Is there any data/study to compare Zynrelef or Xaracoll with Exparel?

Comment by InpharmD Researcher

Overall, bupivacaine and meloxicam combination product (Zynrelef) appears to provide improved pain reduction with less opioid consumption compared to liposomal bupivacaine (Exparel). Additionally, data suggests that bupivacaine implant (Xaracoll) has a potential role in the management of postoperative pain while demonstrating a favorable safety profile. Unfortunately, data are limited with no direct comparisons between the agents. Other factors such as cost, ease of administration, as well as patient and prescriber preference, should also play a role in product selection.
Background

Zynrelef, a combination of bupivacaine and low-dose meloxicam, incorporates meloxicam to decrease local inflammation and stabilize the pH of bupivacaine, enhancing its effectiveness. Gradual and sustained release of bupivacaine and meloxicam is achieved via encapsulation of the agents with a slow-hydrolyzing polymer. Overall, available studies have shown improved pain relief, decreased opioid use, and comparable safety to bupivacaine and placebo. Supporting data is primarily acquired from two double-blind, randomized, controlled trials: EPOCH 1 and EPOCH 2 (Tables 1 and 2). Both trials found overall favorable outcomes with Zynrelef. [1]

A 2020 meta-analysis included seven randomized controlled trials comparing the use of Zynrelef with placebo and/or bupivacaine in patients undergoing abdominoplasty, bunionectomy, and herniorrhaphy. Zynrelef resulted in a significant decrease in 24-hour pain score by 1.8 (95% confidence interval [CI] 1.42 to 2.2), however there was significant heterogeneity (96.94%). Zynrelef was also found to be more efficacious when compared to bupivacaine (1.81; 95% CI 1.44 to 2.14, p= 0.00) and placebo (1.81; 95% CI 1.54 to 2.06, p= 0.00) for decrease in pain scores. Use of Zynrelef was associated with an overall 3.25 times higher chance of patients being opioid-free at 72 hours compared to placebo or control (95% CI 2.3 to 4.58). When compared to bupivacaine, patients were 2.39 times more likely (95% CI 1.54 to 3.7, p= 0.00) and when compared to placebo, patients were 5.25 times more likely (95% CI 2.3 to 4.58, p = 0.00). Use of Zynrelef also resulted in an overall decrease in morphine consumption at 72 hours of 10.61 morphine equivalents (95% CI 8.13 to 13.09); however, when comparing Zynrelef to bupivacaine the difference was not statistically significant. When compared to placebo, morphine consumption was reduced by 11.07 morphine equivalents (95% CI 8.43 to 13.71, p= 0.00). Overall, Zynrelef was concluded to be advantageous against both placebo and bupivacaine for pain relief and reduced opioid consumption. [2]

References:

[1] Kaye AD, Edinoff AN, Yan JY, et al. Novel Local Anesthetics in Clinical Practice: Pharmacologic Considerations and Potential Roles for the Future. Anesth Pain Med. 2022;12(1):e123112. Published 2022 Feb 14. doi:10.5812/aapm.123112
[2] Goudra B, Singh N, Xue L, Goyal A, Gouda D, Singh PM. Efficacy of New Long-Acting Bupivacaine HTX-011 in Providing Pain Relief for Patients Undergoing Elective Surgery - A Meta-analysis of Prospective Randomized Controlled Trials. Anesth Essays Res. 2020;14(2):288-294. doi:10.4103/aer.AER_34_20

Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

Is there any data/study to compare Zynrelef or Xaracoll with Exparel?

Please see Tables 1-7 for your response.


 

HTX-011 Reduced Pain Intensity and Opioid Consumption versus Bupivacaine HCl in Bunionectomy: Phase III Results from the Randomized EPOCH 1 Study

Design

Randomized, multi-center, double-blind, parallel group, active- and placebo-controlled Phase III clinical trial

N=412

Objective

To determine if HTX-011 (bupivacaine and meloxicam; Zynrelef), an extended-release dual-acting local anesthetic, reduces both post-operative pain over 72 hours and post-operative opioid use when compared with bupivacaine HCl and saline placebo.

Study Groups

Zynrelef (n=157)

Bupivacaine HCl (n=155)

Placebo (n=100)

Inclusion Criteria

Age ≥ 18 years; American Society of Anesthesiologists physical status of I, II, or III; undergoing a primary unilateral, distal, first metatarsal bunionectomy

Exclusion Criteria

Pre-existing, concurrent, acute, or chronic painful physical/restrictive condition(s); use of non-steroidal anti-inflammatory (NSAIDs, including meloxicam) ≥ 10 days prior to surgery; known or suspected daily use of opioids for ≥ 7 days within 6 months prior to surgery; long-acting opioids within 3 days prior to surgery; the use of any opioids < 24 hours prior to surgery; the administration of bupivacaine within 5 days prior to surgery; and the use of systemic steroids within five half-lives or 10 days prior to administration of study drug

Methods

Patients were randomized (3:2:2) to receive the study drug Zynrelef, 60 mg/1.8 mg (bupivacaine/meloxicam), 2.1 mL, applied into the surgical site without a needle; bupivacaine HCl 0.5%, 50 mg (10 mL), via injection into the surgical site; or saline placebo, 2.1 mL, applied into the surgical site without a needle.

Patients were prepared with 20 mL of 1% lidocaine without epinephrine as anesthesia. The observed agent was administered via local application into the surgical site.

Duration

Treatment: 72 hours

Follow-Up Intervals (post-surgery): Days 10, 28, and 42

Outcome Measures

Primary: Mean area under the curve (AUC) of the Numeric Rating Scale (NRS) of pain intensity scores through 72 hours for Zynrelef compared with saline placebo.

Secondary: Mean AUC of the NRS pain intensity scores for Zynrelef compared with bupivacaine HCl within 72 hrs post-surgery; mean total post-operative opioid consumption (in morphine mg equivalents) through 72 hours for Zynrelef compared with saline placebo; the proportion of subjects who were opioid free through 72 hours for Zynrelef compared with bupivacaine HCl; the mean total post-operative opioid consumption (in morphine equivalents) through 72 hours for Zynrelef compared with bupivacaine HCl.

Baseline Characteristics

 

Zynrelef

(n=157)

Bupivacaine

(n=155)

Placebo

(n=100)

Age, years

48.0 ± 14.47 45.5 ± 14.79 47.3 ± 12.83

Female

138 (87.9%) 132 (85.2%) 86 (86%)

White

Black

123 (78.3%)

24 (15.3%)

128 (82.6%)

22 (14.2%)

86 (86%)

12 (12.0%)

Results

 

Zynrelef

(n=157)

Bupivacaine

(n=155)

Placebo

(n=100)

P-value

Mean AUC0-72 NRS Pain Score

323.3 ± 182.6

--

445.3 ± 155.8

<0.001

Mean AUC0-72 NRS Pain Score

Opioid Consumption vs placebo

Opioid Consumption vs bupivacaine

Opioid free for 72 H

323.3 ± 182.6

18.8 ± 19.8

18.8 ± 19.8

45 (28.7%)

393.5 ± 153.8

25.09 ± 21.55

17 (11%)

-

30.06 ± 21.01

-

2 (2%)

0.0002

<0.0001

0.0022

<0.0001

Adverse Events

Common Adverse Events: Nausea (37.6%, 45.5%, 43.6) and dizziness (21.7%, 23.4%, 17.8%)

Serious Adverse Events: Zynrelef (1.9%), bupivacaine (1.9%), placebo (1%)

Percentage that Discontinued due to Adverse Events: 0.6 % (Zynrelef group)

Study Author Conclusions

Zynrelef demonstrated a significant reduction in postoperative pain through 72 hours with a significant reduction in opioid consumption and a significant increase in the proportion of opioid-free subjects compared with saline placebo and the most widely used local anesthetic, bupivacaine HCl.

InpharmD Researcher Critique

Bupivacaine dosing was based on surgeon consensus due to the lack of an approved dose form. Typical discharge after surgery is 1-2 hours but patients were retained for 72 hours which may not reflect real-world outcomes. 

 

References:

Viscusi E, Gimbel JS, Pollack RA, Hu J, Lee GC. HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in bunionectomy: phase III results from the randomized EPOCH 1 study [published online ahead of print, 2019 May 21]. Reg Anesth Pain Med. 2019;rapm-2019-100531. doi:10.1136/rapm-2019-100531

 

HTX-011 Reduced Pain Intensity and Opioid Consumption versus Bupivacaine HCl in Herniorrhaphy: Results from the Phase 3 EPOCH 2 Study

Design

Phase 3, randomized, multi-center, double-blind, parallel-group, active- and placebo-controlled clinical trial

N=446

Objective

To assess the safety and efficacy of HTX-011 (bupivacaine and meloxicam in Biochronomer® polymer technology), a long-acting investigational anesthetic, in reducing both postoperative pain over 72 h and postoperative opioid use compared to bupivacaine hydrochloride (HCl)

Study Groups

Zynrelef (n=164)

Bupivacaine HCl (n=172)

Saline placebo (n=82)

Inclusion Criteria

Age ≥ 18 years; American Society of Anesthesiologists physical status of I, II, or III; undergoing unilateral open inguinal herniorrhaphy

Exclusion Criteria

Pre-existing, concurrent, acute, or chronic painful physical/restrictive condition(s); planned or concurrent surgical procedures; and those with a history of prior inguinal herniorrhaphy, except during childhood; use of non-steroidal anti-inflammatory (NSAIDs, including meloxicam) ≥ 10 days prior to surgery; known or suspected daily use of opioids for ≥ 7 days within 6 months prior to surgery; long-acting opioids within 3 days prior to surgery; the use of any opioids < 24 hours prior to surgery; the administration of bupivacaine within 5 days prior to surgery; and the use of systemic steroids within 10 days prior to administration of study drug

Methods

Subjects were randomized (2:2:1) to the following groups: (a) Zynrelef, 300 mg/9 mg (bupivacaine/meloxicam), 10.3 mL, via instillation into the surgical site; (b) bupivacaine HCl 0.25%, 75 mg (30 mL), via injection into the surgical site; (c) saline placebo, 10.3 mL, via instillation into the surgical site. 

Near the completion of surgery and following irrigation and suction of each fascial layer, a single dose of study drug (Zynrelef, bupivacaine HCl, or saline placebo) was administered intraoperatively via local administration into the surgical site. Subjects remained in the hospital/research facility for a minimum of 72 h following surgery to be evaluated for the primary and secondary endpoints.

Duration

Treatment: 72 hours

Follow-Up Intervals (post-surgery): Days 10 and 28

Outcome Measures

Primary: Mean area under the curve (AUC) of the Numeric Rating Scale (NRS) of pain intensity scores through 72 hours for Zynrelef compared with saline placebo.

Secondary: Mean AUC of the NRS pain intensity scores for Zynrelef compared with bupivacaine HCl within 72 hrs post-surgery; mean total post-operative opioid consumption (in morphine mg equivalents) through 72 hours for Zynrelef compared with saline placebo; the proportion of subjects who were opioid-free through 72 hours for Zynrelef compared with bupivacaine HCl; the mean total post-operative opioid consumption (in morphine equivalents) through 72 hours for Zynrelef compared with bupivacaine HCl.

Baseline Characteristics

 

Zynrelef (n=164)

Bupivacaine (n=172)

Placebo (n=82)

Age, years

48.9 (13.29%) 49.4 (11.26%) 48 (14.59%)

Female

12 (7.3%) 8 (4.7%) 3 (3.7%) 

White

139 (84.8%) 153 (89%) 78 (95.1%)

Results

 

Zynrelef

(n = 164)

Bupivacaine

(n = 172)

Placebo

(n = 82)

Mean AUC0-72 NRS Pain Score

p-value versus placebo

p-value versus bupivacaine

269.4 ± 173.72

0.0004

<0.0001

341.9 ± 158.3

-

-

350.8 ± 171.22

-

-

Opioid Consumption, mg of morphine equivalents

p-value versus placebo

p-value versus bupivacaine

10.9 ± 17.06

0.0001

0.0240

14.5 ± 18.19

-

-

17.5 ± 18.91

-

-

Opioid free for 72 H

84 (51.2%)

69 (40.1%)

18 (22%)

Adverse Events

(Zynrelef, bupivacaine, placebo)

Common Adverse Events: Nausea: (18.4%, 21.4%, 34.1%); Constipation: (17.2%, 23.7%, 18.3%); Dizziness: (14.7%, 24.3%, 15.9%); Headache: (12.9%, 13.9%, 12.2%)

Serious Adverse Events (SAEs): Zynrelef (1.2%), bupivacaine (0.6%), placebo (1.2%)

Percentage that Discontinued due to Adverse Events: None (0%) in all 3 groups

Study Author Conclusions

Zynrelef demonstrated significant improvement in postoperative pain control and a clinically meaningful reduction in opioid consumption when compared to the most widely used local anesthetic, bupivacaine HCl.

InpharmD Researcher Critique

An extensive inclusion/exclusion criteria makes it difficult to apply in a general surgical population. Typical discharge would occur in a few hours but patients remained for 72 hours to collect data. Patients would also possibly be discharged with opioid prescriptions which could not be measured in the study due to the 72-hour timeframe.

 

References:

Viscusi E, Minkowitz H, Winkle P, Ramamoorthy S, Hu J, Singla N. HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the phase 3 EPOCH 2 study [published correction appears in Hernia. 2020 Jun;24(3):679]. Hernia. 2019;23(6):1071-1080. doi:10.1007/s10029-019-02023-6

 

HTX-011 Reduced Pain and Opioid Use After Primary Total Knee Arthroplasty: Results of a Randomized Phase 2b Trial

Design

Phase 2b, double-blind, placebo-controlled and active-controlled trial 

N=222

Objective

To determine the efficacy and safety of one application of HTX-011 (bupivacaine and meloxicam in Biochronomer® polymer technology; Zynrelef) with or without ropivacaine in patients undergoing a primary unilateral total knee arthroplasty (TKA)

Study Groups

Saline Placebo (n=53)

Bupivacaine (n=55)

Zynrelef  (n=58)

Zynrelef and ropivacaine (n=56)

Inclusion Criteria

Patient's scheduled for a unilateral TKA, ≥18 years old and demonstrated an American Society of Anesthesiologists (ASA) physical status of I, II, or III.

Exclusion Criteria

Patient's known/suspected of daily opioid use for ≥ 7 consecutive days within 6 months before their scheduled surgery

Use of the following medications within the listed times before surgery: nonsteroidal anti-inflammatory medications (NSAIDs) (including meloxicam) within 10 days, long-acting opioids within 3 days, any opioids within 24 hours and bupivacaine HCl within 5 days.

Methods

Patients were randomized (1:1:1:1) to receive Zynrelef alone (400 mg bupivacaine/12 mg meloxicam, 14 mL) via periarticular application; Zynrelef (14 mL of 400 mg bupivacaine/12 mg meloxicam) via periarticular application plus seperate dose of 0.5% ropivacaine 0.5% (50 mg, 10 mL) injected into the posterior capsule; Bupivacaine HCl 0.25% alone (125 mg, 50 mL) administered through multiple periarticular injections; 14 mL saline placebo, administered via multiple periarticular injections.

All patients were also given 150 mg of oral pregabalin, ≤1000 mg of intravenous acetaminophen and 1 gram of intravenous tranexamic acid (TXA) before surgery. Patients also received a second dose of TXA 1 gram up to 8 hours after surgery. Following surgery, patients were required to stay in the hospital or a treatment facility for a minimum of 72 hours for observation. During the post-operative observation period, patients had the option of receiving pain medications upon request. 

After 72 hours, patients return to their prospective study sites and must complete a daily diary of their opioid use upon discharge.  

Duration

72 hours

Outcome Measures

Primary and Secondary efficacy: Area under the curve (AUC) of the Numeric Rating Scale (NRS) of pain intensity scores over 48 hours and 72 hours.

Other secondary efficacy endpoints: Evaluations of total postoperative opioid consumption and discharge readiness evaluated by the Modified Postanesthetic Discharge Scoring System (MPADSS) criteria.

Baseline Characteristics

 

Saline Placebo (n=53)

Bupivacaine (n=55)

Zynrelef (n=58)

Zynrelef and ropivacaine (n=56)

Age, years

61.5 61.4 

62.5

63.2

Male

 28 (52.8%)  20 (36.4%)  32 (55.2%)  29 (51.8%)

White 

Black

45 (84.9%)

8 (15.1%) 

47 (85.5%)

7 (12.7%)

51 (87.9%)

6 (10.3%)

49 (87.5%)

5 (8.9%)

Body mass index, kg/m2

32.1 32.4  31.7

31.2

Results

Primary Analysis (adjusted for opioid use)

Saline placebo (n= 53)   

Zynrelef (n= 58)

Zynrelef and ropivacaine (n= 56)

bupivacaine

AUC0-48 of NRS (SD)

P-value vs saline placebo

396.4 (77.5)

-

322.1 (99.7)

0.0002

307.3 (127.7)

<.0001

 

AUC 0-72 of NRS (SD)

P-value vs saline placebo

577.9 (125.1)

-

471.2 (149.4)

0.0004

452.5 (194.1)

<0.0001

 

AUC 0-48 of NRS (SD)

P-value vs saline placebo

P-value vs bupivacaine

267.3 (81.3)

-

-

188.9 (81.6)

<.0001

0.0070

194.5 (99.6)

<.0001

0.0190

233.7 (85.5)

-

-

AUC 0-72 of NRS (SD)

P-value vs saline placebo

P-value vs bupivacaine 

365.4 (127.2)

-

-

264.56 (123.2)

<0.0001

0.0269

269.51 (144.8)

0.0002

0.0456

269.5 (144.8)

-

-

SD= Standard deviation

Adverse Events

Any AE: Saline placebo (94.3%), bupivacaine (92.7%), Zynrelef (94.8%), Zynrelef + ropivacaine (92.9%)

Severe AEs possibly related to study drug: Saline placebo (0%), bupivacaine (0%), Zynrelef (0%), Zynrelef + ropivacaine (1.8%)

The three most common AEs in the Zynrelef groups were nausea, constipation, and vomiting. Incidence were lower or comparable to the bupivacaine group.

Study Author Conclusions

Patients treated with Zynrelef demonstrated a significant reduction in pain intensity compared to patients treated with saline placebo for the first 48-hr and 72 hours post-operative (total knee arthroplasty) periods.

InpharmD Researcher Critique

The primary endpoints were focused on the p-value versus placebo rather than comparisons between 



References:

Lachiewicz PF, Lee GC, Pollak RA, Leiman DG, Hu J, Sah AP. HTX-011 Reduced Pain and Opioid Use After Primary Total Knee Arthroplasty: Results of a Randomized Phase 2b Trial. J Arthroplasty. 2020;35(10):2843-2851. doi:10.1016/j.arth.2020.05.044

 

Safety and Efficacy of Bupivacaine HCl Collagen-Matrix Implant (INL-001) in Open Inguinal Hernia Repair: Results from Two Randomized Controlled Trials

Design

Analysis of two similar phase 3, multicenter, randomized, double-blind, placebo-controlled studies (MATRIX-1 and MATRIX-2)

(N= 524)

Objective

To examine the efficacy and safety of the bioresorbable bupivacaine HCl collagen-matrix implant (INL-001) for postsurgical pain after open inguinal hernia repair or placebo collagen-matrix implants

Study Groups

MATRIX-1

INL-001 (n= 204)

Placebo (n= 101)

MATRIX-2

INL-001 (n= 213)

Placebo (n= 106)

Combined modified intent-to-treat (mITT) population

Combined INL-001 (n= 404)

Combined placebo (n= 206)

Inclusion Criteria

Age > 18 years, undergoing elective open mech tension-free inguinal hernia repair under general anesthesia

Exclusion Criteria

N/A

Methods

Patients were randomized (2:1) to either three doses of INL-001 100 mg bupivacaine HCl collagen-matrix implants (total dose 300 mg bupivacaine HCl) or placebo collagen-matrix implants without bupivacaine. Providers were blinded unless patients develop an AE which then led to unblinding and revealing which treatment was assigned. Parenteral morphine was available for post-surgical pain as needed. All patients received acetaminophen PO 650 mg TID for 3 days along with immediate-release morphine as-needed. Pain intensity was recorded using a 11-point pain score at pre-determined points from 1 to 72 hours after study drug implantation.

The modified intent-to-treat population consisted of patients who were randomized and received any dose of study drug and reported at least one 11-point numerical rating scale pain intensity score.

Duration

MATRIX-1: August 2015 to April 2016

MATRIX-2: September 2015 to April 2016

Outcome Measures

Primary: Sum of pain intensity scores from 0 to 24 hours 

Secondary: Sum of pain intensity scores from 0 to 48 hours and 0 to 72 hours. Total use of opioid analgesia from times 0 to 24, 28, and 72 hours (measured as mg IV morphine equivalent). Safety

Baseline Characteristics

 

MATRIX-1

MATRIX-2

 

INL-001 (n= 204)

Placebo collagen-matrix (n= 101) INL-001 (n= 213) Placebo collagen-matrix (n= 106)

Age, years (SD)

53.1 (12.82) 53.3 (14.01) 50.7 (13.69) 48.5 (13.94)

Female

Male

8 (4%)

196 (96%)

4 (4%)

97 (96%)

5 (2%)

208 (98%)

3 (3%)

103 (97%)

Hispanic or Latino

Not Hispanic or Latino

Missing

77 (38%)

127 (62%)

0

38 (38%)

62 (61%)

1 (1%)

44 (21%)

169 (79%)

0

23 (22%)

83 (78%)

0

White

Black or African American

185 (91%)

15 (7%)

91 (90%)

7 (7%)

182 (85%)

23 (11%)

90 (85%)

12 (11%)

Body mass index, kg/m2 (SD)

27.05 (3.899)

27.26 (4.596)

26.84 (4.025)

27.22 (5.062)

Previous ipsilateral hernia repair using mesh

Yes

No

Missing

 

20 (10%)

184 (90%)

0

 

12 (12%)

89 (88%)

0

 

22 (10%)

189 (89%)

2 (<1%)

 

10 (10%)

96 (91%)

0

Multiple hernias

Yes

No

Missing

 

13 (6%)

190 (93%)

1 (<1%)

 

4 (4%)

96 (95%)

1 (1%)

 

5 (2%)

204 (96%)

4 (2%)

 

4 (4%)

102 (96%)

0

Incision duration, hours (SD)

0.80 (0.432)

0.75 (0.379)

0.80 (0.327)

0.84 (0.352)

Results

Endpoint

Combined INL-001 (n= 404)

Placebo collagen-matrix (n= 206)

Sum of patient intensity from time 0 to 24 hours

Mean (standard error of mean)

Median

p-Value versus placebo

 

87.1 (2.34)

82.5

<0.0001

 

111.6 (3.22)

112.3

-

Sum of patient intensity from time 0 to 48 hours

Mean (standard error of mean)

Median

p-Value versus placebo

 

186.1 (4.65)

180.5

0.0033

 

209.2 (6.44)

208.8

-

Sum of patient intensity from time 0 to 72 hours

Mean (standard error of mean)

Median

p-Value versus placebo

 

268.0 (6.91)

253.0

0.0441

 

291.3 (9.55)

274.9

-

Total use of opioid analgesia from time 0 to 24

Median

p-Value versus placebo

 

5.0

<0.0001

 

12.3

-

Total use of opioid analgesia from time 0 to 48

Median

p-Value versus placebo

 

7.0

<0.0001

 

15.0

-

Total use of opioid analgesia from time 0 to 72

Median

p-Value versus placebo

 

9.0

0.0004

 

17.0

-

Adverse Events

Any adverse events:

MATRIX-1

INL-001 (n= 203): 138 (68%)

Placebo (n= 101): 67 (66%)

MATRIX-2

INL-001 (n= 208): 118 (57%)

Placebo (n= 107): 76 (71%)

Commonly-reported adverse events consisted of incision-site swelling, somnolence, incision-site pain, dizziness, nausea, constipation, post-procedural discharge, dysgeusia, restlessness, incision-site complication, incision-site erythema, anxiety, vomiting, and tinnitus

Treatment-related adverse events:

Combined INL-001 (n= 441): 14 (3%)

Combined placebo (n= 208): 6 (3%)

Reported events in more than one patient possibly linked to treatment included dysgeusia, dizziness, and incision site complication

Study Author Conclusions

These findings indicate that INL-001 results in post-inguinal hernia repair analgesia that is temporally aligned with the period of maximal postsurgical pain and may reduce the need for opioids while offering a favorable safety profile.

InpharmD Researcher Critique

The study was not a comparison between bupivacaine collagen matrix implant versus Exparel® (liposomal bupivacaine) or Zynrelef® (bupivacaine and meloxicam extended-release solution) but does illustrate its benefit compared to a placebo agent. As comparative studies are scarce, the data presented may prove useful and demonstrates the potentially reduced risk of local and systemic toxicity when bupivacaine was delivered via collagen technology as illustrated by the similar safety profile. Patients were predominantly white men which may limit the generalizability of results. 

References:

Velanovich V, Rider P, Deck K, et al. Safety and efficacy of bupivacaine HCl collagen-matrix implant (INL-001) in open inguinal hernia repair: results from two randomized controlled trials. Adv Ther. 2019;36(1):200-216. doi:10.1007/s12325-018-0836-4.

 

Clinical Evaluation of XaraColl(®), a Bupivacaine-Collagen Implant, for Postoperative Analgesia in Two Multicenter, Randomized, Double-Blind, Placebo-Controlled Pilot Studies

Design

Two independent, multicenter, randomized, single-dose, double-blind, placebo-controlled, pilot studies

Study 1: N= 53 

Study 2: N= 50 

Objective

To evaluate the safety and efficacy of XaraColl at different doses (100 mg and 200 mg of bupivacaine hydrochloride; study 1 and 2, respectively)

Study Groups

Study 1: Bupivacaine 100 mg (n= 24), placebo (n= 29) 

Study 2: Bupivacaine 200 mg (n= 25), placebo (n= 25) 

Inclusion Criteria

Male, age ≥ 18, generally healthy, scheduled for a unilateral inguinal hernioplasty by open laparotomy.

Exclusion Criteria

Bilateral inguinal hernioplasty requiring more than one incision, previous hernia repair on the same side, concomitant illness that would significantly increase surgical risk, concomitant illness with tratment agents that could affect the analgesic response (central alpha agents, neuroleptic agents, other antipsychotic agents, monoamine oxidase inhibitors, systemic corticosteroids).

Methods

Two bupivacaine (or placebo) implants were administered to each patient. Patients in study one received two, 50 mg doses for a total of 100 mg and patients in study two received two, 100 mg doses for a total dose of 200 mg.  Initial administration time was denoted as 'time 0' and patients were followed up through 72 hours for postoperative pain intensity and supplemental opioid use. 

Efficacy endpoints are defined and calculated as follows:

Summed pain intensity (SPI): trapezoidal area under the visual analog scale curve from one hour through to 24, 48, or 72 hours after time 0, regardless of the actual time the assessments were recorded.

Total use of opioid analgesia (TOpA): patients in the combined treatment groups were ranked according to their SPI value; mean rank was subtracted from each patient’s SPI rank and expressed as a percentage of the mean rank (“% difference”); this yields positive values for patients having a higher SPI than the median and negative pain scores for patients having a lower SPI.

Integrated endpoint of SPI and TOpA (I-SPI-TOpA): the percent differences derived for the SPI and TOpA were summed to generate the summated percent difference.

Duration

Study 1: March 2008 to January 2009 

Study 2: December 2010 to May 2011 

Outcome Measures

Mean SPI, Mean TOpA, I-SPI-TOpA, each at 24, 48, and 72 hour intervals

Baseline Characteristics

 

 

 

 

 

 

 
Study 1 (N= 53) Study 2 (N= 50)  
  100 mg (n= 24) Placebo (n= 29)   200 mg (n= 25) Placebo (n= 25)    

Mean age, years

46.1 52.6   47.8 41.7    

White

23 (95.8%) 27 (93.1%)   25 (100%)  22 (88.0%)    

Mean body mass index, kg/m2

26.8   27.1   25.5  25.7    

Results

 

Mean SPI/mm • hour ± standard deviation

Mean TOpA/mg IV morphine equivalent ± standard deviation

 I-SPI-TOpA

Time period by dataset

Treatment

Placebo

p-Value

Treatment

Placebo

p-Value

p-Value

24 hours post time 0

Study 1

Study 2

Pooled

 

670 ± 401

996 ± 504

833

 

1191 ± 602

1270 ± 567

1231

 

<0.001

0.080

<0.001 

 

18.5 ± 12.6

20.6 ± 19.9

19.5

 

24.6 ± 15.3

36.9 ± 17.6

30.8

 

0.123

0.004

0.001

 

0.013

0.005

<0.0001 

48 hours post time 0

Study 1

Study 2

Pooled

 

1351 ± 857

2018 ± 1093

1684 

 

2130 ± 1288

2457 ± 1157

2293

 

0.012

0.178

0.006

 

30.6 ± 19.9

36.3 ± 34.7

33.4 

 

36.5 ± 25.5

56.4 ± 32.8

46.5

 

0.359

0.042

0.024 

 

0.097

0.039

0.008

72 hours post time 0

Study 1

Study 2

Pooled

 

1864 ± 1239

2842 ± 1722

2337 

 

2838 ± 1807

3485 ± 1807

3161

 

0.030

0.184

0.014 

 

37.2 ± 29.3

48.7 ± 46.1

42.9 

 

44.9 ± 35.0

70.8 ± 44.3

57.8 

 

0.3960

0.094

0.058 

 

0.136

0.078

0.021 

Adverse Events

Common Adverse Events:

Study 1: constipation, nausea, headache (occurred in ≥ 10% of patients)

Study 2: constipation, nausea, scrotal swelling, vomiting, dizziness, chills, pyrexia, and incision site infection (occurred in ≥ 5% of patients)

Serious Adverse Events:

Study 1: hypotension (n= 1, bupivacaine group), hiccups (n= 1, placebo group)

Study 2: none

Percentage that Discontinued due to Adverse Events: none

Study Author Conclusions

Through use of I-SPI-TOpA in addition to those traditional endpoints [SPI and TOpA], we have demonstrated that XaraColl, a perioperative bupivacaine-collagen implant, significantly reduces pain and use of opioid medication over at least 48 hours after hernioplasty, as based on two independent pilot studies performed at safe and well tolerated doses of bupivacaine. Furthermore, a pooled analysis of both studies indicates a statistically significant treatment effect over 72 hours after surgery. These findings suggest that XaraColl offers great potential for the management of postoperative pain and warrants definitive clinical trials with larger sample sizes.

InpharmD Researcher Critique

Values for TOpA in study 1 were not statistically significant at 24-, 48-, and 72-hour intervals; the authors suspected this was due to a patient dosing his medication per the maximum allowed amount rather than as needed for pain control. When looking at the pooled data sets, the significance of bupivacaine was more apparent versus looking at either individual study. 

References:

Cusack SL, Jaros M, Kuss M, et al. Clinical evaluation of XaraColl(®), a bupivacaine-collagen implant, for postoperative analgesia in two multicenter, randomized, double-blind, placebo-controlled pilot studies. J Pain Res. 2012;5:217-225. doi:10.2147/JPR.S33453.

A Randomized, Multicenter, Pilot Study Comparing the Efficacy and Safety of a Bupivacaine-Collagen Implant (XaraColl®) with the ON-Q PainBuster® Post-op Pain Relief System Following Open Gynecological Surgery

Design

Randomized, multicenter, pilot study

N= 27

Objective

To compare the efficacy and safety of XaraColl for the prevention of postsurgical pain versus a slow postoperative perfusion of bupivacaine to the wound environment via the ON-Q PainBuster® Post-op Pain Relief System (ON-Q)

Study Groups

XaraColl® (n=14)

ON-Q (n=13)

Inclusion Criteria

Women at least 18 years of age, generally healthy, scheduled to receive an elective total abdominal hysterectomy or other nonlaparoscopic gynecological procedure for reasons other than malignancy (e.g., adenocarcinoma, cervical cancer, or leiomyosarcoma) under general anesthesia.

Exclusion Criteria

Laparoscopic procedures, supraumbilical or Maylard incisions, or concomitant vaginal procedures (e.g., anterior and posterior colporrhaphy), any additional surgical procedures either related or unrelated to abdominal hysterectomy during the same hospitalization, neuraxial opioid analgesics during the surgery, use of an adhesion barrier, chronic painful conditions or other concomitant illness with agents that could affect the analgesic response (e.g., central alpha agents, neuroleptic agents, and other antipsychotic agents, monoamine oxidase inhibitors, or systemic corticosteroids), unreliable or incapable of complying with the requirements of the protocol. 

Methods

Eligible patients undergoing open gynecological surgery were randomized (1:1) to receive either three XaraColl implants (each containing 50 mg bupivacaine hydrochloride) or ON-Q (900 mg bupivacaine hydrochloride perfused over 72 hours). Following surgery, patients had access to intravenous (IV) morphine via a patient-controlled analgesia (PCA) pump as rescue analgesia for the first 24 hours and to oral opioid medication thereafter. 

Duration

September 2008 to December 2008

Outcome Measures

Primary: Total use of opioid analgesia through 24, 48, 72, and 96 hours after surgery.

Secondary: Time to first use of opioid rescue analgesia, patients' overall pain control over the 96-hour period using a five-point numeric rating scale, adverse events.

Baseline Characteristics

 

XaraColl® 

(n=14)

ON-Q

(n=13)

 

Age, years

Mean (standard deviation [SD])

Median (minimum, maximum)

 

43.3 (11.5)

39.0 (28, 63)

 

43.4 (6.2)

41.0 (36, 59)

 

Race

Asian

Black or African American

White or Caucasian

 

1 (7.1%)

2 (14.3%)

11 (78.6%)

 

0 (0.0%)

5 (38.5%)

8 (61.5%)

 

Ethnicity

Hispanic or Latino

Not Hispanic or Latino

 

3 (21.4%)

11 (78.6%)

 

0 (0.0%)

13 (100.0%)

 

Weight, kg

Mean (SD)

Median (minimum, maximum)

 

71.7 (12.8)

77.0 (53.6, 90.5)

 

73.3 (11.0)

74.1 (56.4, 93.6) 

 

Height, cm

Mean (SD)

Median (minimum, maximum)

 

162.1 (6.4)

161.3 (150.0, 171.0)

 

160.2 (8.6)

162.6 (139.7, 175.0)

 

Body mass index, kg/m2

Mean (SD)

Median (minimum, maximum)

 

27.1 (3.8)

27.6 (21.4, 32.5)

 

28.7 (4.6)

29.0 (22.9, 37.0)

 

Surgical procedure performed

Abdominal hysterectomy

Myomectomy

Abdominal hysterectomy with right salpingo-oophorectomy

Right salpingo-oophorectomy (adnexal only)

 

10 (71.4%)

3 (21.4%)

1 (7.1%)

0 (0.0%)

 

11 (84.6%)

1 (7.7%)

0 (0.0%)

1 (7.7%)

 

Results

 

Treatment group

Non-inferiority and superiority statistics

Total opioid use from 0 to 24 hours XaraColl® ON-Q  
Mean (SD) 46.9 (21.6) 67.0 (32.4)  
Mean difference     −20.2
Upper bound of one-sided 95% CI of the mean difference     −2.20
P-value*     p=0.067
Total opioid use from 0 to 48 hours       
Mean (SD) 55.4 (22.8) 74.9 (35.4)  
Mean difference     −19.4
Upper bound of one-sided 95% CI of the mean difference     −0.01
P-value*     p=0.100
Total opioid use from 0 to 72 hours      
Mean (SD) 62.0 (25.3) 85.4 (41.9)  
Mean difference     −23.4
Upper bound of one-sided 95% CI of the mean difference     −0.84
P-value*     p=0.089
Total opioid use from 0 to 96 hours      
Mean (SD) 67.9 (28.2) 90.8 (46.1)  
Mean difference     −22.9
Upper bound of one-sided 95% CI of the mean difference     2.01
P-value*     p=0.129

The time to first use of opioid analgesia was significantly delayed in patients treated with XaraColl (p=0.024). Fifty percent of patients took their first opioid medication at 0.78 and 0.57 hours after time 0 in the XaraColl and ON-Q groups, respectively. 

Overall, there was no significant difference in the patients’ rating of pain control (p=0.847).

Adverse Events

Common Adverse Events: Constipation (14.3% XaraColl® vs. 0.0% ON-Q), flatulence (14.3% vs. 0.0%), nausea (7.1% vs. 15.4%), pyrexia (7.1% vs. 15.4%), headache (14.3% vs. 7.7%), rash (14.3% vs. 0.0%)

Serious Adverse Events: 0%

Percentage that Discontinued due to Adverse Events: 0%

Study Author Conclusions

Despite using only 17% of the ON-Q dose, XaraColl is as effective as ON-Q in providing postoperative analgesia for 4 days after open gynecological surgery. These preliminary findings suggest that XaraColl offers great potential for the management of postoperative pain and warrants further definitive studies.

InpharmD Researcher Critique

This could be considered an underpowered hypothesis-generating pilot study. Participants and investigators were non-blinded due to fundamentally different treatment modalities. The principal efficacy endpoint was patient use of opioid analgesia which can be readily influenced by confounding factors such as patient attitudes and educations. 

References:

Cusack SL, Minkowitz HS, Kuss M, et al. A randomized, multicenter, pilot study comparing the efficacy and safety of a bupivacaine-collagen implant (XaraColl®) with the ON-Q PainBuster® Post-op Pain Relief System following open gynecological surgery. J Pain Res. 2012;5:453-461. doi:10.2147/JPR.S37310.

Pharmacokinetics and Safety of INL-001 (Bupivacaine HCl) Implants Compared with Bupivacaine HCl Infiltration After Open Unilateral Inguinal Hernioplasty

Design

Multicenter, single-blind, pharmacokinetics and safety study

N= 52

Objective

To evaluate the pharmacokinetic (PK) profile of INL-001 300 mg compared with 0.25% bupivacaine hydrochloride (HCl) 175 mg infiltration.

Study Groups

INL-100 bupivacaine (n= 35)

0.25% bupivacaine HCl infiltration (n= 17)

Inclusion Criteria

Age > 18 years, undergoing elective unilateral inguinal hernioplasty via open laparotomy

Exclusion Criteria

Known hypersensitivity to amide local anesthetics, morphine, acetaminophen, or bovine products; scheduled for bilateral inguinal hernia repair or another concomitant surgical procedure; underwent major surgery within 3 months of initial treatment; planned laparotomy within 30-day postsurgical period; known history of alchohol/drug abuse within 3 years of screening; clinically significant unstable cardiac, neurologic, immunologic, renal, hepatic, hematologic disease, or any other significant condition.

Methods

Patients were randomized to receive INL-001 100 mg bupivacaine HCl implants (Xaracoll®) TID doses for a total of 300 mg or local infiltration of 0.25% bupivacaine HCl (Marcaine) 175 mg

Duration

Enrollment period: June to August 2017

Outcome Measures

Primary: pharmacokinetic assessment of INL-100 bupivacaine

Secondary: safety

Baseline Characteristics

 

INL-001 (n= 34)

0.25% Bupivacaine HCl infiltration (n= 17)

Age, years (SD)

45.6 (14.8) 41.6 (12.2)

Female

Male

1 (2.9%)

33 (97.1%)

0

16 (100%)

White

31 (91.2%) 15 (93.8%)

Non-hispanic or Latino

Hispanic or Latoni

27 (79.4%)

7 (20.6%)

13 (81.3%)

3 (18.8%)

Body mass index, kg/m2 (SD)

27.4 (5.0)

27.8 (4.9)

Results

Endpoint

INL-001 (n= 34)

0.25% Bupivacaine HCl infiltration (n= 16)

Pharmacokinetic parameter

Median Tmax, hours (min, max)

Mean t1/2, hours (SD)

Mean Cmax, ng/mL (SD; range)

AUC: time 0 to last quantifiable plasma concentration

AUC: time from 0 to infinity

 

3.0 (1.5, 24.0)

19.0 (5.9)

663.4 (263.8; 274 to 1230)

18,186.9

19,012.5

 

1.0 (0.5, 4.0)

9.1 (3.8)

641.0 (262.7; 275 to 1140)

8,836.9

8,920.1

Any treatment-emergent adverse events

33 (97.1%) 15 (93.8%)

Nervous system disorders

Somnolence

Dizziness

Tremor

Dysgeusia

Headache

26 (76.5%)

19 (55.9%)

12 (35.3%)

6 (17.6%)

4 (11.8%)

4 (11.8%)

13 (81.3%)

10 (62.5%)

7 (43.8%)

3 (18.8%)

4 (25.0%)

1 (6.3%)

Gastrointestinal disorders

Constipation

Oral hypoesthesia

Nausea

Oral paresthesia

12 (35.3%)

8 (23.5%)

3 (8.8%)

3 (8.8%)

3 (8.8%)

4 (25.0%)

1 (6.3%)

2 (12.5%)

2 (12.5%)

2 (12.5%)

Eye disorders

Vision blurred

10 (29.4%)

8 (23.5%)

3 (18.8%)

3 (18.8%)

Psychiatric disorders

Restlessness

Anxiety

7 (20.6%)

6 (17.6%)

2 (5.9%)

4 (25.0%)

2 (12.5%)

1 (6.3%)

Injury, poisoning, and procedural complications

Incision site complications

6 (17.6%)

3 (8.8%)

1 (6.3%)

0

Ear and labyrinth disorders

Tinnitus

3 (8.8%)

3 (8.8%)

1 (6.3%)

1 (6.3%)

Cardiac disorders

Bradycardia

2 (5.9%)

2 (5.9%)

2 (12.5%)

1 (6.3%)

Study Author Conclusions

These findings demonstrate that INL-001 provides immediate and extended delivery of bupivacaine and is well tolerated in patients undergoing open inguinal hernioplasty with no adverse effect on wound healing.

InpharmD Researcher Critique

The patient population consisted mainly of white, male individuals which limits the applicability of the pharmacokinetic results. Patient exclusion criteria were also strict, limiting the degree of comorbidities allowed. Patients with multiple comorbidities or taking concomitant medications may present differing pharmacokinetic parameters.
References:

Leiman D, Niebler G, Minkowitz HS. Pharmacokinetics and Safety of INL-001 (Bupivacaine HCl) Implants Compared with Bupivacaine HCl Infiltration After Open Unilateral Inguinal Hernioplasty. Adv Ther. 2021;38(1):691-706. doi:10.1007/s12325-020-01565-x