4.1.4. Clinical Relevance The most important consideration in the findings from these studies is the potential implications on human risk. While the mechanism(s) that contributed to convulsions in this study cannot be identified with certainty, the toxicological effects of EXPAREL in rabbits, presumably, are a reflection of a low rate, threshold-sensitive phenomenon that is not operative, and/or anticipated

in humans under actual condition of exposure (i.e., single dose). In the repeat-dose 28-day studies, Inhibitors,research,lifescience,medical the dosing methodology was selected to maximize exposure conditions. Under these conditions, the total cumulative dose of bupivacaine was regarded as excessive relative to the intended single-dose administration in the clinic, that is, the dosing regimen far exceeded the number of doses humans will receive. In dogs, no effects were noted. In rabbits, convulsions and one death

were noted. The death was recorded in a female rabbit one day Inhibitors,research,lifescience,medical after receiving six injections of EXPAREL 30mg/kg subcutaneously at biweekly intervals, which correspond to a total cumulative dose of 30mg/kg × 6 doses = 180mg/kg). Given the fact there was no dose-related response, Inhibitors,research,lifescience,medical the death may have been either incidental and/or related to excess responsiveness to bupivacaine action, that is, the lethality may have been caused by sudden fatal ventricular tachycardia and fibrillation leading to cardiac arrest as discussed above. There is no compelling evidence for this being due to the cumulative EXPAREL material per se Inhibitors,research,lifescience,medical that was injected. There is no evidence that the negative outcome in this animal is related to the specific formulation of bupivacaine

used (EXPAREL) and/or the vehicle itself, but rather this extreme finding was considered to be incidental and/or most likely attributed to the sensitivity of this particular animal to the toxic effects of bupivacaine. The dog findings appear to be clinically more relevant than the rabbit, since humans usually do not experience severe effects unless very high doses of bupivacaine are given. However, caution must be emphasized since this may not be always the case. For example, patients with underlying pathology (e.g., Inhibitors,research,lifescience,medical whatever renal failure, acidosis, or see more cirrhosis) may have higher sensitivity to the toxic effects of bupivacaine and structural analogs [54]. It is our opinion that the major factors involved in the dramatic results seen in the rabbit were due to physiol-ogical variations and species susceptibility to bupivacaine. Alteration in regional blood flow, hemodynamic instability, and a more rapid drug uptake along with a slow egress in target tissue may render rabbits more susceptible to drug accumulation and increase the risk of overt toxicity with prolonged administration of repeated doses. In summary, the nature and level of the findings in rabbits did not present a clinically significant safety concern since EXPAREL will be administered as a single-dose by local infiltration in a clinical setting.