Efficacy profile of liposome bupivacaine, a novel formulation of bupivacaine for postsurgical analgesia

Figures & data

Table 1 Milligram dose equivalents for liposome bupivacaine expressed as the free base and bupivacaine HCl

Dose of liposome bupivacaine expressed as the free base (mg)	Equivalent dose of bupivacaine HCl (mg)
66	75
93	105
106	120
133	150
155	175
160	180
199	225
266	300
306	345
310	350
399	450
532	600

Abbreviation: HCI, hydrochloride.

Table 2 Treatment arms and key efficacy outcome measures

Study/identifier	Phase	Surgical setting	Study drugs and dosages	Patients (N)	Key efficacy measure	Outcome	Analgesic medications available to all patients postsurgery
1 (NCT01203644)^Citation18	II	Inguinal hernia repair	LB 155 mg LB 199 mg LB 266 mg LB 310 mg Bupivacaine HCl 100 mg	76	Time to first use of supplemental pain medication (opioid or nonopioid) through 96 hours after study drug administration	No statistically significant difference between LB treatment groups and bupivacaine HCl	Acetaminophen 1000 mg followed by ibuprofen 800 mg if needed, followed by any opioid-containing medication as needed
2 (NCT00485433)^Citation21	II	Inguinal hernia repair	LB 93 mg LB 160 mg LB 306 mg Bupivacaine HCl 105 mg	98	AUC of NRS-A scores through 72 hours after study drug administration	No statistically significant difference between LB treatment groups and bupivacaine HCl	Acetaminophen 1000 mg three times daily; oxycodone 5–10 mg q4–6h added as needed
3 (NCT00485693)^Citation15	II	Total knee arthroplasty	LB 133 mg LB 266 mg LB 399 mg LB 532 mg Bupivacaine HCl 150 mg	138	AUC of NRS-A through day 4 after surgery	No statistically significant difference between LB treatment groups and bupivacaine HCl; AUC of NRS-A through day 2 significantly lower for LB 532 mg compared with bupivacaine HCl (P = 0.03)	Ketorolac 30 mg followed by acetaminophen 1000 mg three times daily for 96 hours; morphine PCA or oxycodone 5–10 mg q4–6h added as needed
4 (NCT00529126)^Citation19	II	Hemorrhoidectomy	LB 66 mg LB 199 mg LB 266 mg Bupivacaine HCl 75 mg	100	AUC of NRS-R scores through 72 hours after study drug administration	All LB groups significantly lower than bupivacaine HCl; LB 66 mg group significantly lower than bupivacaine HCl at 12, 24, 84, and 96 hours (P < 0.05); LB 199 mg and 266 mg groups significantly lower at all time points assessed (P < 0.05 versus bupivacaine HCl at all time points)	Ketorolac 30 mg followed by acetaminophen 1000 mg three times daily for 96 hours; injectable morphine 2.5–5 mg q4–6h or oxycodone 5–10 mg q4–6h added as needed
5 (NCT01206608)	II	Breast augmentation	LB 133 mg LB 266 mg Bupivacaine HCl 75 mg	80	AUC of NRS-A scores through 96 hours after study drug administration	No statistically significant difference between LB and bupivacaine HCl	Acetaminophen 1000 mg three times daily for 96 hours; oxycodone 5–10 mg q4–6h added as needed
6 (NCT00745290)	III	Total knee arthroplasty	LB 532 mg Bupivacaine HCl 200 mg	245	AUC of NRS-A through 72 hours after study drug administration	No statistically significant difference between LB and bupivacaine HCl	Ketorolac 30 mg followed by acetaminophen 1000 mg three times daily for 96 hours; morphine PCA or oxycodone 5–10 mg q4–6h added as needed
7 (NCT00744848)	III	Hemorrhoidectomy	LB 266 mg Bupivacaine HCl 100 mg	204	AUC of NRS-R scores through 96 hours after study drug administration	No statistically significant difference between LB and bupivacaine HCl	Ketorolac 30 mg followed by acetaminophen 1000 mg three times daily for 96 hours; oxycodone 5–10 mg q4–6h added as needed*
8 (NCT00813111)^Citation20	III	Breast augmentation	LB 532 mg Bupivacaine HCl 200 mg	136	AUC of NRS-A through 72 hours after study drug administration	No statistically significant difference between LB treatment groups and bupivacaine HCl	Acetaminophen 1000 mg three times daily for 96 hours; oxycodone 5–10 mg q4–6h added as needed
9 (NCT00890721)^Citation17	III	Hemorrhoidectomy	LB 266 mg Saline (placebo)	189	AUC of NRS-R scores through 72 hours after administration of study drug	LB significantly lower than placebo (P < 0.0001)	Intramuscular morphine 10 mg q4–6h as needed for 72 hours
10 (NCT00890682)^Citation16	III	Bunionectomy	LB 106 mg Saline (placebo)	193	AUC of NRS-R scores through 24 hours after study drug administration	LB significantly lower than placebo (P < 0.001)	Oxycodone 5 mg with acetaminophen 325 mg q4–6h as needed for 72 hours; one dose of ketorolac 15–30 mg added as needed

Note:

* Other opioid medications could be substituted if oxycodone was not available.

Abbreviations: AUC, area under the curve; HCl, hydrochloride; LB, liposome bupivacaine; NRS-A, numeric rating scale with activity; NRS-R, numeric rating scale at rest; PCA, patient-controlled analgesia; PK, pharmacokinetics; q, every; VAS, visual analog scale.

Table 3 Patient disposition (pooled intent-to-treat population)

	Liposome bupivacaine			Bupivacaine HCl	Placebo
	≤266 mg (n = 545)	>266 mg (n = 278)	All doses (n = 823)	(n = 446)	(n = 190)
Patients who terminated early, n (%)	9 (1.7)	35 (12.6)	44 (5.3)	49 (11.0)	6 (3.2)
Reason for early termination, n (%)
Death	0	0	0	1 (0.2)	0
Adverse event	0	1 (0.4)	1 (0.1)	2 (0.4)	1 (0.5)
Lost to follow-up	2 (0.4)	3 (1.1)	5 (0.6)	12 (2.7)	0
Patient withdrew	3 (0.6)	3 (1.1)	6 (0.7)	6 (1.3)	5 (2.6)
Other	4 (0.7)	26 (9.4)	30 (3.6)	27 (6.1)	0
Not reported	0	2 (0.7)	2 (0.2)	1 (0.2)	0

Abbreviation: HCI, hydrochloride.

Table 4 Patient demographics and other baseline characteristics (pooled safety population)

	Liposome bupivacaine			Bupivacaine HCl* (n = 446)	Placebo (n = 190)
	≤266 mg (n = 545)	>266 mg (n = 278)	All doses (n = 823)
Age, years, mean (SD)	47.6 (14.2)	55.9 (17.6)	50.4 (15.9)	49.5 (16.7)	45.9 (12.9)
Age category, years, n (%)
<40	168 (30.8)	70 (25.2)	238 (28.9)	144 (32.3)	63 (33.2)
40–64	313 (57.4)	99 (35.6)	412 (50.1)	210 (47.1)	112 (58.9)
≥65	64 (11.7)	107 (38.5)	171 (20.8)	92 (20.6)	15. (7.9)
Not reported	0	2 (0.7)	2 (0.2)	0	0
Sex, n (%)
Male	304 (55.8)	94 (33.8)	398 (48.4)	179 (40.1)	79 (41.6)
Female	241 (44.2)	184 (66.2)	425 (51.6)	267 (59.9)	111 (58.4)
Race, n (%)
Caucasian	469 (86.1)	240 (86.3)	709 (86.1)	384 (86.1)	166 (87.4)
Non-Caucasian	76 (13.9)	36 (12.9)	112 (13.6)	62 (13.9)	24 (12.6)
Not reported	0	2 (0.7)	2 (0.2)	0	0
ASA class, n (%)
1–2	477 (87.5)	182 (65.5)	659 (80.1)	354 (79.4)	187 (98.4)
3–4	51 (9.4)	84 (30.2)	135 (16.4)	82 (18.4)	3 (1.6)
Not reported	17 (3.1)	12 (4.3)	29 (3.5)	10 (2.2)	0

Notes:

* Bupivacaine HCl doses of 75 mg to 200 mg were used across studies. Bupivacaine HCl with epinephrine 1:200,000 was used in studies 2, 3, 4, 6, 7, 8, 9, and 10. Bupivacaine HCl without epinephrine was used in studies 1 and 5.

Abbreviations: ASA, American Society of Anesthesiologists; HCI, hydrochloride; SD, standard deviation.

Figure 1 Cumulative pain score (AUC_0–24 of NRS).

Notes: Differences in AUC for pain at rest from 0 to 24 hours between liposome bupivacaine and control groups. Circles represent the difference in means, and bars represent the 95% confidence intervals for the difference in means. The perpendicular zero line indicates no difference between liposome bupivacaine and controls. If a confidence interval does not cross the zero line, there is a statistically significant difference (P < 0.05) between liposome bupivacaine and controls.
Abbreviations: AUC, area under the curve; HCI, hydrochloride; NRS, numeric rating scale; TKA, total knee arthroplasty.

Figure 2 Cumulative pain score (AUC_0–72 of NRS).

Notes: Differences in AUC for pain at rest from 0 to 72 hours between liposome bupivacaine and control groups. Circles represent the difference in means and bars represent the 95% confidence intervals for the difference in means. The perpendicular zero line indicates no difference between liposome bupivacaine and controls. If a confidence interval does not cross the zero line, there is a statistically significant difference (P < 0.05) between liposome bupivacaine and controls.
Abbreviations: AUC, area under the curve; HCI, hydrochloride; NRS, numeric rating scale; TKA, total knee arthroplasty.

Table 5 Time to first postsurgical use of supplemental opioid pain medication through 72 hours (pooled intent-to-treat population)

	Liposome bupivacaine (n = 780)	Bupivacaine HCl (n = 409)	Placebo (n = 190)
Number of patients who used supplemental medication	619	343	180
Quartiles* (hours)
First quartile	1.8	0.7	1.2
Median (95% CI)	9.3 (7.6, 11.0)†	6.4 (4.2, 8.5)	3.6 (2.8, 4.0)
Third quartile	31.8	25.3	5.4

Notes:

* First quartile, 25% started using pain medication; median, 50% started using pain medication; third quartile, 75% started using pain medication;

† P = 0.013 versus bupivacaine HCl and P < 0.0001 versus placebo.

Abbreviations: CI, confidence interval; HCI, hydrochloride.

Table 6 Total postsurgical consumption of opioid rescue medication: studies with statistical differences between treatment groups

Study 4^Citation19
Adjusted geometric mean total consumption through 24 hours (mg)				Adjusted geometric mean total consumption through 72 hours (mg)
LB 66	LB 199	LB 266	B 75	LB 66	LB 199	LB 266	B 75
(n = 25)	(n = 25)	(n = 25)	(n = 25)	(n = 25)	(n = 25)	(n = 25)	(n = 25)
8.0	7.2	4.2*	8.9	15.0	10.0	6.2†	18.4
Study 8^Citation20
Mean total consumption through 24 hours (mg)				Mean total consumption through 72 hours (mg)
LB 532	B 200			LB 532	B 200
(n = 60)	(n = 62)			(n = 60)	(n = 62)
6.1*	9.3			13.5	20.4
Study 9^Citation17
Adjusted geometric mean total consumption through 24 hours (mg)				Adjusted geometric mean total consumption through 72 hours (mg)
LB 266	Placebo			LB 266	Placebo
(n = 94)	(n = 93)			(n = 94)	(n = 93)
5.4‡	12.9			9.9†	18.2
Study 10^Citation16
Adjusted geometric mean total consumption through 24 hours (mg)				Adjusted geometric mean total consumption through 72 hours (mg)
LB 106	Placebo			LB 106	Placebo
(n = 97)	(n = 96)			(n = 97)	(n = 96)
3.8†	4.7			11.3	11.1

Notes:

* P < 0.05;

† P < 0.01;

‡ P < 0.0001.

Abbreviations: B, bupivacaine HCl (hydrochloride); LB, liposome bupivacaine.

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