The Relative Bioavailability of Morphine Sulfate and Naltrexone Hydrochloride Extended Release Capsules (EMBEDA (R)) and an Extended Release Morphine Sulfate Capsule Formulation (KADIAN (R)) in Healthy Adults Under Fasting Conditions

Morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA (R), King Pharmaceuticals (R), Inc., Bristol, TN), indicated for the management of chronic, moderate to severe pain, contain extended release morphine pellets with a sequestered naltrexone core (MS-sNT). If the product is tampered with by crushing, naltrexone, a mu-opioid antagonist, is intended for release to mitigate morphine-induced subjective effects. The primary end point of this randomized 2-way crossover study in healthy fasted volunteers was evaluation of morphine bioequivalence between MS-sNT (treatment A) and morphine sulfate extended release capsules (KADIAN (R), treatment B). Morphine pharmacokinetics were assessed predose to 72 hours postdose of single 100-mg doses of treatment A or B. Analysis of variance of ln-transformed ratios of least squares mean of the area under the concentration time curve (AUC) from time 0 to last measurable concentration (AUC(0-t)) and AUC from time 0 to infinity (AUC(inf)) and maximum serum concentration (C-max) for treatments Aversus B were performed. Ratios and 90% confidence intervals for least squares mean for AUC(0-t) (102.2%; 98.6-105.9%), AUC(inf) (97.4%; 91.2-104.1%), and C-max (93.8%; 82.4-106.7%) indicated bioequivalence between the 2 formulations. When subjects who vomited during the 12-hour dosing interval were excluded, the confidence interval for AUC(0-t) and AUC(inf) fell within the 80%-125% range, but the lower limit for C-max was 76.9%.