Download Abuse Deterrent Formulations

Abuse Deterrent
Formulations
Syeda Saba Kareem, Pharm.D
Pain and Palliative Care Specialty Resident
H. Lee Moffitt Cancer Center & Research Institute
Tampa, FL
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
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.
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
Abuse Deterrent Mechanism
 Physical Barrier


High viscosity gel capsule
Microencapsulation with insoluble coating
Active
ingredient
 Pharmacological Barrier


Sequestered opioid antagonist
Aversive Agent
Katz, N.P., et al. Challenges in the Development of Prescription Opioid Abuse-deterrent Formulations. Clinical Journal of Pain,2007; 23(8):648-660
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
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
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
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
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
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
Remoxy®
 FDA concluded that extended release characteristics are compromised
upon manipulation
Oxycodone Conc. (ng/mL)
120
Oxycodone Oral Solution
OxyContin Crushed & Extracted
Remoxy Crushed & Extracted
100
80
60
40
20
0
0
2
4
6
8
10
12
Time (h)
Treatment Ratio
Remoxy Crush /Oxycodone Oral Solution
OxyContin Crush/Oxycodone Oral Solution
Mean (90% CI)
Cmax
AUC
0.79 (0.74-0.84)
1.24 (1.19-1.30)
0.97 (0.89-1.06)
1.01 (0.96-1.07)
Ji P. Remoxy In Vivo Abuse Resistance Studies, FDA Nov 21, 2008
Acurox ®
 Acura Pharmaceuticals – Aversion® Technology
Aversion Technology; Acura Pharmaceuticals; Abuse deterrent products; Oct 2008 <http://www.acurapharm.com/Aversion.htm>
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>
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>
Product Timeline with FDA
 Embeda® –



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® –

Alpharma Pharmaceuticals
Acura Pharmaceuticals
Phase 3 completed
NDA expected to be submitted in 2008
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 abuseresistance.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