Safety Evaluation of EXPAREL (DepoFoam Bupivacaine) Administered by Repeated Subcutaneous Injection in Rabbits and Dogs: Species Comparison

Table 1

Incidence of convulsions following twice weekly subcutaneous injection of saline, EXPAREL 9, 18, and 30 mg/kg, and bupivacaine HCl solution 9 mg/kg to rabbits (3/sex/group).

Treatment	Dose (mg/kg)	Incidence of convulsions (clonic, unless noted)^a
		Week 1		Week 2		Week 3		Week 4
		Dose 1	Dose 2	Dose 3	Dose 4	Dose 5	Dose 6	Dose 7	Dose8
Bupivacaine HCl^b	9	—	—	3(M,) 1(F)	—	1(M) (tremors)	—	—	—
EXPAREL	9	1(M) (tonic)	—	—	—	—	—	—	—
	18	—	—	—	1(F) (tremors)	1(M) (tremors)	—	—	—
	30	—	—	—	—	—	—	—	—
Saline	0	—	—	—	—	—	—	—	—

^aNumber of animal affected on each dosing day; ^bSensorcaine M: male F: female; “—” No seizures recorded; ^cDose 1, 2, 3, 4, 5, 6, 7, 8 administered on Day 1, 4, 8, 11, 15, 18, 22, respectively.
Notes: On Day 1, one male rabbit receiving EXPAREL 9 mg/kg had seizures intermittently lasting for about 10 minutes. Tonic movements were characterized by prolonged and sustained convulsions started around 15 minutes postdose. On day 8, four animals receiving bupivacaine HCl solution (9 mg/kg) (3(M) and 1(F)) had convulsions intermittently for 20 minutes. Clonic movements were characterized by rapid succession of spasms and relaxation. The convulsions started around 15 minutes postdose and were less frequent with shorter duration as time went on. These animals recovered by 1 hour postdose. On Day 11, 1(F) receiving bupivacaine HCl solution 18 mg/kg had clonic convulsions/tremors intermittently for 5 minutes. This animal recovered by 40 minutes postdose. On Day 15, 1(M) Bsol 9 mg/kg and 1(M) EXPAREL 18 mg/kg had clonic convulsions/tremors.