1. Abuse Liability of Hydromorphone Extended Release Capsules Silvia N. Calderon, Ph.D. Controlled Substance Staff Center for Drug Evaluation and Research Food and Drug Administration ALSDAC September 10, 2003

2. CSS/CDER ALSDAC September 9-10, 2003 Hydromorphone Formulations Immediate release tablets (Dilaudid 2, 4 and 8 mg), injectable (1, 2, 4 and 10 mg/ml), oral solution (5 mg/5ml) and suppositories (3 mg) have been marketed in the United States for many years Extended release formulations marketed in the UK and Canada for once or twice a day use Palladone represents a new extended release formulation under FDA review

3. CSS/CDER ALSDAC September 9-10, 2003 Palladone Capsules Proposed Strengths: 12 mg, 16 mg, 24 mg and 32 mg Boxed Warning: For use only in opioid tolerant patients Indication: For the management of chronic moderate to severe pain in patients requiring continuous around the clock opioid analgesia for an extended period of time Dosage: Once a day

4. CSS/CDER ALSDAC September 9-10, 2003 Hydromorphone as Schedule II (CII) High abuse potential Highest level of control for an approved drug Prescriber and dispenser registration, separate record-keeping by dispenser, distribution order forms, no refills, manufacturing security and quotas, import and export permits

5. CSS/CDER ALSDAC September 9-10, 2003 abuse potential + social and public health factors Abuse Liability

6. CSS/CDER ALSDAC September 9-10, 2003 Hydromorphone’s Relative Potency Physiological Opioid Effects - analgesia, miosis, respiratory depression: – 4 times more potent than oxycodone and morphine (oral route) – 6-7 times more potent than morphine (intravenous route) Subjective Opioid Effects - euphoria and drug liking: –10 times more potent than morphine (oral or intravenous routes) (Jasinski et al., 1977; Hill and Zacny, 2000)

7. CSS/CDER ALSDAC September 9-10, 2003 History of Hydromorphone Abuse Hydromorphone abuse dates back to 1970s In 2002, DEA field offices reported that 4 mg hydromorphone tablets (Dilaudid) street price averaged $40/tablet

8. CSS/CDER ALSDAC September 9-10, 2003 Drug Abuse Related Deaths DAWN-Medical Examiners For 1999-2001 period: –132 hydromorphone-related deaths 7.5 deaths/100,000 Rx –1,272 oxycodone-related deaths 1.8 deaths/100,000 Rx 6.1 deaths/100,000 Rx - oxycodone single entity products Rx Source: IMS Health, National Prescription Audit Plus TM

9. CSS/CDER ALSDAC September 9-10, 2003 L imitations: Deaths/Prescriptions These ratios are “crude” estimates DAWN medical examiners deaths do not represent national estimates DAWN medical examiner reports may include multiple drug mentions and rarely include brand names Sales data represent the whole U.S. market Denominators include all formulations of the drug

10. CSS/CDER ALSDAC September 9-10, 2003 Summary Based upon the data reviewed, hydromorphone appears to have higher abuse liability than other Schedule II opioids When compared to immediate release hydromorphone products currently available, Palladone has higher potential risks of misuse and overdose that might result in death Palladone poses significant risks of overdose in non-opioid tolerant patients or if misused and abused

11. CSS/CDER ALSDAC September 9-10, 2003 Conclusion Risk management programs should be designed to address the risks associated with high-dose opioid analgesic drug products, such as Palladone