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Zynrelef

  • Generic Name: bupivacaine and meloxicam
  • Brand Name: Zynrelef

Zynrelef (Bupivacaine and Meloxicam) side effects drug center

 

PROFESSIONAL

CONSUMER

SIDE EFFECTS

 

Zynrelef Side Effects Center

What Is Zynrelef?

Zynrelef (bupivacaine and meloxicam) Extended-Release contains an amide local anesthetic, and a nonsteroidal anti-inflammatory drug (NSAID), and 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.

What Are Side Effects of Zynrelef?

Side effects of Zynrelef include:

Dosage for Zynrelef

The recommended doses of Zynrelef for bunionectomy is up to 2.3 mL to deliver 60 mg./1.8 mg. The recommended doses of Zynrelef for open inguinal herniorrhaphy is up to 10.5 mL to deliver 300 mg/9 mg. The recommended doses of Zynrelef for total knee arthroplasty is up to 14 mL to deliver 400 mg/12 mg.

Zynrelef In Children

Safety and effectiveness of Zynrelef in pediatric patients has not been established.

What Drugs, Substances, or Supplements Interact with Zynrelef?

Zynrelef may interact with other medicines such as:

  • drugs that interfere with hemostasis [anticoagulants (e.g., warfarin),
  • antiplatelet agents (e.g., aspirin),
  • selective serotonin reuptake inhibitors (SSRIs), and
  • serotonin norepinephrine reuptake inhibitors (SNRIs)],
  • ACE inhibitors,
  • angiotensin receptor blockers (ARBs),
  • beta-blockers,
  • diuretics,
  • nitrates/nitrites,
  • local anesthetics,
  • antineoplastic agents,
  • antibiotics,
  • antimalarials,
  • anticonvulsants,
  • acetaminophen,
  • metoclopramide,
  • quinine,
  • digoxin,
  • lithium,
  • methotrexate,
  • cyclosporine,
  • other NSAIDs or salicylates, and
  • pemetrexed.

Tell your doctor all medications and supplements you use.

Zynrelef During Pregnancy and Breastfeeding

Zynrelef is not recommended for use during pregnancy; it may harm a fetus. Avoid use of NSAIDs, including Zynrelef, in pregnant women at about 30 weeks gestation and later due to increased risk of premature closure of the fetal ductus arteriosus. 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. Limited data reports that bupivacaine and its primary metabolite, pipecoloxylidine (PPX), are present in breast milk at low levels. It is unknown if meloxicam passes into breast milk. Consult your doctor before breastfeeding.

Additional Information

Our Zynrelef (bupivacaine and meloxicam) Extended-Release Solution, for Soft Tissue or Periarticular Instillation Use Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

 

Zynrelef Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives, red rash, itching; sneezing, difficulty breathing; severe dizziness, vomiting; swelling of your face, lips, tongue, or throat.

Tell your caregivers at once if you have any of these serious side effects:

  • feeling anxious, restless, confused, dizzy, drowsy, or like you might pass out;
  • ringing in your ears, problems with speech or vision;
  • metallic taste in your mouth, numbness or tingling around your mouth;
  • muscle twitching, tremors, seizure (convulsions);
  • weak or shallow breathing;
  • fast heart rate, gasping, feeling unusually hot;
  • slow heart rate, weak pulse; or
  • little or no urination.

Seek medical attention right away if you develop a serious condition called methemoglobinemia. Symptoms include headache, fast heartbeats, shortness of breath, feeling tired or light-headed, or skin that looks pale, gray, or blue-colored.

Common side effects include:

  • weakness, long-lasting numbness or tingling;
  • feeling restless or drowsy;
  • tremors;
  • headache, blurred vision;
  • fast or slow heartbeats;
  • breathing problems;
  • chills or shivering;
  • back pain; or
  • nausea, vomiting.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Zynrelef (Bupivacaine and Meloxicam)

 

Zynrelef Professional Information

SIDE EFFECTS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

  • Cardiovascular System Reactions [see WARNINGS AND PRECAUTIONS]
  • Gastrointestinal Bleeding, Ulceration, and Perforation [see WARNINGS AND PRECAUTIONS]
  • Dose-Related Toxicity [see WARNINGS AND PRECAUTIONS]
  • Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
  • Hypertension [see WARNINGS AND PRECAUTIONS]
  • Heart Failure and Edema [see WARNINGS AND PRECAUTIONS]
  • Renal Toxicity and Hyperkalemia [see WARNINGS AND PRECAUTIONS]
  • Anaphylactic Reactions [see WARNINGS AND PRECAUTIONS]
  • Chondrolysis with Intra-Articular Infusion [see WARNINGS AND PRECAUTIONS]
  • Methemoglobinemia [see WARNINGS AND PRECAUTIONS]
  • Exacerbation of Asthma Related to Aspirin Sensitivity [see WARNINGS AND PRECAUTIONS]
  • Serious Skin Reactions [see WARNINGS AND PRECAUTIONS]
  • Drug Reaction with Eosinophilia and Systemic Toxicity (DRESS) [see WARNINGS AND PRECAUTIONS]
  • Fetal Toxicity [see WARNINGS AND PRECAUTIONS]
  • Hematologic Toxicity [see WARNINGS AND PRECAUTIONS]

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.

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 and saline placebocontrolled studies designed to investigate ZYNRELEF to reduce postoperative pain for 72 hours and the need for opioid analgesics. Patients treated with ZYNRELEF ranged in age from 18 to 85 years (median age 47 years), with 61.8% female, 78.9% White, 16.0% African-American, and 5.1% all other races.

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% and higher than saline placebo) following ZYNRELEF administration were constipation, vomiting, and headache.

Common Adverse Reactions

Three randomized, bupivacaine-controlled and saline placebo-controlled studies were conducted in patients undergoing bunionectomy (STUDY 1, Table 1), open inguinal herniorrhaphy (STUDY 2, Table 3), and total knee arthroplasty (STUDY 3, Table 4). The bunionectomy procedures in STUDY 1 were performed under regional anesthesia, a lidocaine Mayo block, and intravenous sedation. The herniorrhaphy procedures in STUDY 2 were performed under general anesthesia. The total knee arthroplasty procedures in STUDY 3 were performed under either general or spinal anesthesia. Patients in STUDY 1 and STUDY 2 were allowed opioid rescue with intravenous (IV) morphine and oral oxycodone, and/or non-opioid rescue with oral acetaminophen. Patients in STUDY 3 were pretreated with oral pregabalin and acetaminophen, and allowed opioid rescue with IV morphine and oral oxycodone postoperatively.

Table 1: Adverse Reactions with ZYNRELEF in Study 1 (Bunionectomy) Occurring with ≥5% Incidence and Higher than with Saline Placebo

Preferred Term Saline Placebo
(N=101), %		 Bupivacaine HCl 50 mg
(N=154), %		 ZYNRELEF 60 mg/1.8 mg
(N=157), %
Dizziness 18 23 22
Incision site edema 13 14 17
Headache 10 13 14
Incision site erythema 8 12 13
Bradycardia 6 8 8
Impaired healing 1 4 6
Muscle twitching 5 5 6

In STUDY 1, bone healing was assessed by X-ray on Days 28 and 42. There was no clinically meaningful difference in bone healing between treatment groups. A total of four subjects had delayed bone healing: 1 in the ZYNRELEF group, 1 in the saline placebo group, and 2 in the bupivacaine HCl group.

The incidence of local inflammatory adverse events was higher in the ZYNRELEF group than in either control group (Table 2).

Table 2: Incidence of Local Inflammatory Adverse Events with ZYNRELEF in Study 1 (Bunionectomy) Occurring with ≥2% Incidence and Higher than with Saline Placebo

Saline Placebo
(N=101), %		 Bupivacaine HCl 50 mg
(N=154), %		 ZYNRELEF 60 mg/1.8 mg
(N=157), %
Incision site edema 13 14 17
Incision site erythema 8 12 13
Impaired healing 1 4 6
Incision site cellulitis 1 1 4
Wound dehiscence 2 1 4
Incision site infection 0 1 3

Table 3: Adverse Reactions with ZYNRELEF in Study 2 (Herniorrhaphy) Occurring with ≥5% Incidence and Higher than with Saline Placebo

Preferred Term Saline Placebo
(N=82), %		 Bupivacaine HCl 75 mg
(N=173), %		 ZYNRELEF 300 mg/9 mg
(N=163), %
Headache 12 14 13
Bradycardia 7 9 9
Dysgeusia 4 12 9
Skin odor abnormala 1 1 8
a All TEAEs of skin odor abnormal were recorded at a single site.

Table 4: Adverse Reactions with ZYNRELEF in Study 3 (Total Knee Arthroplasty) Occurring with ≥5% Incidence and Higher than with Saline Placebo

Preferred Term Saline Placebo
(N=53), %		 Bupivacaine HCl 125 mg
(N=55), %		 ZYNRELEF 400 mg/12 mg
(N=58), %
Nausea 47 55 50
Constipation 23 33 24
Vomiting 19 27 26
Hypertension 15 13 19
Pyrexia 4 15 14
Leukocytosis 0 2 7
Pruritis 2 5 7
Headache 0 7 7
Anemia 2 0 5
Hyperhidrosis 4 0 5
Hypotension 4 2 5

DRUG INTERACTIONS

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 [see WARNINGS AND PRECAUTIONS].

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 [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and OVERDOSAGE].

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
Antimala rials chloroquine, primaquine
Anticonvulsants Phenobarbital, phenytoin, sodium valproate
Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine

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].
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].
Intervention: If aspirin is indicated in the postoperative period, monitor patients for signs and symptoms of GI bleeding [see CLINICAL PHARMACOLOGY].
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]. 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].
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 ZYNRELEF 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].
Intervention: If additional NSAID or salicylate medication is indicated in the post-operative period, monitor patients for signs and symptoms of GI toxicity [see CLINICAL PHARMACOLOGY].
Pemetrexed
Clinical Impact: Concomitant use of MOBIC 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.

Read the entire FDA prescribing information for Zynrelef (Bupivacaine and Meloxicam)

&Copy; Zynrelef Patient Information is supplied by Cerner Multum, Inc. and Zynrelef Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.