with
duration of use
* ZYNRELEF is contraindicated in the setting of coronary artery
bypass graft (CABG) surgery
* NSAIDs cause an increased risk of serious gastrointestinal (GI)
adverse events including bleeding, ulceration, and perforation
of the stomach or intestines, which can be fatal. These events
can occur at any time during use and without warning
symptoms. Elderly patients and patients with a prior history
of peptic ulcer disease and/or GI bleeding are at greater risk
for serious GI events
INDICATIONS AND USAGE
ZYNRELEF is indicated in adults for soft tissue or periarticular
instillation to produce postsurgical analgesia for up to 72 hours
after bunionectomy, open inguinal herniorrhaphy and total
knee arthroplasty.
Limitations of Use: Safety and effi cacy have not been established
in highly vascular surgeries, such as intrathoracic, large multilevel
spinal, and head and neck procedures.
DOSAGE AND ADMINISTRATION
Important Dosage and Administration Information: ZYNRELEF is
intended for single-dose administration only. Avoid intravascular
administration of ZYNRELEF. ZYNRELEF should be administered
in a setting where trained personnel and equipment are available
to promptly treat patients who show evidence of neurologic or
cardiac toxicity. Avoid additional use of local anesthetics within
96 hours following administration of ZYNRELEF. The safety of
concomitant administration of ZYNRELEF and other NSAID
medications has not been evaluated. If additional NSAID
medication is indicated in the post-operative period, monitor
patients for signs and symptoms of NSAID toxicity.
ZYNRELEF should only be prepared and administered with
the components provided in the ZYNRELEF kit. See ZYNRELEF
Instructions for Use included in the kit for complete administration
instructions.
ZYNRELEF is not indicated for the following routes of
administration: epidural, intrathecal, intravascular or intra-articular,
regional nerve blocks, pre-incisional, and pre-procedural
locoregional anesthetic techniques.
Administration Instructions: ZYNRELEF is applied without a needle
into the surgical site using a Luer lock cone-shaped applicator
attached to the syringe following fi nal irrigation and suction of
each layer and prior to suturing. Only apply ZYNRELEF to the
tissue layers below the skin incision and not directly onto the
subdermal layer or skin. Use only the amount necessary to coat
the tissues, such that ZYNRELEF does not leak from the surgical
wound after closure.
Dosing Instructions: The recommended dose of ZYNRELEF
(bupivacaine/meloxicam) is as follows:
− Bunionectomy: up to 2.3 mL to deliver 60 mg/1.8 mg
− Open inguinal herniorrhaphy: up to 10.5 mL to deliver
300 mg/9 mg
− Total knee arthroplasty: up to 14 mL to deliver 400 mg/12 mg
See full Prescribing Information for all important dosage and
administration information, preparation instructions and
compatibility considerations.
CONTRAINDICATIONS
ZYNRELEF is contraindicated in patients with known
hypersensitivity (eg, anaphylactic reactions and serious skin
reactions) to any amide local anesthetic, NSAIDs, or other
components of ZYNRELEF; with 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); undergoing obstetrical paracervical
block anesthesia; or undergoing coronary artery bypass graft
(CABG) surgery.
WARNINGS AND PRECAUTIONS
Cardiovascular (CV) Thrombotic Events with NSAID Use: To
minimize the risk of CV thrombotic events, do not exceed the
recommended dose. Monitor for serious CV events. Aspirin does
not mitigate the risk of these thrombotic events. In patients with a
recent MI, avoid the use of ZYNRELEF unless the benefi ts are expected
to outweigh the risk, and if used, monitor patients for signs
of cardiac ischemia. The risk of these events following single-dose
local application of ZYNRELEF is uncertain.
Gastrointestinal Bleeding, Ulceration, and Perforation with NSAID
Use: To minimize the risk of GI bleeding, do not exceed the
recommended dose and avoid using more than one NSAID
at a time. If additional NSAID medication is indicated in the
post-operative period, monitor patients for signs and symptoms of
NSAID-related GI adverse reactions. In high-risk patients, evaluate if
the benefi t outweighs the risk of bleeding, remain alert for GI
ulcerations and bleeding, and promptly evaluate and treat
suspected serious GI adverse events. In patients using concomitant
low-dose aspirin, monitor for GI bleeding.
Dose-Related Toxicity: The toxic eff ect of local anesthetics are
additive. When using with other local anesthetics, overall local
anesthetic exposure must be considered through 72 hours. Monitor
patients for neurologic and cardiovascular eff ects related to local
anesthetic systemic toxicity.
Risk of Use in Patients with Impaired Cardiovascular Function:
Patients with impaired cardiovascular function may be less able
to compensate for the prolongation of AV conduction. Monitor
patients closely for blood pressure, heart rate, and ECG changes.
Hepatotoxicity: Bupivacaine should be used cautiously in patients
with hepatic disease because of their inability to metabolize local
anesthetics normally. NSAIDs are associated with elevations of ALT
or AST and rare, sometimes fatal cases of severe hepatic injury. If
clinical signs and symptoms consistent with liver disease develop,
or if systemic manifestations occur, perform a clinical evaluation
of the patient. The risk of these events following single-dose local
application of ZYNRELEF is uncertain.
Hypertension: NSAID use in patients taking ACE inhibitors, thiazide
or loop diuretics may result in impaired blood pressure control.
Monitor blood pressure.
Heart Failure and Edema: NSAID use in patients with heart failure
may increase the risk of MI, hospitalization for heart failure, and
death. Additionally, fl uid retention and edema have been observed
with NSAIDs. Avoid use in patients with severe heart failure unless
the benefi t outweighs the risk of worsening heart failure; if used,
monitor for signs of worsening heart failure. The risk of these
events following single-dose local application of ZYNRELEF
is uncertain.
Renal Toxicity: NSAIDs may cause a dose-dependent reduction in
renal blood fl ow and overt renal decompensation. Additionally, the
metabolites of meloxicam are excreted by the kidney which may
hasten the progression of renal dysfunction in those with renal
disease. Correct dehydration and hypovolemia prior to initiating
ZYNRELEF. Avoid use in patients with advanced renal disease
unless benefi ts are expected to outweigh risk of worsening renal
function. Monitor renal function in patients with renal or hepatic
impairment, heart failure, dehydration, or hypovolemia.
Anaphylactic Reactions: Meloxicam has been associated with
anaphylactic reactions in patients with and without known
hypersensitivity to meloxicam and in patients with aspirin-sensitive
asthma. Seek emergency help if an anaphylactic reaction occurs.
Chondrolysis with Intra-Articular Infusion: Intra-articular infusions
of local anesthetics have been associated with chondrolysis.
ZYNRELEF is not approved for intra-articular infusion.
Methemoglobinemia: Local anesthetics have been associated with
methemoglobinemia. Treat with supportive care, and if necessary,
methylene blue, exchange transfusion, or hyperbaric oxygen.
Exacerbation of Asthma Related to Aspirin Sensitivity: NSAIDs are
contraindicated in patients with aspirin-sensitive asthma. When
ZYNRELEF is used in patients with preexisting asthma (without
known aspirin sensitivity), monitor patients for exacerbation of
asthma symptoms.
Serious Skin Reactions: NSAIDs can cause serious skin adverse
reactions such as exfoliative dermatitis, Stevens-Johnson
Syndrome, and toxic epidermal necrolysis, which can be fatal.
If symptoms present, evaluate clinically.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS):
NSAIDs may cause DRESS. If signs or symptoms are present,
evaluate the patient immediately and treat as clinically indicated.
Fetal Toxicity: NSAIDs may cause fetal renal dysfunction leading
to oligohydramnios at about 20 weeks gestation and premature
closure of the fetal ductus arteriosus at about 30 weeks gestation
or later. Limit use between about 20 to 30 weeks gestation, and
avoid use after about 30 weeks.
Hematologic Toxicity: NSAIDs may cause anemia due to occult
or gross blood loss, fl uid retention, or an incompletely described
eff ect on erythropoiesis. Co-morbid conditions such as coagulation
disorders or concomitant use of warfarin, other anticoagulants,
antiplatelet agents (eg, aspirin), SSRIs and SNRIs may increase this
risk. Monitor these patients' hemoglobin and hematocrit and for
signs or symtoms of anemia.
Masking of Infl ammation and Fever: NSAIDs reduce infl ammation,
and possibly fever, which may diminish detection of infections.
ADVERSE REACTIONS
The safety of ZYNRELEF has been evaluated in a total of 1067
patients undergoing various surgical procedures across 7
randomized, double-blind, bupivacaine- and placebo-controlled
studies designed to investigate ZYNRELEF to reduce postoperative
pain for 72 hours and the need for opioid analgesics. Among 504
patients who received ZYNRELEF in single doses of 60 mg/
1.8 mg to 400 mg/12 mg via instillation into the surgical site, the
most common adverse reactions (incidence greater than or equal to
10%) following ZYNRELEF administration were constipation,
vomiting, and headache. The most common adverse reactions
(≥ 5% and higher than placebo) in the following 3 studies were:
* Bunionectomy: 157 patients received ZYNRELEF 60 mg/1.8 mg
and the most common adverse reactions were dizziness, incision
site edema, headache, incision site erythema, bradycardia,
impaired healing, and muscle twitching. With the exception of
muscle twitching, these events were also higher for bupivacaine
HCl compared to placebo. A total of four subjects had delayed
bone healing (assessed by X-ray on days 28 and 42), with no
clinically meaningful diff erence between treatment groups.
Additional local infl ammatory adverse events observed at a
higher incidence for ZYNRELEF compared to placebo or
bupivacaine HCl included incision site cellulitis, wound dehiscence
and incision site infection.
* Herniorrhaphy: 163 patients received ZYNRELEF 300 mg/9 mg
and the most common adverse reactions were headache,
bradycardia, dysgeusia, and skin odor abnormal. With the
exception of skin odor abnormal, these events were also higher
for bupivacaine HCl compared to placebo.
* Total knee arthroplasty: 58 patients received ZYNRELEF
400 mg/12 mg and the most common reactions were nausea,
constipation, vomiting, hypertension, pyrexia, leukocytosis, and
pruritus. With the exception of hypertension, these events were
also higher for bupivacaine HCl compared to placebo.
Manufactured and marketed by:
Heron Therapeutics, Inc., 4242 Campus Point Court, Suite 200,
San Diego, CA, 92121, USA.
PP-HTX011-0102 05/21
DRUG INTERACTIONS
Bupivacaine Drug Interactions:
Local anesthetics: 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 (ie, bupivacaine
liposome injectable suspension) has not been studied. Drugs
associated with methemoglobinemia: Bupivicane may increase
risk of methemoglobinemia when concurrently used with nitrates,
local anesthetics, antineoplastic agents, antibiotics, antimalarials,
anticonvulsants, and other methemoglobinemia-associated drugs.
Meloxicam Drug Interactions:
Drugs That Interfere with Hemostasis: Meloxicam use with
anticoagulants has an increased risk of serious bleeding compared
to the use of either drug alone. Monitor patients with concomitant
use of ZYNRELEF with anticoagulants, antiplatelet agents, SSRIs,
and SNRIs for signs of bleeding. ACE Inhibitors, Angiotensin
Receptor Blockers (ARBs), or Beta-Blockers: Meloxicam may
diminish the antihypertensive eff ect of these drugs. Monitor blood
pressure. ACE Inhibitors and ARBs: Meloxicam use with ACE
inhibitors and ARBs in elderly, volume-depleted, or those with renal
impairment may result in deterioration of renal function. In such
high-risk patients, adequately hydrate and monitor for signs of
worsening renal function. Diuretics: NSAIDs can reduce natriuretic
eff ect of furosemide and thiazide diuretics. Monitor patients to
assure diuretic effi cacy, including antihypertensive eff ect. Digoxin:
NSAIDs increase the serum concentration and prolong the half-life
of digoxin. Monitor serum digoxin levels. Lithium: NSAIDs elevate
plasma lithium levels and reductions in renal lithium clearance.
Monitor for signs of lithium toxicity. Methotrexate: NSAIDs use with
methotrexate may increase risk for neutropenia, thrombocytopenia,
and other methotrexate-associated toxicities. Monitor for signs of
methotrexate toxicities. Cyclosporine: NSAIDs use with
cyclosporine may increase nephrotoxicity. Monitor for signs
of worsening renal function. Pemetrexed: Meloxicam used with
pemetrexed may increase myelosuppression, renal, and GI
toxicities. In patient with creatinine clearance 45 to 79 mL/min,
monitor for pemetrexed-associated toxicities.
OVERDOSE
No data are available with regard to overdose of ZYNRELEF.
Management of Local Anesthetic Overdose: At the fi rst sign
of change, oxygen should be administered. The fi rst step for
convulsions, underventilation, or apnea is immediate maintenance
of a patent airway and assisted or controlled ventilation capable
of immediate positive airway pressure. After assuring airway and
ventilation, evaluate and establish adequate circulation as indicated.
Drugs that treat convulsions may depress the circulation. If
convulsions persist despite adequate respiration, and if the
circulation permits, small increments of an ultra-short acting
barbiturate or a benzodiazepine may be administered
intravenously. Supportive treatment of circulatory depression may
require intravenous fl uids and, when appropriate, a vasopressor.
If not treated immediately, both convulsions and cardiovascular
depression can result in hypoxia, acidosis, bradycardia,
arrhythmias, and cardiac arrest. If cardiac arrest should occur,
standard cardiopulmonary resuscitative measures should be
instituted. Endotracheal intubation, employing drugs, and
techniques familiar to the clinician, may be indicated after initial
administration of oxygen by mask if maintenance of a patent
airway is inadequate or if prolonged ventilatory support
is indicated.
CLINICAL PHARMACOLOGY
ZYNRELEF contains bupivacaine, an amide local anesthetic, and
meloxicam, an NSAID. The contribution of each active ingredient in
ZYNRELEF has been studied in clinical studies in herniorrhaphy or
bunionectomy, utilizing ZYNRELEF and formulations of meloxicam
alone or bupivacaine alone in the ZYNRELEF vehicle. Meloxicam
alone provided negligible local analgesia and bupivacaine alone
provided greater analgesia compared with placebo through
24 hours post surgery, despite exposure to bupivacaine for
approximately 72 hours. Compared with bupivacaine alone in both
studies, ZYNRELEF demonstrated greater and longer analgesia
through 24, 48, and 72 hours. The instillation of ZYNRELEF into the
surgical site results in signifi cant systemic plasma levels of
bupivacaine and meloxicam through 96 hours. Systemic plasma
levels of bupivacaine or meloxicam following application of
ZYNRELEF do not correlate with local effi cacy.
PATIENT COUNSELING
Inform patients of the risks and mitigations for: CV thrombotic
events; GI bleeding, ulceration, and perforation, including the
increased risk of GI toxicity with use of NSAIDs in the postoperative
period; anaphylactic reactions; serious skin reactions, including
DRESS; methemoglobinemia; fetal toxicity; and temporary loss of
sensation near the surgical site.
This information is not comprehensive. Visit www.zynrelef.com to
obtain the full Prescribing Information, including Boxed Warning.
© 2021 Heron Therapeutics, Inc. All rights reserved. ZYNRELEF™ is
a trademark of Heron Therapeutics, Inc.
http://www.zynrelef.com
APMA News - November/December 2021

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