C L I N I C A L F E AT U R E S

A Review of the Compatibility of Liposome Bupivacaine With Other Drug Products and Commonly Used Implant Materials

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DOI: 10.3810/pgm.2014.01.2733

Vladimir Kharitonov, PhD Vice President, Research and Process Development, Pacira Pharmaceuticals, Inc., San Diego, CA

Abstract: The compatibility of a medication with other drugs and implanted materials is an important factor impacting drug safety and efficacy. The liposomal formulation of the local anesthetic bupivacaine is designed to provide prolonged postsurgical analgesia. Its compatibility with other drugs and materials depends on the compatibility of the drug itself, along with the integrity of liposome and liposomal components. A series of studies was conducted to evaluate the compatibility of liposome bupivacaine with diluents, implanted materials, and other drugs likely to be encountered in the surgical settings in which it is used. Liposome bupivacaine demonstrated compatibility with diluents (normal saline, lactated Ringer’s solution) and with implanted materials (silicone, stainless steel, titanium, polypropylene, expanded polytetrafluoroethylene), with little or no change in percent of free bupivacaine, packed particle volume, or particle size distribution; liposome bupivacaine exhibited little or no change in the properties of the test materials. Liposome bupivacaine had clinically meaningful interactions with other local anesthetics, including lidocaine, ropivacaine, mepivacaine, or bupivacaine HCl (at liposome bupivacaine to bupivacaine HCl ratios , 2:1), which resulted in substantial displacement and release of free bupivacaine from liposomes. Liposome bupivacaine may be locally administered after $ 20 minutes following local administration of lidocaine, ropivacaine, or mepivacaine. Co-administration of liposome bupivacaine and bupivacaine HCl into the same site should be at ratios $ 2:1. Interactions between liposome bupivacaine and epinephrine, corticosteroids, antibiotics, non-steroidal anti-inflammatory drugs, tranexamic acid, and opioid analgesics were not clinically meaningful; liposome bupivacaine may be safely co-administered with these agents. No adverse synergistic effects on liposome bupivacaine were observed in evaluations involving multiple medications compared with each drug’s individual effects. Keywords: analgesia; liposome bupivacaine; drug compatibility; postoperative pain

Introduction

Correspondence: Vladimir Kharitonov, PhD, Research and Process Development, Pacira Pharmaceuticals, Inc., 10450 Science Center Drive, San Diego, CA 92121. Tel: 858-625-2424 Fax: 858-625-2439 E-mail: [email protected]

Infused or injected medications must be compatible, non-reactive, or minimally ­reactive with co-administered drugs and implanted materials. The physical and ­chemical properties of the drug in question should not be altered by other medications and materials; conversely, the medication should not alter the physicochemical properties of other drugs and materials. To a significant extent, compatibility rests on the acid/ base properties of the medication in question.1 A liposomal formulation of the short-acting local anesthetic bupivacaine (Exparel), which extends the duration of analgesia for # 72 hours via prolonged release of bupivacaine over time,2,3 was approved by the US Food and Drug Administration (FDA) in 2011 for administration into the surgical site during surgery to reduce the incidence and severity of postsurgical pain.3 The pharmacodynamics and pharmacokinetics of this formulation have been extensively studied in both nonclinical and clinical s­ tudies across

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Vladimir Kharitonov

numerous surgical models.4–24 The compatibility of liposome bupivacaine and other substances depends not only on potential interactions with bupivacaine itself, but also on maintaining the structure and properties of the DepoFoam drug delivery system that allows gradual release of the active drug. This article reviews the results from a number of ­studies that were conducted to examine the compatibility of liposome bupivacaine with other drugs and materials in the surgical ­setting. This paper will help clinicians use liposome bupivacaine safely and effectively and gain useful knowledge regarding compatibility issues. Liposome bupivacaine has demonstrated a favorable tolerability profile in clinical studies, with a low incidence of treatment-related adverse events (AEs) and study discontinuations.25–29 Because liposome bupivacaine is typically administered as part of a multimodal analgesic regimen involving $ 1 other analgesic medication, the results of the compatibility studies of liposome bupivacaine are encouraging.25 Similarly, the low incidence of AEs associated with liposome bupivacaine that was reported in studies involving surgeries with implanted materials (eg, breast augmentation, total knee arthroplasty) suggests a compatibility of liposome bupivacaine with s­ ilicone and metallic implants.25,29

Materials and Methods

Data were compiled and reviewed from published5,29 and unpublished studies (Pacira Pharmaceuticals, Inc., unpublished data, 2009) conducted to systematically evaluate the compatibility of liposome bupivacaine with diluents, other drugs, and implantable materials frequently used or encountered during surgical procedures. The results of the compatibility studies performed to date are described in this report. In these studies, an increase # 15% in free bupivacaine levels was considered not clinically relevant; if released during a period of 72 hours, this difference would constitute # 13 mg of free bupivacaine per day. Total bupivacaine, free bupivacaine, lysodierucoylphosphatidylcholine (lyso-DEPC), and erucic acid levels were measured by reversed-phase high-performance liquid chromatography. Laser light scattering was used to measure particle size and pH was measured by glass electrode. All experiments were in vitro tests unless otherwise stated.

Results Compatibility With Diluents Normal Saline

The milligram dose of liposome bupivacaine is expressed as the free base (ie, 266 mg of bupivacaine base is chemically equivalent to 300 mg of bupivacaine HCl).2 ­Liposome 130

b­ upivacaine is supplied in 20-mL vials at a free-base ­bupivacaine concentration of 13.3  mg/mL (1.3%).3 With typical usage, liposome bupivacaine is emptied from the vial in which it is supplied and either injected as is or diluted with preservative-free normal sterile saline (0.9% NaCl) prior to injection. Possible drivers of incompatibility during withdrawal, dilution, and injection of liposome bupivacaine include the dilution factor, storage time and temperature within the syringe, needle gauge, and rate of ejection through the needle. These factors might conceivably affect the concentration of free bupivacaine, as well as the liposome particle size distribution. Volume expansion with normal saline-to-liposome bupivacaine factors # 15:1 were evaluated; however, the greatest dilution recommended to be used clinically in product labeling is 14:1 to support a safety margin in the event of overexpansion of volume beyond 14:1. Results from the volume expansion study are summarized in Table 1. The change in the proportion of free bupivacaine was negligible for a dilution range from no dilution to 15:1; even at a dilution of 15:1, the percentage of free bupivacaine only increased by 3% (from 3.0% to 6.0%), which is not clinically relevant.

Lactated Ringer’s Solution Diluent evaluations were also conducted with lactated Ringer’s solution using various dilution factors and incubation times/temperatures; these evaluations used liposome bupivacaine diluted in normal saline as controls. Results are summarized in Table 2. No clinically meaningful differences were observed in the proportion of free bupivacaine, whether it was diluted in normal saline or in lactated Ringer’s solution.

Compatibility With Tubing/Implant Materials

Polypropylene and Expanded Polytetrafluoro-ethylene Polypropylene (PP) and expanded polytetrafluoro-ethylene (ePTFE) mesh implants are frequently employed to reinforce Table 1.  Effects of Dilution With NSa on Free Bupivacaine Levels Dilution Factor

Total Bupivacaine Concentration, mg/mL

Free Bupivacaine, %

1 (no dilution) 2x 5x 10x 15xb

13.4 6.8 2.8 1.4 0.9

3.0 3.6 3.9 4.8 6.0

0.9% NaCl solution. A dilution factor of 14 is the highest dilution factor expected to be used in clinical settings. Abbreviation: NS, normal saline.

a

b

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Review of Liposome Bupivacaine Compatibility Studies

Table 2.  Comparative Effects of Dilution With Lactated Ringer’s Solution and NS on Free Bupivacaine Levelsa Temperature/ Time Point 25°C/5 min 25°C/2 h 37°C/2 h

NS

Lactated Ringer’s Solution

DF 2

DF 10

DF 50

DF 2

DF 10

DF 50

5.1% 5.6% 5.7%

5.5% 6.1% 7.0%

8.7% 9.3% 14.1%

5.0% 5.5% 5.7%

5.8% 6.1% 7.2%

10.4% 10.3% 13.6%

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a Percentages shown are proportions of free bupivacaine. Abbreviations: DF, dilution factor; NS, normal saline.

surgical hernia repair and abdominal wall reconstruction. Polypropylene and ePTFE mesh samples were incubated in either undiluted liposome bupivacaine (13.3  mg/mL3) or a normal saline control for 96 hours at 37°C. Following incubation, the mechanical properties of the mesh samples were evaluated using a ball burst force test, which measures the force required to rupture the mesh, and a suture retention strength test, which measures the resistance of a mesh during removal of sutures. Key attributes of the liposome bupivacaine solution were also assessed, including percent free bupivacaine, percent packed particle volume (PPV), pH, and particle size. Incubation of PP and ePTFE mesh in liposome bupivacaine had no clinically relevant effect on mesh strength by either the ball burst force test or the suture retention strength test. There was a slight reduction in mean ball burst force after incubation in liposome bupivacaine compared with normal saline for both mesh types (mean kg force ± SD for saline control vs liposome bupivacaine; PP: 58.1 ± 3.3 vs 56.8 ± 4.8; ePTFE: 24.1 ± 0.8 vs 22.8 ± 1.7). However, this reduction was substantially lower than the ± 15% normal variability in strength for unexposed mesh reported by vendors of both mesh types. Table 3 summarizes key liposome bupivacaine parameters following incubation with PP and ePTFE mesh samples. Comparing the PP and ePTFE results with the “no mesh

sample” control reveals that incubation with PP and ePTFE mesh had no clinically meaningful effect on the key properties of liposome bupivacaine, including percent free bupivacaine, PPV, and particle size distribution.

Silicone Silicone tubing is used during the manufacture of liposome bupivacaine, especially during filling and product potency adjustment. Silicone is also used extensively in breast implants, nearly all of which have an outer surface of silicone elastomer. Samples of smooth-type and textured-type silicone breast implant material were incubated with liposome bupivacaine (full strength) or with normal saline as a control for 7 days at 37°C, and were subsequently evaluated with respect to tensile strength and tensile set. For tensile strength, the percent elongation of the samples was determined as a function of the tensile stress. For tensile set, the samples were stretched to a certain percent of the initial length and then allowed to relax. The initial and final dimensions of the samples were measured and tensile set was calculated as the percent difference between the initial and final values. Smooth and textured implant materials had similar tensile strength and tensile set after incubation with liposome bupivacaine or normal saline; test results are summarized in Table 4. To further characterize possible interactions between silicone and liposome bupivacaine, key attributes of liposome bupivacaine were evaluated following a “worst-case scenario” of exposure at 37°C to smooth and textured silicone implant material. The results were compared with a control incubated at 37°C without silicone and a liposome bupivacaine control stored at 2–8°C (Table 5). Incubation with silicone had no effect on total bupivacaine, free bupivacaine percent, or on PPV percent. Particulate matter remained within product specifications (# 6000/vial for particles $ 10 µm; # 600/vial for particles $ 25 µm). An increase in particle size was observed for the samples incubated at 37°C.

Table 3.  Properties of Liposome Bupivacaine 13.3 mg/mL3 Following Incubation With PP and ePTFE Mesh Material Sample

Free Bupivacaine, %

ePTFE mesh PP meshb No mesh controlc Vial controld b

3.9 4.9 5.8 1.9

PPV, % 33.3 32.9 31.4 36.4

pH 5.9 5.8 5.8 6.0

Particle Size (volume weighted diameter, μm)a d10

d50

d90

16.5 17.1 17.6 16.5

63.8 61.2 93.0 44.9

265.4 227.5 307.0 325.3

Particle size distribution listed as volume weighted diameter; d10, d50, and d90 represent particle diameters at the 10th, 50th, and 90th volume percentiles, respectively, of the particle size distribution. b ePTFE and PP mesh samples were incubated with liposome bupivacaine at 37°C for 96 hours. c No mesh controls included liposome bupivacaine incubated at 37°C for 96 hours with no mesh sample. d Vial control samples were incubated at ambient temperature for 96 hours with no mesh sample. Abbreviations: ePTFE, expanded polytetrafluoro-ethylene; PP, polypropylene; PPV, packed particle volume. a

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Table 4.  Tensile Strength and Tensile Set of Smooth- and Textured-Type Silicone Breast Implant Material Following Incubation With Liposome Bupivacaine Tensile Strength Parameter Smooth Implant Mean tensile strength at break, psi (SD) Mean percent elongation at break, % (SD) Textured Implant Mean tensile strength at break, psi (SD) Mean percent elongation at break, % (SD)

Saline Control

Liposome Bupivacaine

1683 (110) 733 (15)

1690 (120) 707 (32)

1193 (15) 713 (35)

1217 (96) 683 (45)

Saline Control

Liposome Bupivacaine

1.003 1.05 4.7 (0.9)

1.001 1.02 1.8 (0.5)

1.002 1.027 2.4 (1.2)

1.002 1.012 1.0 (0.6)

Tensile Set

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Parameter Smooth Implant Initial distance between marks, in Distance between marks after exposure, in Mean tensile set, % (SD) Textured Implant Initial distance between marks, in Distance between marks after exposure, in Mean tensile set, % (SD) Abbreviation: SD, standard deviation.

However, this is typical for liposome bupivacaine at elevated temperatures and the increase was less for silicone-incubated liposome bupivacaine than for liposome bupivacaine alone. As anticipated, incubation at 37°C increased the level of lipid breakdown products lyso-DEPC and erucic acid;30 the increase in lyso-DEPC with silicone incubation is likely due to a pH change caused by the silicone implants. The lack of observable effects of co-incubation at 37°C on either the mechanical properties of silicone or

the ­characteristics of liposome bupivacaine demonstrates that liposome bupivacaine is compatible with both smooth and textured silicone. Additional assurance for the lack of clinically relevant interaction between liposome bupivacaine and silicone is provided by 2-year observational studies of women (N  = 94) undergoing breast augmentation using silicone implants. In 1 study, women received liposome bupivacaine in 1 breast and bupivacaine HCl in the other; in the other study, women were randomized to liposome

Table 5.  Liposome Bupivacaine Attributes Following Exposure to Smooth- and Textured-Type Silicone Implant Material Attribute

Liposome Bupivacaine Exposed to Textured Silicone Implant Incubated at 37°C for 7 Days

Liposome Bupivacaine Exposed to Smooth Silicone Implant Incubated at 37°C for 7 Days

Liposome Bupivacaine Incubated at 37°C for 7 Days (Control)

Liposome Bupivacaine Incubated at 2–8°C for 7 Days (Control)

Total bupivacaine, mg/mL Free bupivacaine, % Packed particle volume, % Particulates $ 10 μm Particulates $ 25 μm Particle size distribution,a μm  d10  d50  d90 Lyso-DEPC,b μg/mL Erucic acid,b μg/mL Total bupivacaine-related substances

14.0 1.2 36.8 2338 118

13.8 1.3 36.8 4751 279

13.7 1.6 35.3 NA NA

13.9 0.6 39.1 NA NA

15.2 27.9 75.1 149.4 167.8 ND

14.8 27.4 71.4 143.5 167.2 ND

15.6 32.9 103.9 101.6 156.3 ND

15.0 25.4 49.3 68.3 138.7 ND

Particle size distribution listed as volume weighted diameter; d10, d50, and d90 represent particle diameters at the 10th, 50th, and 90th volume percentiles, respectively, of the particle size distribution. Lyso-DEPC and erucic acid are lipid breakdown products. Abbreviations: Lyso-DEPC, lyso-diethyl pyrocarbonate; NA, not assayed; ND, not detectable.

a

b

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Review of Liposome Bupivacaine Compatibility Studies

bupivacaine or to bupivacaine HCl for treatment in both breasts.29 There were no differences attributable to study drugs between liposome bupivacaine–treated and bupivacaine HCl–treated breasts with respect to subject-reported outcomes (eg, pain, tingling, numbness, unusual sensations) or to physical examination findings,29 suggesting that the use of liposome bupivacaine is compatible with silicone breast augmentation.

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Stainless Steel and Titanium Both stainless steel and titanium are used in certain types of surgical implants and liposome bupivacaine is also manufactured in equipment constructed of 316L stainless steel. To evaluate the effects of liposome bupivacaine on these metal alloys and vice versa, samples of stainless steel (316L, 72 cm2) and titanium (high strength: grade 5, 6 Al-4V, 57 cm2) were incubated in liposome bupivacaine or saline for 7 days at 37°C. There were no observable changes (damage or discoloration) to the stainless steel or to the titanium alloy samples. Attributes of liposome bupivacaine following incubation with metal alloys and a control sample are shown in Table 6; there were no clinically meaningful changes in these characteristics relative to the control sample. The relative increase in particle size distribution when particle diameters are at 90 percent of volume distribution is typical of liposome bupivacaine upon exposure to 37°C for 7 days.

Compatibility With Drugs

The principal focus when assessing the compatibility of liposome bupivacaine with other drugs was on the impact of exposure on the fraction of unencapsulated, or free, bupivacaine and on particle size.

Other Local Anesthetics Bupivacaine HCl The compatibility of liposome bupivacaine with bupivacaine HCl was assessed using relative liposome bupivacaine:bupivacaine HCl dilution ratios that ranged from 24:1 to 1:12. Assessments were made immediately after mixing and again after 24  hours. Results of these assessments (Table 7) show that the extended-release properties of liposome bupivacaine may be compromised at liposome bupivacaine:bupivacaine HCl ratios # 1:12 because of the excessive release of free bupivacaine (∼50% at the 1:12 ratio); however, release of free bupivacaine at liposome bupivacaine:bupivacaine HCl ratios $ 2:1 was approximately equal to 5% or less. Therefore, liposome bupivacaine may be co-administered into the same surgical site with bupivacaine HCl formulations (eg, Marcaine, Sensorcaine) at liposome bupivacaine:bupivacaine HCl ratios $ 2:1. Lidocaine, Ropivacaine, and Mepivacaine The compatibility of the local anesthetics lidocaine, ropivacaine, and mepivacaine with liposome bupivacaine was evaluated by co-incubation assays in various dilution ratios, which were assessed immediately after mixing and after 1 and 24 hours. As summarized in Table 8, non–bupivacaine-based local anesthetics have a strong interaction with liposome bupivacaine and result in the rapid release of free bupivacaine from liposomal vesicles at higher ratios of local anesthetic:liposome bupivacaine. Co-incubation of non-bupivacaine local anesthetics with liposome bupivacaine at the same dilution ratios changed the size distribution of liposome particles very little, which shows that the release of free bupivacaine is not the result of liposome particle disruption. Therefore, the extensive release of bupivacaine from the ­liposome matrix upon

Table 6.  Liposome Bupivacaine Attributes Following Incubation With Stainless Steel and Titanium Attribute

Liposome Bupivacaine Incubated With Stainless Steel (316L) at 37°C for 7 Days

Liposome Bupivacaine Incubated With Titanium (6AL-4V) at 37°C for 7 Days

Controla

Total bupivacaine, mg/mL Free bupivacaine, % Packed particle volume, % Particle size distribution,b μm  d10  d50  d90 Erucic acid,c μg/mL Lyso-DEPC,c μg/mL

14.1 5.6 35.7

14.1 5.7 36.4

14.2 5.7 36.4

14.6 43.0 251.3 42.8 33.6

14.6 45.9 240.7 43.3 34.1

14.3 39.9 186.8 42.1 33.0

Control was liposome bupivacaine incubated with no metals for 7 days at 37°C. Particle size distribution listed as volume weighted diameter; d10, d50, and d90 represent particle diameters at the 10th, 50th, and 90th volume percentiles, respectively, of the particle size distribution. c Lyso-DEPC and erucic acid are lipid breakdown products. Abbreviation: Lyso-DEPC, lyso-diethyl pyrocarbonate. a

b

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Table 7.  Percentage of Encapsulated Bupivacaine Remaining in Liposome Bupivacaine Following Incubation With Bupivacaine HCl Dose Ratio (liposome bupivacaine: bupivacaine HCl)

Liposome Bupivacaine, mg

24:1 5.2:1 3.5:1 2:1 1:12

266 155 155 133 11

Bupivacaine HCl, mg

Encapsulated Bupivacaine After Mixing, %

12.5 33 50 75 150

Immediately at RT

After 24 h at RT

99 NM 98 94 48

98 94 99 99 52

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Abbreviations: NM, not measured; RT, room temperature.

co-incubation with other local anesthetics appears to result from the stronger affinity for the matrix shown by the nonbupivacaine local anesthetics, which leads to displacement of bupivacaine from the matrix. The in vivo interactions between liposome bupivacaine and lidocaine were investigated in mini-pigs by administration of liposome bupivacaine at various time intervals and in various dose ratios (1:2, 1:1, and 2:1) after administration at the same site. A pig model was chosen for this study because pig skin morphology and physiology closely resemble that of humans.5 Blood samples were collected prior to administration of the study drug at 5, 10, 15, and 30 minutes, as well as at 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 hours after study drug administration. Maximum bupivacaine plasma levels were elevated compared with liposome bupivacaine alone when liposome bupivacaine was administered premixed with lidocaine, or when the drug was administered at 1, 5, or 10 minutes following lidocaine administration, which indicated an increase in free bupivacaine release in the presence of lidocaine. However, the maximum bupivacaine plasma level was reduced with increased time between administrations and there was no evidence of an increased release of free bupivacaine when liposome bupivacaine was administered 20 or 40 minutes after lidocaine administration.5

Overall, these results show that the release of free bupivacaine from liposome bupivacaine is similar between lidocaine, ropivacaine, or mepivacaine. Therefore, $ 20 minutes should elapse between infiltration of any of these anesthetics and liposome bupivacaine into the same surgical site.

Epinephrine Compatibility of liposome bupivacaine with epinephrine was evaluated at low, high, and clinically relevant epinephrine concentrations, assessed immediately after mixing and after 24 hours. As summarized in Table 9, co-incubation of liposome bupivacaine with epinephrine at high concentration, but not at low concentration, led to a slight increase in the release of free bupivacaine; however, particle size was not affected. When co-incubated at concentrations approximating clinically relevant levels (20 mL liposome bupivacaine [266 mg bupivacaine] plus 0.6 mg epinephrine diluted to 80 mL), there was only a small increase in free bupivacaine levels (13.8% vs 10.6% for liposome bupivacaine control). These results suggest that there is only a minor physicochemical interaction between liposome bupivacaine and epinephrine; therefore, epinephrine solutions may be co-­a dministered in the same location as liposome bupivacaine.

Table 8.  Percentage of Free Bupivacaine in Mixtures of Liposome Bupivacaine With Selected Local Anesthetics Liposome Bupivacaine: Drug Ratio, w/w

Concentration, mg/mL

Liposome Bupivacaine Volume, mL

12:1 1:32 12:1 1:32 30:1 1:16 N/A N/A

13.3 2.2 13.3 2.2 13.3 2.2 13.3 13.3

20 5 20 5 20 5 1 1

Drug

Lidocaine Mepivacaine Ropivacaine Saline (control)

Amount

Free Bupivacaine, %

Concentration, mg/mL

Volume, mLa

Initial

1h RT

24 h RT

5 20 5 20 2 10 N/A N/A

5 20 5 20 5 20 1 30

9.4 89.0 14.5 101.9 7.1 75.0 2.3 8.7

9.1 89.0 14.2 101.7 7.5 84.4 2.7 11.1

8.1 89.0 12.0 101.6 7.5 85.4 2.9 12.5

a As product labeling for liposome bupivacaine recommends a maximum liposome bupivacaine:diluent dilution factor of 1:14 for clinical use. Abbreviations: N/A, not applicable; RT, room temperature; w/w, weight/weight.

134

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Table 9.  Percentage of Free Bupivacaine Following Incubation of Liposome Bupivacaine With Epinephrine Liposome Bupivacaine Concentration (mg/mL)

Epinephrine Volume (mL)

13.3 20 2.2 5 Liposome bupivacaine control (diluted with saline to 2.5 mg/mL)

Free Bupivacaine (%)

Concentration (mg/mL)

Volume (mL)

Initial

1h RT

24 h RT

1 1 N/A

0.025 0.125 N/A

4.7 12.3 8.5

6.6 16.8 10.7

5.2 16.1 12.3

Abbreviations: N/A, not applicable; RT, room temperature.

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Corticosteroids: Triamcinolone and Methylprednisolone The compatibility of liposome bupivacaine in ­combination with the commonly used corticosteroids triamcinolone acetonide and methylprednisolone was assessed using a bracketing approach, which involved the co-incubation of low and high concentrations of liposome bupivacaine with each corticosteroid for 24 hours at room temperature. When liposome bupivacaine at high concentration was incubated with triamcinolone or methylprednisolone at low concentration, there was no clinically meaningful effect on free bupivacaine release, but there was an increase in particle size. Because the corticosteroid suspensions have particle size distributions similar to liposome bupivacaine and because the addition of liposome bupivacaine may have reduced the  anti-aggregation effect of polysorbate 80  in the corticosteroid suspensions, it is unclear whether the change in particle size distribution represents the aggregation of corticosteroid particles, liposome bupivacaine particles, or a combination of both. When liposome bupivacaine at low concentration was incubated with each corticosteroid at high concentration, there was an increase in free bupivacaine ­levels approximately equal to 20% to 30% after 24 hours, but there was no effect on particle size. There was no increase in free bupivacaine levels with co-incubation at a clinically relevant dose ratio of 3.75:1 (266 mg liposome bupivacaine: 80 mg methylprednisolone). Based on these results, liposome bupivacaine may be co-administered at the same location as methylprednisolone or triamcinolone as long as the drugs are not premixed beforehand.

Anti-infective Drugs Bacitracin, Gentamicin, and Cefazolin The compatibility of liposome bupivacaine with the antibiotics bacitracin, gentamicin, and cefazolin was evaluated by incubating 15 mL of liposome bupivacaine (200 mg bupivacaine) with 20 mL of a saline solution containing a mixture of the 3 antibiotics (2000 units bacitracin, 3.2 mg ­gentamicin,

48 mg cefazolin) at 37°C for 24 hours. Co-incubation resulted in only a very small increase in particle size distribution and free bupivacaine levels. These antibiotics, which are commonly used to prevent postsurgical infection, may therefore be co-administered with liposome bupivacaine. Cefuroxime The antibiotic cefuroxime is commonly used in knee surgery. The compatibility of liposome bupivacaine with cefuroxime was assessed by incubating 20 mL of liposome bupivacaine (266 mg bupivacaine) with 1.5 g/16 mL of cefuroxime or saline alone (control) at room temperature or at 37°C for 24 hours. At room temperature, percent free bupivacaine increased to 6.3% immediately after mixing (percent free bupivacaine was 5.4% in the control solution) and further increased to 8.3% after 4 hours and to 15.4% after 24 hours. At 37°C, percent free bupivacaine increased dramatically to 90%. Observation revealed that liposome bupivacaine particle size decreased by a few microns at 24 hours. Based on the observation of minimal changes after 4 hours of incubation at room temperature, cefuroxime can be co-administered at the same site with liposome bupivacaine. Povidone Iodine The compatibility of liposome bupivacaine with the ­topical antiseptic povidone iodine, which is commonly used to disinfect skin prior to surgical incisions, was assessed by co-incubation of 15  mL liposome bupivacaine with 3  mL povidone iodine for 24 hours at 37°C. Co-incubation resulted in substantial and clinically meaningful changes in both particle size and free bupivacaine levels; however, because povidone iodine and similar disinfecting solutions are applied topically and allowed to dry prior to surgical or needle penetration, there is little possibility of contact with liposome bupivacaine under normal use. Therefore, topical antiseptics may be used in preparation for surgical procedures in which liposome bupivacaine is administered as long as there is no direct mixing between the 2 compounds. Notably, this also means that if these compounds are used for the irrigation

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Vladimir Kharitonov

of a wound, the wound should ideally be rinsed until clear prior to the infiltration of liposome bupivacaine; in any case, instillation of the liquid liposome bupivacaine into a cavity where one of the disinfecting solutions is resting in liquid form should be avoided.

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Non-Steroidal Anti-inflammatory Drugs and Opioids Evaluation of the compatibility of liposome bupivacaine with the non-steroidal anti-inflammatory drugs ketorolac or morphine was performed by co-incubating 266 mg liposome bupivacaine in 80  mL saline with either 30  mg ketorolac tromethamine or 10 mg morphine sulfate for 24 hours at 37°C. The results of co-incubation are summarized in Table 10 and show that there were minimal increases in free bupivacaine levels; therefore, ketorolac or morphine may be co-administered at the same site as liposome bupivacaine.

Anti-hypertensive and Anti-hemorrhagic Drugs Clonidine The compatibility of liposome bupivacaine with clonidine was assessed by the co-incubation of 20 mL of liposome bupivacaine (266 mg bupivacaine) with clonidine 0.08  mg/0.8  mL, clonidine 0.8  mg/8  mL, or saline alone (control) at room temperature or at 37°C for 24 hours. Percent free bupivacaine increased to 4.5% immediately after mixing with clonidine 0.08 mg and to 5.1% with clonidine 0.8 mg (percent free bupivacaine was 4.4% and 4.8% in the control solutions, respectively) and remained essentially unchanged after 24 hours of incubation at room temperature and at 37°C. There was no change in liposome bupivacaine particle size after 24 hours at room temperature and a slight increase in particle size after 24 hours at 37°C. Based on these results, liposome bupivacaine can be co-administered at the same site with clonidine. Tranexamic Acid The compatibility of liposome bupivacaine with tranexamic acid was assessed by co-incubation of 20 mL of liposome bupivacaine (266 mg bupivacaine) with tranexamic acid 0.2 g/5 mL, tranexamic acid 2.0 g/50 mL, or saline alone

(control) at room temperature or at 37°C for 24 hours. In the high-dilution tranexamic acid mixture (2.0 g/20 mL), percent free bupivacaine increased to 5.7% immediately after mixing (percent free bupivacaine was 6.1% in the saline control solution). Percent free bupivacaine increased to 7.7% and 10.9% after 24 hours of incubation at room temperature and at 37°C, respectively. There was no change in particle size after 24 hours at room temperature, but there was a slight increase in particle size after 24 hours at 37°C. These results indicate that liposome bupivacaine can be co-administered at the same site with tranexamic acid.

Compatibility With Other Potentially Co-Administered Drugs Used in Total Knee Arthroplasty

Because liposome bupivacaine is designed for use in surgical settings that typically involve co-administration of multiple other drugs, liposome bupivacaine was co-incubated with a range of other medications according to the matrix summarized in Table 11. The drugs listed in Table 11 were mixed with liposome bupivacaine and then diluted to a total volume of 80 mL with normal saline; all mixtures were incubated at ambient temperature or at 37°C for 24 hours. The co-incubated drugs included epinephrine, ketorolac, ropivacaine, methylprednisolone, morphine sulfate, and bupivacaine HCl. Results of the co-incubation combination studies were consistent with observed results from individual compatibility studies. For example, the combination that included the local anesthetic ropivacaine demonstrated immediate release of encapsulated bupivacaine and an increase in particle size; therefore, combinations of liposome bupivacaine and ropivacaine should be avoided. In contrast, the combination containing bupivacaine HCl showed no effect on the amount of free bupivacaine, consistent with results observed at liposome bupivacaine:bupivacaine HCl ratios $ 2:1. In general, there was no evidence of synergism between the tested drugs with respect to effects on liposome bupivacaine; co-administration of liposome bupivacaine with various drug combinations should be guided by results from individual drug compatibility evaluations.

Table 10.  Percentage of Free Bupivacaine Following Incubation of Liposome Bupivacaine With Ketorolac and Morphine Co-Incubated Druga

Initial Free Bupivacaine, %

Final Free Bupivacaine, % (24 h at 37°C)

Control alone (liposome bupivacaine 266 mg) Ketorolac tromethamine 30 mg + liposome bupivacaine 266 mg Morphine sulfate 10 mg + liposome bupivacaine 266 mg

10.6 5.8 6.5

14.2 8.3 9.8

Test samples were diluted with NS to a total volume of 80 mL and incubated at 37°C for 24 hours.

a

Abbreviation: NS, normal saline.

136

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Review of Liposome Bupivacaine Compatibility Studies

Table 11.  Co-Incubation Matrix for Liposome Bupivacaine Compatibility Evaluation With Drugs Used in Knee Arthroplasty Liposome Epinephrine Ketorolac Ropivacaine Methylprednisolone Morphine Sulfate Morphine Sulfate Bupivacaine Bupivacaine 1 mg/mL Tromethamine 10 mg/mL 80 mg/mL Injection Pentahydrate HCl 13.3 mg/mL 30 mg/mL 1 mg/mL 10 mg/mL 5 mg/mL 20 mL

0.5 mL 0.6 mL 0.3 mL 0.5 mL 0.3 mL 0.3 mL

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Discussion

1 mL 1 mL

30 mL 1 mL

10 mL

1 mL 1 mL

10 mL

When combined with existing knowledge of the physicochemical properties of liposome bupivacaine, the results of the compatibility studies described here led to a number of recommendations regarding the administration of liposome bupivacaine. First, per package labeling, liposome bupivacaine should not be admixed with substances or drugs other than normal saline prior to injection into surgical sites. Second, non–bupivacaine-based local anesthetics, including lidocaine, ropivacaine, and mepivacaine, may induce an immediate release of bupivacaine from liposome bupivacaine via displacement of bupivacaine if administered together locally; therefore, administration of liposome bupivacaine may follow the administration of these non–bupivacainebased local anesthetics after a delay $ 20 minutes. Third, bupivacaine HCl may impact the pharmacokinetic and/or physicochemical properties of liposome bupivacaine when the milligram dose of bupivacaine HCl is . 50% of the liposome bupivacaine dose. Liposome bupivacaine may be co-administered into the same site immediately following administration of bupivacaine HCl if the dose ratio of ­liposome bupivacaine to bupivacaine HCl is $  2:1. Co-­ administration of both drug forms will increase overall exposure to bupivacaine. Fourth, when a topical antiseptic such as povidone iodine is applied for disinfection prior to surgical incision or needle insertion, the site should be allowed to dry completely before liposome bupivacaine is administered into the surgical site. If antiseptics are used for irrigation of a wound, the wound should be rinsed until clear prior to the infiltration of liposome bupivacaine. Fifth, in recognition that physicians may choose to use liposome bupivacaine along with other implantable materials and other agents, several studies have been conducted to test such combinations. Implantable materials, including polypropylene, ePTFE, silicone, stainless steel, and titanium, are not affected by the presence of liposome bupivacaine any more than they are by saline. Likewise, these implantable materials do not affect the

24 mL

1 mL 1 mL

properties of liposome bupivacaine; liposome bupivacaine may be safely administered in the presence of these materials. Sixth, liposome bupivacaine may be administered undiluted (13.3 mg/mL3)or diluted in preservative-free normal saline (0.9%) for injection or lactated Ringer’s solution in a maximum volume # 280 mL (ie, 1:14 dilution by volume). Per product labeling, liposome bupivacaine must not be diluted with water or other hypotonic agents, which will disrupt the liposomal particle structure. Seventh, epinephrine may be used locally in the same area in which liposome bupivacaine has been administered.

Conclusion

This article reviews studies conducted to assess the compatibility of liposome bupivacaine with other drugs and materials. Importantly, aside from normal saline, liposome bupivacaine should not be admixed with other substances or drugs prior to administration and appropriate precautions should be taken when liposome bupivacaine is co-administered in the same surgical area as other local anesthetics. The data and recommendations outlined in this paper will help clinicians maximize the safety and efficacy of liposome bupivacaine and reduce the risk of AEs and/or compromised efficacy arising from compatibility issues with liposome bupivacaine.

Acknowledgments

The author would like to thank the Research and Development personnel at Pacira Pharmaceuticals, Inc. for the work performed to complete the compatibility studies.

Conflict of Interest Statement

Vladimir Kharitonov, PhD, is employed by Pacira Pharmaceuticals, Inc. This study was funded by Pacira Pharmaceuticals, Inc. Editorial assistance was provided by Peloton Advantage, LLC, and supported by Pacira Pharmaceuticals, Inc. The author was fully responsible for the content, editorial

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Vladimir Kharitonov

d­ ecisions, and opinions expressed in the current article, and did not receive an honorarium related to the development of this manuscript.

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A review of the compatibility of liposome bupivacaine with other drug products and commonly used implant materials.

The compatibility of a medication with other drugs and implanted materials is an important factor impacting drug safety and efficacy. The liposomal fo...
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