Patients In-Use Stability and Safety of Repacked Delayed-Release Tablets of a Narrow Therapeutic Index Antiseizure Agent

Abstract

Divalproex Sodium (DVS) is an antiepileptic agent with a narrow therapeutic window and a wide range of side effects. Its delayed-release forms demonstrated better tolerability in terms of gastrointestinal side effects. DVS has high sensitivity to temperature and humidity. Owing to a high frequency of daily administration, outpatients may keep their medication supply accessible in places that might not qualify for proper drug storage. In this study, five FDA-approved DVS delayed-release tablet products (A-E) were assessed for physical integrity, physicochemical changes and drug release pattern before and after repackaging in amber-colored closed pharmacy vials and storage at 30°C/75%RH. Initially, one product showed dissimilarity to the others (f1 = 19.6, f2 = 41.6). Upon storage, tablets showed signs of physical damage after 1 month. At 3 months, A, B and E tablets lost their integrity completely. Product C displayed high variability in acid (44.9 ± 31.5% drug release). Tablets that remained intact after storage failed the f1 and f2 tests. The images showed evidence of chemical changes in all products. The results indicated that repackaging and improper in-use keep could result in unpredictable drug release. It is debated that the total daily systemic bioavailability of DVS, rather than the peak-to-trough differences, is the primary determinant of seizure control. However, variability in drug release can result in gastric irritation, systemic side effects, drug intolerance and patients’ noncompliance. This unnecessary burdening of the health care system can be avoided when revising dispensing and storage recommendations of DVS products.

Graphical Abstract