Toxicity thresholds for bupivacaine HCL

  • CNS symptoms occurred at a plasma concentration ~2000 ng/mL with bupivacaine HCl1
  • The maximum tolerated dose for cardiac toxicity with bupivacaine HCl was >=4000 ng/mL2
Plasma levels of bupivacaine released from the liposomes over time are dose dependent3*
Line graph showing bupivacaine plasma levels being maintained over 96 hours with two doses - 133mg and 266mg
*Data from total knee arthroplasty study.
Systemic plasma levels of bupivacaine following administration of EXPAREL are not correlated with local efficacy.

Absorption

Following its release from the DepoFoam® particles, the rate of systemic absorption of bupivacaine is dependent upon the total dose of drug administered, the route of administration, and the vascularity of the administration site.
Pharmacokinetic parameters of EXPAREL after local administration were evaluated following surgical procedures. Descriptive statistics of pharmacokinetic parameters of representative EXPAREL doses in each pivotal study are provided below
Summary of pharmacokinetic parameters for bupivacaine after administration of single doses of EXPAREL
EXPAREL
Bunionectomy
106 mg (8 mL)
(N=26)
Hemorrhoidectomy
266 mg (20 mL)
(N=25)
Cmax (ng/mL) 166 (92.7) 867 (353)
Tmax (h) 2 0.5
AUC(0-t) (hXng/mL) 5864 (2038) 16,867 (7868)
AUC(inf) (hXng/mL) 7105 (2283) 18,289 (7569)
t1/2 (h) 34 (17) 24 (39)
Note:Arithmetic mean (standard deviation) except Tmax (median).

Distribution

After bupivacaine has been released from EXPAREL and is absorbed systemically, bupivacaine distribution is expected to be the same as for any bupivacaine HCl solution formulation.
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 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
  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 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.

Metabolism

Amide-type local anesthetics, such as bupivacaine, are metabolized primarily in the liver via conjugation with glucuronic acid. Pipecolylxylidine (PPX) is the major metabolite of bupivacaine; approximately 5% of bupivacaine is converted to PPX. Elimination of drug depends largely upon the availability of plasma protein binding sites in the circulation to carry it to the liver where it is metabolized.
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.

Excretion

After bupivacaine has been released from EXPAREL and is absorbed systemically, bupivacaine excretion is expected to be the same as for other bupivacaine formulations.
The kidney is the main excretory organ for most local anesthetics and their metabolites. Only 6% of bupivacaine is excreted unchanged in the urine.
Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Acidifying the urine hastens the renal elimination of local anesthetics. 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.

Specific populations

Hepatic impairment

Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, these drugs should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations.

Renal impairment

Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to EXPAREL may be greater in patients with impaired renal function. Care should be taken in dose selection of EXPAREL.

Age

In the clinical studies, differences in various pharmacokinetics parameters have been observed between elderly and younger patients.