12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

ZYNRELEF is a fixed-dose combination of bupivacaine and meloxicam.

Bupivacaine

Local anesthetics block the generation and the conduction of nerve impulses presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

Meloxicam

The mechanism of action of meloxicam, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.2 Pharmacodynamics

Additional pharmacodynamic data in clinical studies

Additional pharmacodynamic data for ZYNRELEF was evaluated in patients undergoing abdominoplasty, Cesarean section, total shoulder arthroplasty, and 1- to 3-level lumbar spinal surgery. Refer to Dosage and Administration for specific doses used for each study [see Dosage and Administration (2.4)].

Contribution of Meloxicam and Bupivacaine to Activity of ZYNRELEF

The contribution of each active ingredient in ZYNRELEF was demonstrated in Phase 2 double-blind, randomized, active- and placebo-controlled clinical studies in subjects undergoing herniorrhaphy or bunionectomy, utilizing ZYNRELEF and formulations of meloxicam alone or bupivacaine alone in the ZYNRELEF vehicle. In both studies, meloxicam alone demonstrated negligible local analgesia and bupivacaine alone demonstrated 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 (at the same bupivacaine doses) demonstrated greater and longer analgesia through 24, 48, and 72 hours.

Effect on Cardiac Repolarization

The effect of ZYNRELEF on cardiac repolarization as assessed by the QTc interval was evaluated following a single administration in patients undergoing surgical procedures. ZYNRELEF, at single doses up to the maximum recommended dose, did not demonstrate an effect on the QTc interval.

Bupivacaine

Systemic absorption of local anesthetics, including bupivacaine, produces effects on the cardiovascular and central nervous systems (CNS), which can be serious at toxic blood concentrations [see Warnings and Precautions (5.3)]. At blood concentrations achieved with normal therapeutic doses, manifestations of CNS stimulation and depression or changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. Clinical reports and animal research suggest that cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine.

12.3 Pharmacokinetics

The instillation of ZYNRELEF into the surgical site results in systemic plasma levels of bupivacaine and meloxicam for up to the duration as described in Table 7 for soft tissue surgical procedures and Table 8 for orthopedic surgical procedures. Systemic plasma levels of bupivacaine or meloxicam following application of ZYNRELEF do not correlate with local efficacy.

Absorption

The rate of systemic absorption of bupivacaine or meloxicam from ZYNRELEF is dependent upon the total dose of drug administered and the vascularity of the administration site.

Pharmacokinetic parameters of bupivacaine and meloxicam after single dose administration by instillation of ZYNRELEF were evaluated following multiple surgical procedures.

Descriptive statistics of pharmacokinetic parameters of representative ZYNRELEF doses are provided in Table 7 for soft tissue surgical procedures and Table 8 for orthopedic surgical procedures.

Table 7. Summary of Pharmacokinetic Parameters for Bupivacaine and Meloxicam After Single Dose Administration of ZYNRELEF by Instillation for Soft Tissue Surgical Procedures
Active Ingredient	Parameter	Herniorrhaphy: 300 mg/9 mg ZYNRELEF (N=16)	Abdominoplasty: 400 mg/12 mg ZYNRELEF (N=22)	Augmentation Mammoplasty: 400 mg/12 mg ZYNRELEF (N=49)	Cesarean Section: 400 mg/12 mg ZYNRELEF (N=11)
Note: Arithmetic mean (standard deviation) except Tmax where it is median (min, max). Doses of ZYNRELEF are shown as bupivacaine dose (mg)/meloxicam dose (mg).
NS = not sampled; NR= not reported, since the terminal elimination phase was not adequately characterized in sufficient number of patients.
* AUC(0-t): 0 to 120 h post-dose for herniorrhaphy, augmentation mammoplasty, and Cesarean section; 0 to 144 h post-dose for abdominoplasty. † N=48; ‡ N=21; § N=10
Bupivacaine	Cmax (ng/mL)	271 (147)	382 (149)	710 (246)	291 (70)
	Tmax (h)	18 (3, 30)	31 (20, 54)	3.6 (1.3, 35)	24 (1.1, 48)
	AUC(0-t) * (h×ng/mL)	15174 (8545)	24411 (10072)	27363 (9227)	17923 (5069)
	AUC(inf) (h×ng/mL)	15524 (8921)	24930 (10105)	31072 (17998)	17983 (5065)
	t½ (h)	16 (9)	20 (8)	25 (20)	10 (2)
	C72h (ng/mL)	96 (75)	202 (118)	149 (68) †	127 (56)
	C96h (ng/mL)	37 (43)	86 (52) ‡	NS	27 (16)
	C144h (ng/mL)	NS	16 (11) ‡	NS	0.8 (1.0) §
Meloxicam	Cmax (ng/mL)	225 (96)	116 (62)	527 (149)	114 (49)
	Tmax (h)	54 (24, 96)	24 (4.0, 72)	20 (5.6, 49)	60 (8.5, 73)
	AUC(0-t) (h×ng/mL)	18721 (7923)	7924 (4197)	30499 (9460)	9710 (4560)
	AUC(inf) (h×ng/mL)	NR	8304 (4422)	41809 (38414)	9778 (4592)
	t½ (h)	NR	21 (9)	42 (70)	21 (9)
	C72h (ng/mL)	197 (95)	70 (44)	214 (105) †	86 (43)
	C96h (ng/mL)	146 (86)	33 (25) ‡	NS	48 (32)
	C144h (ng/mL)	NS	7.1 (10) ‡	NS	11 (12) §

Table 8. Summary of Pharmacokinetic Parameters for Bupivacaine and Meloxicam After Single Dose Administration of ZYNRELEF by Instillation for Orthopedic Surgical Procedures
Active Ingredient	Parameter	Bunionectomy: 60 mg/1.8 mg ZYNRELEF (N=17)	Total Knee Arthroplasty: 400 mg/12 mg ZYNRELEF (N=53)	Total Shoulder Arthroplasty: 400 mg/12 mg ZYNRELEF (N=20)	1-Level Spinal Surgery: 92 mg/2.8 mg ZYNRELEF (N=13)	2- or 3-Level Spinal Surgery: 191 mg/5.7 mg ZYNRELEF (N=13)
Note: Arithmetic mean (standard deviation) except Tmax where it is median (min, max). Doses of ZYNRELEF are shown as bupivacaine dose (mg)/meloxicam dose (mg). For spinal surgery, ZYNRELEF mean doses for single-level and multilevel surgeries are shown; individual doses ranged from 45 mg/1.4 mg to 248 mg/7.4 mg.
NS = not sampled.
* AUC(0-t): 0 to 120 h post-dose for bunionectomy and lumbar spinal decompression; 0 to 144 h post-dose for total knee arthroplasty and total shoulder arthroplasty. † N=50; ‡ N=12; § N=11; ¶ N=16; # N=32; Þ N=19; ß N=18; à N=13; è N=35; ð N=17; ø N=10; ý N=15; £ N=28
Bupivacaine	Cmax (ng/mL)	54 (33)	695 (411)	372 (165)	95 (105)	163 (67)
	Tmax (h)	3.0 (1.6, 24)	21 (4, 59)	20 (1.8, 48)	23 (1.9, 38)	24 (4.1, 69)
	AUC(0-t) * (h×ng/mL)	1681 (1154)	35889 (28399)	21132 (12331)	4467 (4977)	8488 (4086)
	AUC(inf) (h×ng/mL)	1718 (1211)	38173 (29401) †	21193 (12329)	5535 (6091) ‡	8659 (4288) §
	t½ (h)	15 (8)	17 (7) †	10 (3)	25 (25) ‡	14 (5) §
	C72h (ng/mL)	5.0 (5.3)	227 (283)	145 (117)	34 (48) §	61 (49) ‡
	C96h (ng/mL)	1.7 (2.9) ¶	NS	30 (32)	5.2 (7.3) §	24 (27) §
	C144h (ng/mL)	NS	5.3 (21) #	1.1 (2.2) Þ	NS	NS
Meloxicam	Cmax (ng/mL)	26 (14) ¶	275 (134)	248 (125) ß	53 (41) à	90 (36) ‡
	Tmax (h)	18 (8, 60) ¶	36 (12, 72)	57 (12, 72) ß	18 (12, 72) à	43 (23, 69) ‡
	AUC(0-t) (h×ng/mL)	1621 (927) ¶	19525 (12259)	22292 (12250) ß	3556 (2665)	6269 (3133) ‡
	AUC(inf) (h×ng/mL)	2079 (1631) ¶	25673 (17666) è	24133 (15285) ð	3826 (3890) §	8265 (5874) ø
	t½ (h)	33 (36) ¶	42 (37) è	29 (11) ð	35 (15) §	38 (22) ø
	C72h (ng/mL)	13 (9) ¶	202 (120)	228 (131) ß	44 (44) §	69 (37) §
	C96h (ng/mL)	7.7 (5.8) ý	NS	158 (126) ß	21 (23) §	43 (28) ø
	C144h (ng/mL)	NS	28 (37) £	52 (56) ð	NS	NS

Distribution

After bupivacaine and meloxicam have been released from ZYNRELEF and are absorbed systemically, their distribution is expected to be the same as for other bupivacaine HCl solution formulations or meloxicam oral formulation.

Bupivacaine

Local anesthetics including bupivacaine are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma concentration of drug, the higher the percentage of drug bound to plasma proteins.

Local anesthetics including bupivacaine appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Bupivacaine with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, non-ionized drugs, such as bupivacaine, readily enter the fetal blood from the maternal circulation.

Meloxicam

Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range of oral meloxicam. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam. Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown.

Elimination

Metabolism

Bupivacaine

Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. Pipecoloxylidine is the major metabolite of bupivacaine. The elimination of drug from tissue distribution depends largely upon the ability of plasma protein binding sites in the circulation to carry it to the liver where it is metabolized [see Use in Specific Populations (8.6)].

Meloxicam

Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P450 mediated metabolism formed by oxidation of an intermediate metabolite 5'‑hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients' peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. The four metabolites are not known to have any in vivo pharmacological activity.

Excretion

After bupivacaine and meloxicam have been released from ZYNRELEF and are absorbed systemically, their excretion is expected to be the same as for other bupivacaine HCl solution formulations or meloxicam oral formulations.

Bupivacaine

The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted unchanged in the urine.

When administered in recommended doses and concentrations, bupivacaine HCl does not ordinarily produce irritation or tissue damage. The mean apparent terminal half-life (t1/2) for bupivacaine from ZYNRELEF is approximately 10 to 25 hours.

Meloxicam

Meloxicam excretion is predominately in the form of metabolites, and occurs to equal extents in the urine and feces. Following oral meloxicam, only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg oral meloxicam doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%.

The mean apparent terminal half-life (t1/2) for meloxicam from ZYNRELEF is approximately 21 to 42 hours.

Specific Populations

Effect of Age, Sex, Race, and Ethnicity on Pharmacokinetics

Based on the population pharmacokinetic analysis, age, sex, race, and ethnicity do not have a clinically meaningful effect on the pharmacokinetics of bupivacaine and meloxicam in ZYNRELEF [see Use in Special Populations (8.5)].

Hepatic Impairment

After bupivacaine and meloxicam have been released from ZYNRELEF and are absorbed systemically, the effects of hepatic impairment are expected to be the same as for other bupivacaine and meloxicam formulations [see Warnings and Precautions (5.5)].

Bupivacaine

Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic disease. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics [see Use in Specific Populations (8.6)].

Meloxicam

Following a single 15 mg dose of oral meloxicam there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of oral meloxicam was not affected by hepatic impairment. No dosage adjustment of ZYNRELEF is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied [see Use in Specific Populations (8.6)].

Renal Impairment

After bupivacaine and meloxicam have been released from ZYNRELEF and are absorbed systemically, the effects of renal impairment are expected to be the same as for other bupivacaine and meloxicam formulations.

Bupivacaine

Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of renal disease, factors affecting urinary pH, and renal blood flow [see Warnings and Precautions (5.8) and Use in Specific Populations (8.7)].

Meloxicam

Meloxicam pharmacokinetics with oral meloxicam have been investigated in patients with mild and moderate renal impairment. Following oral meloxicam, total drug plasma concentrations of meloxicam decreased and total clearance of meloxicam increased with the degree of renal impairment while free AUC values were similar in all groups. The higher meloxicam clearance in patients with renal impairment may be due to increased fraction of unbound meloxicam which is available for hepatic metabolism and subsequent excretion. No dosage adjustment of ZYNRELEF is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of ZYNRELEF in patients with severe renal impairment is not recommended [see Warnings and Precautions (5.8) and Use in Specific Populations (8.7)].

Hemodialysis: Following a single oral dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma. Meloxicam is not dialyzable [see Use in Specific Populations (8.7)].

Drug Interaction Studies

Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 6 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)].

Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of oral meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for oral meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established.

Cimetidine: Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg oral meloxicam.

Digoxin: Oral meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam.

Lithium: In a study conducted in healthy patients, mean pre-dose lithium concentration and AUC were increased by 21% in patients receiving lithium doses ranging from 804 to 1072 mg twice daily with oral meloxicam 15 mg QD every day as compared to patients receiving lithium alone [see Drug Interactions (7)].

Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites.

Warfarin: The effect of oral meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy patients receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these patients, oral meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one patient showed an increase in INR from 1.5 to 2.1. Caution should be used when administering oral meloxicam with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced.

12.5 Pharmacogenomics

CYP2C9 activity is reduced in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from three published reports showed that meloxicam AUC was substantially higher in individuals with reduced CYP2C9 activity, particularly in poor metabolizers (e.g., *3/*3), compared to normal metabolizers (*1/*1). The frequency of CYP2C9 poor metabolizer genotypes varies based on racial/ethnic background but is generally present in <5% of the population.