758
In vivo pharmacokinetics of KADIAN® (morphine sulfate extended-release) Capsules taken with alcohol
Stephen Sun, MD, Franklin Johnson, MS, Joe Stauffer, DO, and George Wagner, BS. Alpharma Branded Products Division Inc, 1 New England Avenue, Piscataway, NJ 08854
In 2005, PalladoneTM (hydromorphone hydrochloride extended-release capsules) was removed from the market due to pharmacokinetic data indicating that ingestion with 240mL of 40% alcohol resulted in average peak hydromorphone concentrations approximately 6 times greater than when taken with water.1 This has prompted studies of the interactions of other extended-release products with alcohol. This open-label, randomized, single-dose, 3-way crossover study assessed single-dose relative bioavailability of KADIAN® (morphine sulfate extended-release) Capsules taken with alcohol vs water. Thirty-two opioid-naïve, healthy male volunteers, aged 21-40y, who were moderate drinkers (7-21 drinks/week) took a 100mg KADIAN® Capsule with 240mL of 40% alcohol (4 shots [101mL] 190-proof Everclear®, 139mL water, consumed within 20min of dosing) fasted and fed, and with 240mL of water (fasted) as a reference. Open-label arm of immediate-release 20mg morphine solution was included for comparison. Oral naltrexone hydrochloride, an opioid antagonist, was administered 12h and 2h prior to treatment to counter morphine effects. Twenty-seven subjects had evaluable pharmacokinetic data for ≥1 treatment arm. Eleven subjects vomited after taking KADIAN®+alcohol; none vomited after taking KADIAN®+water. Median time to maximum morphine concentration (Tmax) in subjects taking KADIAN® with alcohol fasted, with alcohol fed, and with water fasted was 6.0, 8.0, and 8.0h, respectively, consistent with maintenance of a sustained-release profile. Excluding patients who vomited during the 12h dosing interval,2 maximum morphine concentrations (Cmax; mean of log-transformed values) were similar in all 3 groups: 16.7, 16.0, and 15.6ng/mL. ANOVA showed ratios of least square means for Cmax and overall morphine exposure (AUC) of both regimens of KADIAN®+alcohol within 80%-125% confidence interval boundaries when compared with KADIAN®+water. In contrast, the pharmacokinetic profile of 20mg solution was markedly different from the test treatments. Results indicate that KADIAN® taken with 240mL of 40% alcohol continued to display extended-release characteristics. (1Food and Drug Administration [FDA], July 2005; 2FDA, March 2003)