Abuse Deterrent Formulations

1. Abuse Deterrent Formulations Syeda Saba Kareem, Pharm.D Pain and Palliative Care Specialty Resident H. Lee Moffitt Cancer Center & Research Institute Tampa, FL

2. Objectives • To review the mechanisms involved in opioid abuse • To understand the mechanisms of abuse deterrent formulations • To discuss formulations which are currently in different stages of development • Embeda® – • Alpharma Pharmaceuticals • Remoxy® – Pain Therapeutics/King Pharmaceuticals • Acurox® – Acura Pharmaceuticals • To discuss the timeline involved in product development

3. Abuse Mechanism • Rapid Bioavailability • Crushing • Grinding/Chewing • Dissolving • Needle aspiration • Filtration and Solvent Extraction • Oral • Intravenous • Nasal Inhalation Lavine,G.  Abuse deterrence focus of upcoming opioid formulations. American Journal of Health-System Pharmacy. 65(5):381,385, March 1, 2008.

4. Abuse Mechanism • Increased Concentration • Oral ingestion of excessive quantity • Polysubstance • Alcohol • Illicit substances Hahn C, McPherson M, Rubingh C. Pharmacotherapy for pain management: new treatment approaches. American Pharmacist Association. Sept 2008 http://apha.imirus.com/Mpowered/imirus.jsp?volume=ptpi08&issue=1&page=6

5. Abuse Deterrent Mechanism • Physical Barrier • High viscosity gel capsule • Microencapsulation with insoluble coating • Pharmacological Barrier • Sequestered opioid antagonist • Aversive Agent Active ingredient Katz, N.P., et al. Challenges in the Development of Prescription Opioid Abuse-deterrent Formulations. Clinical Journal of Pain,2007; 23(8):648-660

6. Embeda® • Combination of extended-release morphine and sequestered naltrexone • ALO-01 (morphine sulfate extended release with sequestered naltrexone hydrochloride) capsules for the management of moderate to severe pain when a continuous, around the clock opioid analgesic is needed for an extended period of time, Alpharma Pharmaceutical LLC- NDA 22-32, Nov 2008

7. Embeda® – Study 205 • Phase II, randomized, double blind study , N=32 • Subjective tool = Pharmacodynamic effects • Crushed/whole Embeda 120 mg < were lower than MSIR 120mg ALO-01 (morphine sulfate extended release with sequestered naltrexone hydrochloride) capsules for the management of moderate to severe pain when a continuous, around the clock opioid analgesic is needed for an extended period of time, Alpharma Pharmaceutical LLC- NDA 22-32, Nov 2008

8. Embeda – Study 106 • Phase 1, randomized, double blind • IV morphine and IV naltrexone can decrease euphoric effects and lower abuse potiential ALO-01 (morphine sulfate extended release with sequestered naltrexone hydrochloride) capsules for the management of moderate to severe pain when a continuous, around the clock opioid analgesic is needed for an extended period of time, Alpharma Pharmaceutical LLC- NDA 22-321, Nov 2008

9. Embeda – Study 205/106 • Abuse by swallowing crushed product • Snorting crushed product • Is naltrexone released and absorbed via nasal route? • Abuse by intravenous Morphine/Naltrexone • Injecting crushed/dissolved product • Is crushed product safe for IV route? • Nallani S. FDA Perspective of AL-01 Studies, FDA. Nov 21, 2008 • Joint Meeting of the Anesthetic and Life Support Drugs Advisory Committee and Drug Safety & Risk Management Advisory Committee, FDA. Nov 14, 2008

10. Remoxy® • Pain Therapeutics and King Pharmaceuticals – Orador™ Technology • Extended-release oxycodone in a high viscosity hard gelatin capsule • Remoxy XRT (oxycodone controlled-release) CII, Pain Therapeutics NDA22-324, Oct 2008

11. Remoxy® – Study 821-CZ • Phase 1, randomized, crossover study (40mg) • Crushed Remoxy Vs. Crushed Oxycontin • Lower Cmax • Broad plateau = characteristic of extended release mechanism • Remoxy XRT (oxycodone controlled-release) CII, Pain Therapeutics NDA22-324, Oct 2008

12. Remoxy® • FDA concluded that extended release characteristics are compromised upon manipulation • Ji P. Remoxy In Vivo Abuse Resistance Studies, FDA Nov 21, 2008

13. Acurox ® • Acura Pharmaceuticals –Aversion® Technology • Aversion Technology; Acura Pharmaceuticals; Abuse deterrent products; Oct 2008 <http://www.acurapharm.com/Aversion.htm>

14. Acurox® • Immediate release Oxycodone/subtherapeutic niacin • Gel forming polymer to reduce extraction • Mucosal irritating surfactant • Niacin (Vitamin B3) to induce flushing • Acurox Tablets; Acura Pharmaceuticals: Abuse deterrent products: Oct 2008 <http://www.acurapharm.com/Acurox%20Tablets.htm>

15. Acurox® – Study 111 • Phase II, Single-Center, Randomized, Double-Blind • N = 30 • Assess the abuse liability/deterrence potential of Acurox® (8 X 5mg/30mg)Tablets vs oxycodone HCl 40mg alone • *Dislike/like scores (p = .033) • Treatment Enjoyment Assessment scores (p = .005) • LSD/dysphoria scores (p <.001) • Minimal difference in vital signs • Study AP-APF-111: A Phase II, Single-Center, Randomized, Double-Blind, Assessment of the Abuse Liability of Acurox® (oxycodone HCl and niacin) Tablets in Subjects with a History of Opioid Abuse; Acurox, Acura Pharmaceuticals <http://www.acurapharm.com/StudyAPADF111.htm>

16. Product Timeline with FDA • Embeda® – Alpharma Pharmaceuticals • NDA – April 21, 2008 • NDA resubmitted – June 30, 2008 • 6 month priority review – Dec 30, 2008 • Remoxy® – Pain Therapeutics/King Pharmaceuticals • NDA – June 10, 2008 • 6 month priority review – Dec 10, 2008 • Acurox® – Acura Pharmaceuticals • Phase 3 completed • NDA expected to be submitted in 2008

17. References • Lavine,G.  Abuse deterrence focus of upcoming opioid formulations. American Journal of Health-System Pharmacy. 65(5):381,385, March 1, 2008. • Katz, N.P., et al. Challenges in the Development of Prescription Opioid Abuse-deterrent Formulations. Clinical Journal of Pain,2007; 23(8):648-660 • Hahn C, McPherson M, Rubingh C. Pharmacotherapy for pain management: new treatment approaches. American Pharmacist Association. Sept 2008 <http://apha.imirus.com/Mpowered/imirus.jsp?volume=ptpi08&issue=1&page=6> • ALO-01 (morphine sulfate extended release with sequestered naltrexone hydrochloride) capsules for the management of moderate to severe pain when a continuous, around the clock opioid analgesic is needed for an extended period of time, Alpharma Pharmaceutical LLC- NDA 22-321, Nov 2008 • Joint Meeting of the Anesthetic and Life Support Drugs Advisory Committee and Drug Safety & Risk Management Advisory Committee, FDA. Nov 14, 2008 • Nallani S. FDA Perspective of AL-01 Studies, FDA Nov 21, 2008 • Remoxy XRT (oxycodone controlled-release) CII, Pain Therapeutics NDA22-324, Oct 2008 • Gilderman P, Butera D, Gilmore L, et al. Remoxy: A new opioid drug with effective analgesia and abuse-resistance.The Journal of Pain,7(4):2006 • Ji P. Remoxy In Vivo Abuse Resistance Studies, FDA Nov 21, 2008 • Aversion Technology; Acura Pharmaceuticals; Abuse deterrent products: Oct 2008 <http://www.acurapharm.com/Aversion.htm> • Acurox Tablets; Acura Pharmaceuticals: Abuse deterrent products: Oct 2008 <http://www.acurapharm.com/Acurox%20Tablets.htm> • Study AP-APF-111: A Phase II, Single-Center, Randomized, Double-Blind, Assessment of the Abuse Liability of Acurox® (oxycodone HCl and niacin) Tablets in Subjects with a History of Opioid Abuse; Acurox, Acura Pharmaceuticals <http://www.acurapharm.com/StudyAPADF111.htm> • Jasinski, R. Evaluation for flushing, safety and tolerability of niacin in combination with 40mg of oxycodone; Johns Hopkins University; Acura Pharmaceuticals • Werble C. NDA Sponsors Will Play Major Role In Policing Post-Market Controls. THE RPM November 24 2008