1. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 History of Modified-Release Morphine and Opioid/Antagonist Combinations Ellen Fields, M.D., M.P.H. Medical Team Leader DAARP Ellen Fields, M.D., M.P.H. Medical Team Leader DAARP

2. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 2 Overview of Presentation Modified Release Morphine Products –Important labeling changes Approved opioid/antagonist combination products Modified Release Morphine Products –Important labeling changes Approved opioid/antagonist combination products

3. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 3 Modified-Release Morphine Products MS CONTIN Oramorph SR Kadian Avinza MS CONTIN Oramorph SR Kadian Avinza

4. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 4 Schedule II Indication: Management of moderate-to severe pain when a continuous around- the-clock opioid analgesic is needed for an extended period of time Extended-release opioid formulations provide for improved compliance, convenience for the patient and longer pain relief than immediate-release products Schedule II Indication: Management of moderate-to severe pain when a continuous around- the-clock opioid analgesic is needed for an extended period of time Extended-release opioid formulations provide for improved compliance, convenience for the patient and longer pain relief than immediate-release products

5. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 5 MS CONTIN Approved May 1987 Priority review Strengths: 15mg, 30mg, 60mg, 100mg, 200mg Dosing: Q12 hours Major labeling changes –May 2003: Box Warning added Restricted 100mg and 200mg to opioid tolerant patients Abuse liability, not prn, not to be broken, chewed, crushed, dissolved –May 2007: strengthens language throughout the label regarding abuse, misuse and diversion Approved May 1987 Priority review Strengths: 15mg, 30mg, 60mg, 100mg, 200mg Dosing: Q12 hours Major labeling changes –May 2003: Box Warning added Restricted 100mg and 200mg to opioid tolerant patients Abuse liability, not prn, not to be broken, chewed, crushed, dissolved –May 2007: strengthens language throughout the label regarding abuse, misuse and diversion

6. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 6 *100 mg and 200 mg are for use in opioid-tolerant patients only WARNING: MS CONTIN contains morphine sulfate, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing MS CONTIN in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. MS CONTIN Tablets are a controlled-release oral formulation of morphine sulfate indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. MS CONTIN Tablets are NOT intended for use as a prn analgesic. MS CONTIN 100 and 200 mg Tablets ARE FOR USE IN OPIOID-TOLERANT PATIENTS ONLY. These tablet strengths may cause fatal respiratory depression when administered to patients not previously exposed to opioids. MS CONTIN TABLETS ARE TO BE SWALLOWED WHOLE AND ARE NOT TO BE BROKEN, CHEWED, DISSOLVED, OR CRUSHED. TAKING BROKEN, CHEWED, DISSOLVED, OR CRUSHED MS CONTIN TABLETS LEADS TO RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF MORPHINE.

7. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 7 MS CONTIN contains morphine sulfate, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing MS CONTIN in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion

8. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 8 MS CONTIN Tablets are a controlled-release oral formulation of morphine sulfate indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. MS CONTIN Tablets are NOT intended for use as a prn analgesic. MS CONTIN 100 and 200 mg Tablets ARE FOR USE IN OPIOID- TOLERANT PATIENTS ONLY. These tablet strengths may cause fatal respiratory depression when administered to patients not previously exposed to opioids.

9. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 9 MS CONTIN tablets are to be swallowed whole and are not to be broken, chewed, dissolved, or crushed. Taking broken, chewed, dissolved, or crushed MS CONTIN tablets leads to rapid release and absorption of a potentially fatal dose of morphine.

10. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 10 OramorphOramorph Approved August 1991 Strengths:15mg, 30mg 60mg, and 100mg tablets Dosing: every 8 to 12 hours. Label being updated Approved August 1991 Strengths:15mg, 30mg 60mg, and 100mg tablets Dosing: every 8 to 12 hours. Label being updated

11. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 11 KadianKadian Approved July 1996 Initial strengths: 20mg, 50mg, and 100mg capsules Added strengths: 10mg, 30mg, 60mg, 80mg, and 200mg capsules (2005) Dosing every 12 to 24 hours The capsules are to be swallowed whole or may be sprinkled on applesauce 2006: Box Warning added Approved July 1996 Initial strengths: 20mg, 50mg, and 100mg capsules Added strengths: 10mg, 30mg, 60mg, 80mg, and 200mg capsules (2005) Dosing every 12 to 24 hours The capsules are to be swallowed whole or may be sprinkled on applesauce 2006: Box Warning added

12. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 12 KADIAN® capsules are to be swallowed whole or the contents of the capsules sprinkled on apple sauce. The pellets in the capsules are not to be chewed, crushed, or dissolved due to the risk of rapid release and absorption of a potentially fatal dose of morphine

13. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 13 AvinzaAvinza Approved March 2002 Strengths: 30mg, 60mg, 90mg, and 120mg capsules Dosing every 24 hours The capsules may be swallowed whole or sprinkled on applesauce. Maximum dose: 1600 mg/day –Related to an inactive ingredient 60mg, 90mg, 120mg for opioid-tolerant only October 2005: language added that alcohol compromises the controlled release properties of the formulation and causes it to act as an immediate release product (dose-dumping) Approved March 2002 Strengths: 30mg, 60mg, 90mg, and 120mg capsules Dosing every 24 hours The capsules may be swallowed whole or sprinkled on applesauce. Maximum dose: 1600 mg/day –Related to an inactive ingredient 60mg, 90mg, 120mg for opioid-tolerant only October 2005: language added that alcohol compromises the controlled release properties of the formulation and causes it to act as an immediate release product (dose-dumping)

14. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 14 Interaction with Alcohol 2004: Palladone (modified-release hydromorphone) dose-dumps in presence of alcohol in vivo and removed from market All modified-release opioids underwent in vitro dissolution studies with ETOH, followed by in vivo if needed 40% (all), 20%, 4% (Avinza and Kadian) Kadian: positive in vitro, negative in vivo Avinza: positive in vitro, not tested in vivo MS Contin, Oramorph: negative in vitro 2004: Palladone (modified-release hydromorphone) dose-dumps in presence of alcohol in vivo and removed from market All modified-release opioids underwent in vitro dissolution studies with ETOH, followed by in vivo if needed 40% (all), 20%, 4% (Avinza and Kadian) Kadian: positive in vitro, negative in vivo Avinza: positive in vitro, not tested in vivo MS Contin, Oramorph: negative in vitro

15. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 15 Avinza 30mg

16. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 16 Standard Alcohol Language Pharmacodynamic Interaction Tradename may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression because respiratory depression, hypotension, and profound sedation or coma may result Tradename should not be taken with alcohol or other CNS depressants…. Tradename may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression because respiratory depression, hypotension, and profound sedation or coma may result Tradename should not be taken with alcohol or other CNS depressants….

17. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 17 Wording Added to Avinza Label Physico-chemical interaction “Patients must not consume alcoholic beverages while on Avinza therapy. Additionally, patients must not use prescription or non-prescription medications containing alcohol while on Avinza therapy. Consumption of alcohol while taking Avinza may result in the rapid release and absorption of a potentially fatal dose of morphine.”

18. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 18 Opioid/Antagonist Combinations

19. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 19 21CFR300.50(a)21CFR300.50(a) “Two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effect…” A special case of this rule is where a component is added…To minimize the potential for abuse of the principal active ingredient “Two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effect…” A special case of this rule is where a component is added…To minimize the potential for abuse of the principal active ingredient

20. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 20 ApprovedApproved Talwin NX (pentazocine/naloxone) Suboxone (buprenorphine/naloxone) Naloxone HCl was added to both products in order to deter intravenous abuse of the drugs Talwin NX (pentazocine/naloxone) Suboxone (buprenorphine/naloxone) Naloxone HCl was added to both products in order to deter intravenous abuse of the drugs

21. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 21 NaloxoneNaloxone Pure opioid agonist Causes complete or partial reversal of opioid effects Administered IV Very limited systemic bioavailability by non-parenteral routes of administration Pure opioid agonist Causes complete or partial reversal of opioid effects Administered IV Very limited systemic bioavailability by non-parenteral routes of administration

22. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 22 Talwin NX Talwin (pentazocine) was approved in 1967 for the relief of moderate-to-severe pain. –No known potential for abuse –Not-scheduled 1968: First reports of dependence, limited Late 1970’s: Increasing frequency of cases of abuse, diversion, overdose and death –T’s and Blues: Talwin and tripelennamine (antihistamine, blue tablet) –Intravenous abuse of crushed tablets –Substitute for heroin Talwin (pentazocine) was approved in 1967 for the relief of moderate-to-severe pain. –No known potential for abuse –Not-scheduled 1968: First reports of dependence, limited Late 1970’s: Increasing frequency of cases of abuse, diversion, overdose and death –T’s and Blues: Talwin and tripelennamine (antihistamine, blue tablet) –Intravenous abuse of crushed tablets –Substitute for heroin

23. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 23 Efforts to mitigate abuse: –1979: Schedule IV –Labeling changed to include postmarketing events of addiction 1982: Reformulated with naloxone (pentazocine 50mg/naloxone 0.5mg) –Marketed starting April 1983 January 1983: Talwin removed from market –Reports of abuse declined during two years after withdrawal of Talwin from the market Efforts to mitigate abuse: –1979: Schedule IV –Labeling changed to include postmarketing events of addiction 1982: Reformulated with naloxone (pentazocine 50mg/naloxone 0.5mg) –Marketed starting April 1983 January 1983: Talwin removed from market –Reports of abuse declined during two years after withdrawal of Talwin from the market

24. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 24

25. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 25

26. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 26 Scheduled 1979 Removal of Talwin

27. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 27 Scheduled 1979 Removal of Talwin

28. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 28 Possible Factors Contributing to the Decrease in Abuse of Talwin Scheduling of Talwin Removal of single entity Talwin from the market Introduction of Talwin NX Change in the availability of heroin Scheduling of Talwin Removal of single entity Talwin from the market Introduction of Talwin NX Change in the availability of heroin

29. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 29 SuboxoneSuboxone Combination of buprenorphine HCl (a partial mu opioid agonist) and Naloxone HCl (a full opioid antagonist) Approved in October, 2002 for the treatment of opioid dependence, along with Subutex, which is buprenorphine HCl without the addition of Naloxone The two products are interchangeable in terms of the pharmacokinetics of buprenorphine Combination of buprenorphine HCl (a partial mu opioid agonist) and Naloxone HCl (a full opioid antagonist) Approved in October, 2002 for the treatment of opioid dependence, along with Subutex, which is buprenorphine HCl without the addition of Naloxone The two products are interchangeable in terms of the pharmacokinetics of buprenorphine

30. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 30 Suboxone was designed to be administered sublingually – absorption of the Naloxone component caused no clinically significant effect although plasma levels were measurable In clinical pharmacology studies, if Suboxone was improperly administered via the intravenous route, the naloxone component would become available and block the euphoric effects of the opioid component or precipitate opioid withdrawal There have been no formal studies to assess the impact of Suboxone in terms of abuse Suboxone was designed to be administered sublingually – absorption of the Naloxone component caused no clinically significant effect although plasma levels were measurable In clinical pharmacology studies, if Suboxone was improperly administered via the intravenous route, the naloxone component would become available and block the euphoric effects of the opioid component or precipitate opioid withdrawal There have been no formal studies to assess the impact of Suboxone in terms of abuse

31. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 31 Suboxone Abuse Reports of abuse –Sublingual –Nasal inhalation –Injection Baltimore Sun, December 2007 –Maine health department reported in August that misuse spread rapidly as more Suboxone was prescribed. Abusers of the drug "have figured out how to separate out the naloxone" to inject the buprenorphine…. –In Massachusetts, …"A lot of people are injecting it. They're getting hooked on it." Reports of abuse –Sublingual –Nasal inhalation –Injection Baltimore Sun, December 2007 –Maine health department reported in August that misuse spread rapidly as more Suboxone was prescribed. Abusers of the drug "have figured out how to separate out the naloxone" to inject the buprenorphine…. –In Massachusetts, …"A lot of people are injecting it. They're getting hooked on it."

32. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 32 SummarySummary

33. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 33 Modified-Release Morphine Four approved products Highest doses for opioid-tolerant patients Box Warning One product has labeling regarding dose-dumping in alcohol Four approved products Highest doses for opioid-tolerant patients Box Warning One product has labeling regarding dose-dumping in alcohol

34. Anesthetic and Life Support Drugs and Drug Safety and Risk Management Advisory Committees, November 14, 2008 34 Opioid-Antagonist Combinations Two approved products –Talwin NX and Suboxone Naloxone added to mitigate IV abuse Some evidence that introduction of Talwin NX led to decreased pentazocine abuse –Multifactorial No formal assessment of Suboxone impact on abuse –Multiple reports of IV and intranasal abuse Two approved products –Talwin NX and Suboxone Naloxone added to mitigate IV abuse Some evidence that introduction of Talwin NX led to decreased pentazocine abuse –Multifactorial No formal assessment of Suboxone impact on abuse –Multiple reports of IV and intranasal abuse