Clinical Relevance of Alcohol-induced Dose Dumping

1. Clinical Relevance of Alcohol-induced Dose Dumping Robert J. Meyer, MD Director, Office of Drug Evaluation II, OND/CDER

2. Clinical Relevance of Alcohol-induced Dose Dumping • Recent experience has shown that some modified-release formulations are defeated in vitro by alcohol • In some cases, this can correlate with a clinically relevant effects documented in vivo • Talk will review some of this experience and some clinical thoughts on the importance of this issue

3. Case Background • New, once-daily modified-release drug product of a reasonably narrow-therapeutic index drug with abuse liability • Tested prior to approval for abuse liability potential (ability to extract drug out of the formulation) • This testing showed that extended exposure to high concentrations of alcohol in vitro could extract the drug • However, dissolution testing done prior to approval used standard methods and did not explore alcohol effect

4. Case Presentation • Post-approval, sponsor conducted a PK study to assess the interaction of various strengths of alcohol concomitantly administered • Alcohol tested was 8 oz (240 ml) of 40%, 20%, 5% and 0% (water) • These concentrations approximate the concentrations of whiskey, mixed drink and a European beer

5. Case Presentation Results: • 40% alcohol with the drug led to a five-fold increase in Cmax • 20% led to a doubling of Cmax • 5% led to a small mean effect, but at least one subject doubled their Cmax

6. Case Presentation • Conclusion of FDA was that there was a significant alcohol – drug interaction • Demanded some risk minimization / action • More on this in subsequent slide • Regulatory learning that alcohol can undermine modified-release mechanisms • Implications for existing MR products • Implications for new MR products

7. Clinical Consideration of Alcohol-Induced Dose Dumping Existing Products: • Need to prioritize in vitro (+/- in vivo) testing • Based on: • Therapeutic index (consequences of high Cmax or low Cmin) • Population at risk • Extent of use, vulnerability of population

8. Clinical Consideration of Alcohol-Induced Dose Dumping • Existing products: • For products with clinical concern and positive in vitro test: • Labeling, along with • In vivo testing • If in vivo testing is concerning, further regulatory action will be needed

9. Clinical Consideration of Alcohol-Induced Dose Dumping • For products that are shown to be vulnerable and where implications are severe, what is the regulatory response? • Labeling (+/- MedGuide) • Limitations of effectiveness • More formal risk minimization plans • Withdrawal

10. Clinical Consideration of Alcohol-Induced Dose Dumping • Future MR products: • In vitro testing for alcohol-induced undermining of MR characteristics may well be advisable as routine characterization test • Where dictated by therapeutic/considerations (narrow therapeutic index, dire consequences of high Cmax or low Cmin), alcohol sensitive MR formulations should not be approved

11. Clinical Consideration of Alcohol-Induced Dose Dumping • Important issue: • If a product is a rugged MR drug (i.e., one with an MR mechanism that is resistant to alcohol release), should a generic to that product also be required to use a rugged MR mechanism?

12. Clinical Consideration of Alcohol-Induced Dose Dumping • Summary: • Through recent regulatory experience, FDA now aware and acting on knowledge that ETOH can undermine some MR products • Requires assessment of some current MR products • Requires thought as to future regulatory actions/expectations