1History of “Abuse-Deterrent”Combination OpioidsFrank Pucino, PharmD, MPH Clinical Reviewer Division of Anesthesia and Analgesia Products CDER/FDA/DHHS2Overview of PresentationApproved abuse-deterrent combination opioid productsPostmarketingassessment on their potential for abuse 3Public Health ConcernPrevalence of opioid abuse Economic burden Morbidity Mortality4“Abuse-Deterrent”Combination Opioid ProductsCombination drugs developed with the intent to limit the abuse potential of the opioid component5Combination Rule: 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 addedto minimize the potential for abuse of the principal active ingredient6Approved “Abuse-Deterrent”Combination OpioidsTALWIN NX(CIV) Pentazocine/naloxoneSUBOXONE(CIII) Buprenorphine/naloxoneEMBEDA(CII) Morphine/naltrexoneNaloxone and naltrexone were added to deter intravenous or oral abuse of these opioids7NaloxonePure opioid antagonistCauses partial or complete reversal of opioid effectsAdministered IV Very limited systemic bioavailability by non-parenteral routes of administration Added to limit parenteral abuse8TALWIN NX TALWIN(pentazocine) was approved in 1967 for the relief of moderate-to-severe pain No known potential for abuse Not scheduled1968: First reports of dependence, limitedLate 1970s: Increasing frequency of cases of abuse, diversion, overdose and death Ts and Blues TALWINand tripelennamineHCl (antihistamine, blue tablet) Intravenous abuse of crushed tablets Substitute for heroin91979: Schedule IV controlled substance Labeling changed to include postmarketing events of addiction1982: Reformulated with naloxone Pentazocine50mg/naloxone 0.5mg Marketed as TALWIN NXstarting April 1983January 1983: TALWINwithdrawn from market Reports of abuse declined during the two years following withdrawal from the marketEfforts to Mitigate Abuse10Impact of Addition of Naloxone on Use and Abuse of PentazocineBaum B, Hsu JP, Nelson RC. Public Health Reports July-August 1987;102 (No.4)11Pentazocine Rxs Dispensed from Retail Pharmacies*Intercontinental Marketing Service (IMS) Prescription Audit12Introduction of TALWIN NXDAWN Medical Examiner Mentions per Million Rxs13Possible Factors Contributing to the Decrease in Abuse of TALWINChange in the availability of heroin Scheduling of TALWIN Removal of single entity TALWINfrom the market Introduction of TALWIN NX14SUBOXONECombination of buprenorphine HCl (partial mu opioid agonist) plus naloxone HCl (full opioid antagonist) Buprenorphine/naloxone: 2 mg/0.5 mg, 8 mg/2 mgApproved in October, 2002 for the treatment of opioid dependence, along with SUBUTEX, which is buprenorphine HCl without the addition of naloxone Both products are interchangeable in terms of the pharmacokinetics of buprenorphine15SUBOXONEwas designed for sublingual administration Absorption of the naloxone component caused no clinically significant effect Plasma concentrations measurableIf administered intravenously, the naloxone component would become available Blocking the euphoric effects of the opioid component or precipitate opioid withdrawalLimited formal studies conducted to assess the impact of SUBOXONEon abuse liability16Reports of abuse Sublingual, nasal inhalation, injectionBaltimore Sun, December 2007 “The BupeFix”-Naloxonedoes not always deter abuseMaine health department reported that misuse spread rapidly as more SUBOXONEwas prescribed. Abusers of the drug “have figured out how to separate out the naloxone“ to inject the buprenorphine.In Massachusetts, a police detective, said, “A lot of people are injecting it. Theyre getting hooked on it.“SUBOXONEAbuse17Smith MY, et al. J Addict Dis.2007;26(3):107-11 - SUBOXONE(Ratio 0.16 cases/1000 Rxs)-?- SUBUTEX (Ratio 0.08 cases/1000 Rxs)Ratio of SUBOXONEprisons, universities, other)4Sales Data IMS HEALTH, IMS National Sales PerspectiveTM, Extracted March 2010 Year 2009 56% of sales as combination oxycodone 59% to retail pharmacy settings 40% to non-retail pharmacy settings 44% of sales as single ingredient oxycodone 87% of sales as immediate release (IR) oxycodone 64% to retail and 35% to non-retail pharmacy settings 13% of sales as extended release (ER) oxycodone 83% to retail and 15% to non-retail pharmacy settings5OxycodoneCombination 56%Single Ingredient 44%Non-Retail 40%Retail 59%Immediate-Release 70%Extended-Release 30%Non-Retail 43%Retail 57%Non-Retail 19%Retail 79%Sales Data, Y2009 IMS HEALTH, IMS National Sales PerspectiveTM, Extracted March 20106Results: Prescription and Patient Level Data7Outpatient Utilization Data Sources SDI Vector One: National (VONA) SAMHSAAnesthetic and Life Support Drugs and Drug Safety and Risk ManagAnesthetic and Life Support Drugs and Drug Safety