Abuse Deterrent Opioid Formulations Claire Saadeh, PharmD, BCOP / August 2017

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1 Opioid Formulations Claire Saadeh, PharmD, BCOP / August 2017 Introduction 1,2 Dilemma: Providing balance between providing appropriate access to opioid products in patients who truly need them AND addressing the problem of opioid abuse / misuse Guidance for industry finalized and published in April 2015: Abuse-Deterrent-Opioids Evaluation and Labeling 1 Abuse-Deterrent Opioid Products Some long & short acting opioid products possess abuse but do not meet the new FDA abuse-deterrent labeling requirements Currently 10 agents meet the FDA labeling claim Table 1: Abuse-Deterrent Opioid Products by General Category: Physical / Chemical Barriers Physical / Chemical Barriers (in order of FDA approval date) **These agents fully MEET the FDA labeling claim** OxyContin 3-15 (Oxycodone ER) Purdue Pharma Hysingla ER (Hydrocodone ER) Tabs Q 24h 1995 (original) April / August 2010 (reformulated) November 20, 2014 INTAC technology Crush resistant properties, forming a gel that is not easily manipulated RESISTEC TM confers tablet hardness & imparts viscosity in aqueous solutions Comments First FDA approved ER Fourth FDA approved ER Purdue Pharma MorphaBond (Morphine sulfate ER) Daiichi Sankyo, Inc. & Inspirion Delivery Technologies LLC Xtampza ER (Oxycodone ER) Caps Q 12h Collegium Pharmaceutical, Inc. Arymo ER (Morphine ER) Tabs Q 8 or Q 12 Egalet Ltd. Vantrela ER 26,27 (Hydrocodone ER) October 2, 2015 SentryBond TM Technology Fifth FDA approved ER Commercially not available 1 April 26, 2016 DETERx technology Sixth FDA approved ER Capsule can be opened potential use in patients with dysphagia January 9, 2017 Guardian technology Eighth FDA approved ER January 17, 2017 Not specified Ninth FDA approved ER

2 Commercially not Teva Pharmaceuticals available 1 RoxyBond 26,28 April 20, 2017 SentryBond TM Technology Tenth FDA approved (Oxycodone IR) Tabs Q 4-6h PRN First FDA approved IR Inspirion Delivery Sciences, LLC Commercially not available 1 **These agents DO NOT meet FDA labeling claim as abuse deterrent products** Opana ER 4,5,29-31 INTAC technology (Oxymorphone ER) Endo Pharmaceuticals 4, Nucynta ER (Tapentadol ER) Depomed Inc. Xartemis XR 35,36 (Oxycodone XR + acetaminophen) Mallinckrodt 37, 38 Zohydro ER (Hydrocodone ER) Caps Q 12h June 2006 December 2011 (reformulated) July 6, 2017 WITHDRAWN August 26, 2011 Acuform technology Polyethelene oxide matrix that confers resistance to crushing or extraction of active drug March 28, 2014 October 2013 January 30, 2015 (reformulated) Pernix Therapeutics 1 As of July 28, 2017 ER = extended release; IR = immediate release If dissolved, forms gelatinous substance that is difficult to manipulate BeadTek TM technology mix of inactive & active beads; inactive beads form a viscous gel if crushed or dissolved Withdrawn from market by Endo Pharmaceuticals after FDA recommendation benefits do not outweigh risks FDA has not approved an abuse-deterrent labeling claim First ER oxycodone (7.5 mg) + acetaminophen combination product FDA has not approved an abuse-deterrent labeling claim Available? Withdrawn? FDA has not approved an abuse-deterrent labeling claim Table 2: Abuse-Deterrent Opioid Products by General Category: Agonist / Antagonist Combinations Agonist / Antagonist Combinations (in order of FDA approval date) **These agents fully MEET the FDA labeling claim** Embeda ER August 2009 Naltrexone (opioid (Morphine ER + Naltrexone) (withdrawn in 2011) antagonist) if crushed, blocks euphoric effects Caps Q 24h October 2014 Pfizer Laboratories of morphine & precipitate withdrawal Targiniq ER 42 (Oxycodone ER + Naloxone) Purdue Pharma July 2014 Naloxone (opioid antagonist) if crushed & snorted or injected will block euphoric effects of oxycodone Miscellaneous Third FDA approved ER deterrent properties Capsule can be opened potential use in patients with dysphagia Second FDA approved ER deterrent properties. Commercially not available 1 2

3 Troxyca ER 43 (Oxycodone ER + Naltrexone) Caps Q 12h Pfizer Inc August 19, 2016 Naltrexone (opioid antagonist) if crushed, blocks euphoric effects of morphine & precipitate withdrawal **These agents DO NOT meet FDA labeling claim as abuse deterrent products** Buprenorphine + Various dates Naloxone Variety of products available 1 As of July 28, 2017 ER = extended release; IR = immediate release Naloxone (opioid antagonist) if injected will precipitate opioid withdrawal Table 3: Abuse-Deterrent Opioid Products by General Category: Aversion Seventh approved ER deterrent properties. Capsule can be opened potential use in patients with dysphagia Commercially not available 1 Bunavail (buccal film) Suboxone [sublingual (SL) film or tabs] Zubsolv (SL tabs) Aversion 4, 5, 54 Oxaydo IR (Oxycodone IR) Tabs Q 4-6h PRN Egalet Ltd. Formerly FDA approved in 2011 under brand name Oxecta January 2015 collaboration with Egalet Combined with sodium lauryl sulfate to irritate the nasal passage if manipulated & components form a gel if exposed to water Miscellaneous FDA has not approved an abusedeterrent labeling claim Table 4: Abuse-Deterrent Opioid Products by General Category: Delivery System Delivery System 5, 55, 56 Exalgo (Hydromorphone ER) Tabs Q 24h Mallinckrodt LLC March 2010 OROS push pull osmotic delivery system Delivers over 24 h Miscellaneous FDA has not approved an abusedeterrent labeling claim Table 5: Abuse-Deterrent Opioid Products by General Category: Combination of Technologies Avridi (Oxycodone IR) Purdue Pharma NOT FDA APPROVED Physical/chemical barrier Aversion sodium lauryl sulfate Miscellaneous September 10, 2015 FDA ruled against approving this agent due to safety concerns (must be taken on empty stomach) 3

4 Other Categories of Products 1 Per FDA guidance categories; No products available to date New molecular entities & prodrugs Novel approaches Challenges Need to ensure appropriate access to opioids for patients with legitimate use Prescribers need to perform a risk / benefit analyses for all patients prior to prescribing an opioid need to assess who is at high risk, who is at a lower risk of opioid abuse; who should receive an abuse deterrent formulation? Current products are brand name only higher cost, higher co- pay; formulary challenges Continued impact on heroin abuse? Post marketing surveillance more pharmacoepidemiology studies are needed Manipulation can (& DOES) still occur! Unique Counseling Points Specific for Products Become familiar with the specific agent and technology used Substitutions are not be allowed Risks of opioid therapy new language in patient medication guide Formulation may appear intact in the stool re-assure the patient that the drug has been released No crushing, breaking or dissolving the tablet or capsule Some formulations (Embeda ER, Troxyca ER, Xtampza ER) may be opened / sprinkled onto food unique counseling 4

5 References 1. U.S. Department of Health and Human Services. Abuse-deterrent opioids evaluation and labeling. Guidance for industry. April Available at: 2. U.S. Department of Health and Human Services. General principles for evaluating the abuse deterrence of generic solid oral opioid drug products. Guidance for industry. Draft guidance. March Available at: df. 3. U.S. Food and Drug Administration. FDA actions on OxyContin products, 4/6/2013. Available at: Accessed June 7, Alexander L. Mannion RO, Weingarten B, Fanelli RJ, Stiles GL. Development and impact of prescription opioid abuse deterrent formulation technologies. Drug and Alcohol Dependence. 2014;138: Moorman-Li R, Motycka CA, Inge LD, Congdon JM, Hobson S, Pokropski B. P&T. 2012;37(7): Daily Med. Current medication information (OxyContin). Available at: 7. Cicero TJ and Ellis MS. Effect of abuse-deterrent formulation of OxyContin. N Engl J Med. 2012;367(2): Coplan PM, Kale H, Sandstrom L, et. al. Changes in oxycodone and heroin exposures in the National Poison Data System after introduction of extended-release oxycodone with abuse-. Pharmacoepidemiology and Drug Safety. 2013;22: Severtson SG, Bartelson BB, Davis JM, et. al. Reduced abuse, therapeutic errors, and diversion following reformulation of extended-release Oxycodone in The Journal of Pain. 2013;14(10): Butler SF, Cassidy TA, Chilcoat H, et. al. The Journal of Pain. 2013;14(4): Sessler NE, Downing JM, Kale H, et. al. Reductions in reported deaths following the introduction of extended-release oxycodone (OxyContin) with an abuse-deterrent formulation. Pharmacoepidemiology and Drug Safety. 2014;23: Havens JR, Leukefeld CG, DeVeaugh-Geiss AM, et. al. The impact of a reformulation of extended-release oxycodone designed to deter abuse in a sample of prescription opioid abusers. Drug and alcohol dependence. 2014;139: Larochelle MR, Zhang F, Ross-Degnan D, Wharam JF. Rates of opioid dispensing and overdose after introduction of abuse-deterrent extended-release oxycodone and withdrawal of propoxyphene. JAMA Intern Med. 2015;175(6): Hwang CS, Chang HY, Alexander GC. Impact of abuse-deterrent OxyContin on prescription opioid utilization. Pharmacoepidemiology and Drug Safety. 2015;24: Dart RC, Surratt HL, Cicero TJ, et. al. Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med. 2015;372(3): U.S. Food and Drug Administration. FDA approves extended-release, single-entity hydrocodone product with abuse. Available at: Purdue. Purdue Pharma L.P. receives FDA approval for Hysingla ER (hydrocodone bitartrate) extendedrelease tablets CII, a once daily opioid analgesic formulated with abuse. Available at: 5

6 hysinglatm-er-hydrocodone-bitartrate-extended-release-tablets-cii-a-once-daily-opioid-analgesic-formulatedwith-abuse-deterrent-properties/. 18. Daily Med. Current medication information (Hysingla ER). Available at: Daily Med. Current medication information (MorphaBond). Available at: Inspiron Delivery Technologies. Available at: U.S. Food and Drug Administration. FDA Advisory Committee briefing document. Xtampza ER (extended release oxycodone). Available at: cdrugproductsadvisorycommittee/ucm pdf. 22. Collegium Pharmaceutical. DETERx technology platform. Available at: Daily Med. Current medication information (Xtampza ER). Available at: Daily Med. Current medication information (Arymo ER). Available at: Guardian Technology: Available at: Becker WC & Fiellin DA. N Engl J Med 2017;376(22): Vantrela ER prescribing information. Available at: Accessed: July 28, RoxyBond prescribing information. Available at: Accessed July 28, INTAC. INTAC formulation technology protects intended drug action. Available at: Opana ER. Extended release characteristics of INTAC. Available at: Accessed June 7, Food & Drug Administration: FDA requests removal of Opana ER for risks related to abuse. Available at: Accessed July 28, Depomed. Enhancing therapies for optimized drug delivery. Available at: Vosburg SK, Jones JD, Manubay JM, et. al. A comparison among tapentadol tamper-resistant formulations (TRF) and OxyContin (non-trf) in prescription opioid abusers. Addiction. 2013;108: Butler SF, McNaughton EC, Black RA. Tapentadol abuse potential: a postmarketing evaluation using a sample of individuals evaluated for substance abuse treatment. Pain Medicine. 2015;16: Formulary Watch. Xartemis XR receives FDA approval: May reduce opioid abuse. Available at: U.S. Food and Drug Administration. Medication guides. Xartemis XR. March Available at: Accessed June 7, Pernix Therapeutics. Pernix launches Zohydro ER with BeadTek. Available at: 6

7 Accessed June 7, Daily Med. Current medication information (Zohydro ER). Available at: U.S. Food and Drug Administration. FDA approves labeling with abuse- for Embeda, an extended release opioid analgesic. Available at: m. 40. U.S. Food and Drug Administration. FDA approves labeling with abuse-deterrent features for third extendedrelease opioid analgesic. Available at: Daily Med. Current medication information (Embeda). Available at: U.S. Food and Drug Administration. FDA approves new extended-release oxycodone with abuse-deterrent properties. Available at: Troxyca ER. Available at: Accessed July 28, Pasero C, McCaffery M. Pain Assessment and Pharmacologic Management. St. Louis, Missouri: Mosby Elsevier; Daily Med. Current medication information (Bunavail). Available at: Daily Med. Current medication information (Suboxone buccal film). Available at: Daily Med. Current medication information (Suboxone sublingual tablets). Available at: Daily Med. Current medication information (Zubsolv). Available at: Anonymous. New formulation: Zubsolv (buprenorphine/naloxone) sublingual tabs. Pharmacist s Letter / Prescriber s Letter. December 2013 (#291213). 50. Li X, Shorter D, Kosten TR. Buprenorphine in the treatment of opioid addiction: opportunities, challenges and strategies. Expert Opin. Pharmacother. 2014;15(15): Helm II S, Trescot AM, Colson J, Sehgal N, Silverman S. Opioid antagonists, partial agonists, and agonists/antagonists: the role of office-based detoxification. Pain Physician. 2008;11: Nicholls L, Bragaw L, Ruetsch C. Opioid dependence treatment guidelines. J Manag Care Pharm. 2010;16(1- b):s14-s Lavonas EJ, Severtson SG, Martinez EM, et. al. Abuse and diversion of buprenorphine sublingual tablets and film. J Subst Abuse Treat. 2014;47: Acura Pharmaceuticals, Inc. Oxaydo (oxycodone HCL, USP) CII tablets. Available at: Accessed June 7, CenterWatch. Exalgo (hydromorphone hydrochloride) extended release. Available at: 7

8 hydrochloride-extended-release. 56. Shargel L, Wu-Pong S, Yu AC. Chapter 17. Modified-Release Drug Products. In: Shargel L, Wu-Pong S, Yu AC. eds. Applied Biopharmaceutics & Pharmacokinetics, 6e. New York, NY: McGraw-Hill; accesspharmacy.mhmedical.com.libcat.ferris.edu/content.aspx?bookid=513&sectionid= Accessed May 2, Purdue Pharma LP. NDA AvridiTM (Immediate-Release Oxycodone Hydrochloride) Tablets. Advisory Committee Briefing Materials For Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee. September 10, Available at: cdrugproductsadvisorycommittee/ucm pdf. 58. Food and Drug Administration Center for Drug Evaluation and Research. Summary Minutes of the Joint Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting. September 10, Available at: cdrugproductsadvisorycommittee/ucm pdf. 59. Brushwood DB, Rich BA, Coleman JJ, Bolen J, Wong W. Legal liability perspectives on abuse-deterrent opioids in the treatment of chronic pain. J of Pain and Palliative Care Pharmacotherapy. 2010;24: Passik SD. Tamper-resistant opioid formulations in the treatment of acute pain. Adv Ther. 2014;31: Bannwarth B. Will abuse-deterrent formulations of opioid analgesics be successful in achieving their purpose? Drugs. 2012;72(13): U.S. Department of Health and Human Services. Centers for Disease Control and Prevention. CDC guideline for prescribing opioids for chronic pain United States, March 15, Available at: Califf RM, Woodcock J, Ostroff S. A proactive response to prescription opioid abuse. N Engl J Med. 2016;374: FDA Opioids Action Plan. Available at: Accessed July 28,

paindr.com ABUSE DETERRENT FORMULATIONS CURRENT AND PIPELINE Update August, 2017 Table 1: Opioids with Abuse Deterrent Properties

paindr.com ABUSE DETERRENT FORMULATIONS CURRENT AND PIPELINE Update August, 2017 Table 1: Opioids with Abuse Deterrent Properties ABUSE DETERRENT FORMULATIONS CURRENT AND PIPELINE Update August, 2017 Table 1: Opioids with Abuse Deterrent Properties Brand Name Generic Name Formulation Approval Year Buprenorphine Products Suboxone