Abstract ID: A47

Abstract Title: A Prospective, Randomized, Double-blind, Crossover, Head-to-head, Single Oral Dose Trial of Avinza vs. Kadian 30mg in 36 Healthy Opiate-naďve Subjects in the Fed State

Poster Type: Poster

ABSTRACT BODY

ABSTRACT

Avinza™ (Ligand/Organon) and Kadian® (Alpharma Branded Products Division) are both encapsulated pellet formulations of sustained-release (SR) morphine sulfate (MS) indicated for use in the treatment of moderate to severe chronic pain. Both products are designed to deliver effective MS plasma concentrations for up to 24 hours. The main differences between the two formulations include the following: 1) Avinza has 10% of the pellets in an immediate release (IR) formulation, whereas Kadian has no IR component; 2) Avinza is indicated only for once daily dosing, whereas Kadian is indicated for either once daily or q12h dosing; and 3) Avinza contains fumaric acid (linked to serious renal toxicity) and therefore has a absolute contraindication for doses exceeding 1600mg/d, whereas Kadian contains no fumaric acid and has no ceiling dose limitation.

METHODS

The study was conducted to compare the pharmacokinetic (PK) profile of the two products in the fed state for MS and its main metabolites (morphine-3-glucuronide/M3G and morphine-6-glucuronide/M6G) and to secondarily assess differential adverse event (AE) profiles (although the study was not powered to demonstrate statistically significant AE differences). A CRO, MDS, performed the clinical and analytical portions of the study at their Lincoln, NE site. Thirty-six healthy opiate-naďve subjects (and 4 alternates) were randomly assigned in a double-blinded fashion to receive either Avinza or Kadian 30mg PO after a standard meal. After a 2-week washout period, subjects were crossed over to the other product. Plasma samples were obtained hourly for the first 12 h and then at 14, 16, 20, 24, 30, 36, 48 and 60 h. Samples were analyzed in a blinded fashion. Spontaneously reported AEs were documented and, if necessary, treated.

RESULTS

As a result of the inherent formulation differences, Avinza has a Tmax that is significantly earlier than that seen with Kadian (7.1 vs. 12.9 h, respectively). However, the Cmax, AUC and t˝ showed no statistically significant differences between the two products. The fact that the t˝ data (approximately 14 h for each) was statistically indistinguishable demonstrates that both products support once daily dosing. From 8 through 60 h, Kadian provided slightly higher mean MS plasma levels than Avinza at each time point, although the difference was not statistically significant. The metabolites, M3G and M6G, similarly showed no statistically significant differences between Avinza and Kadian except for the earlier Tmax for Avinza. Avinza had twice the number of nausea/vomiting (N/V) episodes (4 vs. 2) and 100% of the multiple vomiting episodes (2) requiring medical treatment. Overall, 27 of the 40 subjects reported at least one AE.

CONCLUSIONS

There appear to be little PK difference between the two products except for the earlier Tmax/Cmax seen with Avinza, presumably due to its IR component. The data demonstrated that the t˝ for the products were indistinguishable and that Kadian produced slightly higher MS plasma levels at all time points from 8 through 60 h, though these values were not statistically significant. Avinza demonstrated a trend toward increased N/V, particularly multiple vomiting episodes.

ATTACHED FILES

Reg Anesth Pain Med 2004; 29(2):A47