Joseph Rannazzisi Deputy Assistant Administrator Office of Diversion Control
I have no financial rela.onships to disclose and
I will not discuss off-‐label use and/or inves.ga.onal drug use in my presenta.on
Disclosure Statement
U.S. Drug Enforcement Administra.on Office of Diversion Control
1. Iden.fy the pharmacological proper.es of Zohydro™ ER.
2. Outline approaches law enforcement should consider to reduce the poten.al effects of abuse and diversion.
3. Describe poten.al methods of abuse and diversion of Zohydro™ ER.
Learning Objectives
U.S. Drug Enforcement Administra.on Office of Diversion Control
Background of opioid use and abuse –Scope of the problem
Describe the hydrocodone situa.on pre Zohydro™ (hydrocodone bitartrate ER)
Discuss pharmacology of Zohydro™ (hydrocodone bitartrate ER)
Iden.fy methods of pharmaceu.cal diversion and discuss how the pharmacist can prevent diversion in the retail seQng
Discuss law enforcement role in preven.ng abuse and trafficking
Goals and Objectives
U.S. Drug Enforcement Administra.on Office of Diversion Control
Outline Hydrocodone historical perspec.ve Background on Zohydro™ ER
Pharmacology Indicated Use Poten.al for Abuse Toxicity
Law Enforcement Involvement Methods of Abuse and Diversion Risk Management Plan for Zohydro™ ER What The Future Holds Review / Ques.ons / Comments
U.S. Drug Enforcement Administra.on Office of Diversion Control
INCB: Availability of opioids* for pain management (2010-2012 average)
(Consumption in defined daily doses for statistical purposes (S-DDD) per million inhabitants per day)
U.S. Drug Enforcement Administra.on Office of Diversion Control
Date Prepared/ Source: 4/14/14, h^p://www.incb.org/incb/en/narco.c-‐drugs/Availability/availability.html
Drug Overdose Mortality Rates per 100,000 People 1999
Source: Trust for America’s Health, www.healthyamericans.org. “Prescrip.on Drug Abuse: Strategies to Stop the Epidemic (2013)”
U.S. Drug Enforcement Administra.on Office of Diversion Control
Source: Trust for America’s Health, www.healthyamericans.org. “Prescrip.on Drug Abuse: Strategies to Stop the Epidemic (2013)”
Drug Overdose Mortality Rates per 100,000 People, 2010
U.S. Drug Enforcement Administra.on Office of Diversion Control
U.S. Rates of Opioid Overdose Deaths, Sales, and Treatment Admissions, 1999-2010
Source: Na.onal Vital Sta.s.cs System (NVSS), DEA’s Automa.on of Reports and Consolidated Orders System, SAMHSA’s Treatment Episode Data Set
U.S. Drug Enforcement Administra.on Office of Diversion Control
Hydrocodone Aggregate Production Quota History
16,314
20,208
21,417
23,825
25,702
30,622
34,000
37,604
42,000
46,000
55,000
55,500
55,000
59,000 79,700 99,652
99,625
0
20,000
40,000
60,000
80,000
100,000
120,000
(in kilogram
s)
U.S. Drug Enforcement Administra.on Office of Diversion Control Date Prepared/ Source: 04/14/2014, ODQ
Revised APQ
Worldwide Hydrocodone Use
SOURCE: UN Interna.onal Narco.cs Control Board website. Es.mated World Requirements of Narco.c Drugs in grams for 2014. h^p://www.incb.org . Accessed April 14, 2014
U.S. Drug Enforcement Administra.on Office of Diversion Control
Worldwide Hydrocodone Use
Of the 20 Countries that reported an estimated needs requirement for hydrocodone at one kilogram or more
8 countries reported an estimated need of 1 kilogram to 5 kilograms
4 countries reported an estimated need over 5 kilograms to 10 kilograms
8 countries reported an estimated need over 10 kilograms SOURCE: UN Interna.onal Narco.cs Control Board website. Es.mated World Requirements of Narco.c Drugs in grams for 2014. h^p://www.incb.org . Accessed April 14, 2014
U.S. Drug Enforcement Administra.on Office of Diversion Control
Top 10 List
SOURCE: UN Interna.onal Narco.cs Control Board website. Es.mated World Requirements of Narco.c Drugs in grams for 2014. h^p://www.incb.org . Accessed April 14, 2014
U.S. Drug Enforcement Administra.on Office of Diversion Control
Most commonly prescribed prescription medicine?
Hydrocodone/acetaminophen
U.S. Drug Enforcement Administra.on Office of Diversion Control
U.S. Drug Enforcement Administra.on Office of Diversion Control
Current FDA-approved hydrocodone-containing products on the U.S. market (as of January, 2014)
U.S. Drug Enforcement Administra.on Office of Diversion Control Date Prepared/ Source:
Drug Name and Brand Name
HYDROCODONE BITARTRATE and ACETAMINOPHEN;
ANEXSIA; LORTAB; NORCET; NORCO; ZYDONE
Active Ingredient(s) • ACETAMINOPHEN; HYDROCODONE BITARTRATE
Form(s) and Strength(s) Available
CAPSULE; ORAL: 500MG; 5MG
SOLUTION; ORAL:
TABLET; ORAL:
U.S. Drug Enforcement Administra.on Office of Diversion Control
Top Five Prescription Drugs Sold in the U.S. (2008-2011)
U.S. Drug Enforcement Administra.on Office of Diversion Control Source: IMS Health, Na.onal Prescrip.on Audit, Updated 02/24/14
0
20
40
60
80
100
120
140
160
2008 2009 2010 2011 2012
Hydrocodone/ Paracetamol
Levothyroxine Sodium
Lisinopril
Simvasta.n
Metoprolol
Millions of Prescrip.ons
Top 25 U.S. Pharmaceuticals by Dispensed Prescriptions*
Source: IMS Health, Na.onal Prescrip.on Audit Updated March 22, 2013
U.S. Drug Enforcement Administra.on Office of Diversion Control
U.S. Drug Enforcement Administra.on Office of Diversion Control
State Ranking* - Hydrocodone January – September 2013
Source: Drug Enforcement Administra.on, Office of Diversion Control, Pharmaceu.cal Inves.ga.ons Sec.on, Targe.ng and Analysis Unit Most current ARCOS informa.on as of March 18, 2014
State Ranking* - Hydrocodone January – September 2013
U.S. Drug Enforcement Administra.on Office of Diversion Control
Source: Drug Enforcement Administra.on, Office of Diversion Control, Pharmaceu.cal Inves.ga.ons Sec.on, Targe.ng and Analysis Unit Most current ARCOS informa.on as of March 18, 2014
Hydrocodone Combinations CSA defines hydrocodone substance as Schedule II, while its combina.on products as Schedule III.
DEA has received a pe..on to reschedule CIII hydrocodone combina.on products to CII.
In 2004, DEA completed an ini.al review forwarded the data to DHHS with a request for scien.fic and medical evalua.on and scheduling recommenda.on.
In 2008, HHS provided a scien.fic and medical evalua.on
In 2009, DEA sent addi.onal data to FDA/HHS and requested a scien.fic and medical evalua.on.
U.S. Drug Enforcement Administra.on Office of Diversion Control
DEA receives a pe..on from an interested party (proceedings may also be ini.ated at the request of the AG or Secretary of HHS)
Pe..on is reviewed and accepted
DEA conducts ini.al 8-‐factor analysis review
Documents and material gathered during the ini.al review and analysis of pe..on is sent to HHS/FDA with a request for a scien.fic and medical evalua.on and a recommenda.on as to whether the drug should be controlled
The recommenda.on and review document is received back from HHS/FDA
Procedures to control a substance
U.S. Drug Enforcement Administra.on Office of Diversion Control
Schedule II The drug or other substance has a high poten.al for abuse The drug or other substance has a currently accepted medical use
in treatment in the United States or a currently accepted medical use with severe restric.ons
Abuse of the drug or other substance may lead to severe psychological or physical dependence
Schedule III The drug or other substance has a poten.al for abuse less than
the drugs or other substances in schedules I or II The drug or other substance has a currently accepted medical use
in treatment in the United States Abuse of the drug or other substance may lead to moderate or
low physical dependence or high psychological dependence
21 USC 812(b)(2),(3) U.S. Drug Enforcement Administra.on Office of Diversion Control
NFLIS Cases (Federal, State, and Local)
*2012 data is s.ll being submi^ed, data queried on 1/22/2013
-‐
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
45,000
50,000
2006 2007 2008 2009 2010 2011 2012 2013*
Num
ber of Cases
MEPERIDINE
OXYMORPHONE
CODEINE
HYDROMORPHONE
METHADONE
MORPHINE
HYDROCODONE
OXYCODONE
U.S. Drug Enforcement Administra.on Office of Diversion Control
U.S. Drug Enforcement Administra.on Office of Diversion Control
How Supplied Strength Image Capsule color(s) Capsule Text NDC Number
10 mg White opaque “Zogenix 10 mg” in black ink
43376-‐210-‐10 100 ct bo^les
15 mg Light green and white opaque
“Zogenix 15 mg” in black ink
43376-‐215-‐10 100 ct bo^les
20 mg Light green opaque “Zogenix 20 mg” in black ink
43376-‐220-‐10 100 ct bo^les
30 mg Dark blue and white opaque
“Zogenix 30 mg” in black ink
43376-‐230-‐10 100 ct bo^les
40 mg Dark brown and white opaque
“Zogenix 40 mg” in black ink
43376-‐240-‐10 100 ct bo^les
50 mg Dark brown opaque “Zogenix 50 mg” in black ink
43376-‐250-‐10 100 ct bo^les
ZohydroTM ER Formulation Mul.-‐par.culate formula.on of coated carrier beads in hard gela.n capsules
– Single-‐en.ty Hydrocodone bitartrate – Rate-‐controlling polymers – Drug release by diffusion
Extended release delivered by SODAS® technology – Example of SODAS® technology used in Ritalin® LA
U.S. Drug Enforcement Administra.on Office of Diversion Control
Alkermes SODAS® (Spheroidal Oral Drug Absorption System) Technology
A schema.c representa.on of SODAS® mul.layer drug delivery technology (adapted from Elan drug technologies)
U.S. Drug Enforcement Administra.on Office of Diversion Control
Background OxyConIn® (oxycodone) vs. Zohydro™ ER (hydrocodone)
– SimilariIes: • High-‐dose, extended release (delivery system) • Schedule II opioids (developed from opium)
• High abuse and dependence poten.al • Indicated for the management of pain severe enough to require daily, around-‐the-‐clock, long term opioid treatment and for which alterna.ve treatment op.ons (e.g. non-‐opioid analgesics or immediate-‐release opioids) are inadequate
• Used in condi.ons requiring extended period of pain relief
U.S. Drug Enforcement Administra.on Office of Diversion Control
Dosing Data for Clinically Employed Opioid Analgesics
Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th edition
U.S. Drug Enforcement Administra.on Office of Diversion Control
Currently Marketed Hydrocodone Products, U.S. only Tablets\capsule\solu.on (hydrocodone + acetaminophen\ibuprofen)
– Hydrocodone dosage: 2.5 mg, 5 mg, 7.5 mg, and 10 mg – Product Names: Anexsia, Lortab, Norcet, Norco, Reprexain, Vicoprofen,
Zydone
Solu.on\capsule (hydrocodone + chloropheniramine\pseudoephedrine)
– Hydrocodone dosage: 4 mg, 5 mg, 8 mg, 10 mg, 60 mg – Product Names: Renzira, Tussi Caps, Tussinox, Vituz, Zutripro
Syrup (hydrocodone + homatropine) – Hydrocodone dosage: 1.5 mg/5 mL, 5 mg/5 mL – Product Names: Hycodan, Tussigen
As of January 2014 U.S. Drug Enforcement Administra.on Office of Diversion Control
Background
U.S. Drug Enforcement Administra.on Office of Diversion Control
Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee
(AADPAC) Date: Dec. 7, 2012
Commi^ee was asked to determine whether the benefit-‐risk assessment of this product favors its approval for marke.ng.
The commi^ee is comprised of authori.es knowledgeable in the fields of anesthesiology, surgery, epidemiology or sta.s.cs and related special.es.
AADPAC voted 2-‐11 [with 1 absten.on] against the approval of ZohydroTM ER (hydrocodone bitartrate extended-‐release capsules)
U.S. Drug Enforcement Administra.on Office of Diversion Control
Zohydro™ ER Pharmacology Zohydro™ ER, extended release capsules contain a higher amount of pure hydrocodone dosages compared to other hydrocodone-‐containing products as immediate release tablets (e.g., 50 mg vs. 10 mg)
Zohydro™ ER is a Schedule II opioid – Other Schedule II opioids include Fentanyl, Oxycodone, Methadone,
Morphine
Hydrocodone is approximately: – 1 .mes as potent as oxycodone
– 1.5 .mes as potent as morphine
– 10 .mes as potent as codeine
The principal therapeu.c ac.on of hydrocodone is analgesia. As with other opioids, hydrocodone causes respiratory depression. U.S. Drug Enforcement Administra.on
Office of Diversion Control
Indicated Use
Zohydro™ ER is indicated for the management of pain, severe enough to require daily, around-‐the-‐clock, long-‐term opioid treatment for which alterna.ve treatment op.ons (e.g. non-‐opioid analgesics or immediate-‐release opioids) are inadequate
Dosage strengths and administra.on
– 10, 15, 20, 30, 40, 50 mg
– Twice-‐daily (q12h) administra.on
Not indicated
– Acute pain
– PRN analgesia
U.S. Drug Enforcement Administra.on Office of Diversion Control
Potential for Abuse Like other opioids, hydrocodone has high abuse and dependence poten.al
Can be abused in a manner similar to other opioids, legal or illicit
Pa.ents at increased risk of opioid abuse will require intensive monitoring for signs of abuse or addic.on
DEA was able to extract 95% or more of the ac.ve drug ingredient by grinding the capsule contents, and dissolving the powder in water or common solvents
U.S. Drug Enforcement Administra.on Office of Diversion Control
Toxicity Zohydro™ ER contains high amounts of hydrocodone
Use in opioid non-‐tolerant pa.ents may lead to overdose, par.cularly acute and fatal respiratory depression
– Capsules are indicated to be swallowed whole – Breaking of capsules and crushing beads
Co-‐inges.on of alcoholic beverages may result in fatal plasma hydrocodone levels
U.S. Drug Enforcement Administra.on Office of Diversion Control
What is a Risk Evaluation and Mitigation Strategy (REMS)?
REMS is a strategy to manage known or poten.al serious risks associated with a drug product.
FDA requires a REMS for extended-‐release and long-‐ac.ng opioid analgesics.
The goal of the REMS is to reduce serious adverse outcomes resul.ng from inappropriate prescribing, misuse, and abuse of these products.
Developed by the manufacturer and approved by FDA
A REMS is an a^empt to balance the need for access to the drug with the risks associated with its use and is product specific
Typically implemented prior to the drug’s approval and as a condi.on of approval
U.S. Drug Enforcement Administra.on Office of Diversion Control
Risk Mitigation Elements of the ER/LA Opioid REMS and the ZohydroTM ER Safe Use Initiative
ER/LA Opioid REMS ZohydroTM ER Safe Use IniIaIve
Pa.ent Ini.a.ves • Medica.on guide • Counseling
• Pa.ent Treatment Kit • Web-‐based and print educa.on • Opioid disposal program • Locking bo^le cap/lock box
Prescriber Ini.a.ves • REMS educa.on • Safe use training • Risk training
• Targeted prescriber marke.ng • Prescriber training and educa.on, including
mentoring • Prescriber took kit • Pa.ent selec.on tools • Urine drug screening • Web-‐based and print educa.on • Clinical tools
Pharmacist Ini.a.ves • Pharmacist brochure • Web-‐based and print educa.on
Distributor Ini.a.ves • Distributor starter kit
Assessments • Prescriber training • Quality of materials • HCP awareness • Pa.ent risk understanding • Misuse, abuse, overdose, addic.on, death
rates • U.liza.on pa^erns • Prescribing behaviors • Prescribing pa^erns
• Surveillance for medical and non-‐medical use • Teenager surveillance • Internet and media surveillance • Safe Use Advisory Board • Cash claim data • Pharmacovigilance review
Reproduced from: Advisory CommiXee Briefing Document NDA 20-‐2880 U.S. Drug Enforcement Administra.on
Office of Diversion Control
Prescriber Components of ER/LA Opioid Analgesic REMS
Train (Educate Yourself) -‐ Comple.on of a REMS-‐compliant educa.on program offered by an accredited provider of con.nuing educa.on (CE) for your discipline
Counsel Your Pa.ents -‐ Discuss the safe use, serious risks, storage, and disposal of ER/LA opioid analgesics with pa.ents and caregivers every .me you prescribe these medica.ons
Emphasize Pa.ent and Caregiver Understanding of Medica.on Guide -‐ Stress pa.ents and their caregivers the importance of reading the Medica.on Guide that they will receive from their pharmacist every .me an ER/LA opioid is dispensed to them
Consider Using Other Tools – In addi.on to pa.ent counseling, there are publicly available tools to improve pa.ent, household and community safety, as well as compliance with condi.ons of treatment, including pa.ent-‐prescriber agreement (PPA) and risk assessment instruments
U.S. Drug Enforcement Administra.on Office of Diversion Control
Zohydro™ ER Safe Use Initiative
PaIent IniIaIves Pa.ent Treatment Kit
Web-‐based and print educa.on
Opioid disposal program
Locking bo^le cap/lock box
Prescriber IniIaIves Targeted prescriber marke.ng
Prescriber training and educa.on, including mentoring
Prescriber tool kit
Pa.ent selec.on tools
Urine drug screening
Web-‐based and print educa.on
Clinical tools
Pharmacist IniIaIves Pharmacist brochure
Web-‐based and print educa.on
Distributor IniIaIves Distributor Starter Kit
Assessments Surveillance for medical and non-‐
medical use Teenager surveillance
Internet and media surveillance
Safe Use Advisory Board
Cash claim data
Pharmacovigilance review
U.S. Drug Enforcement Administra.on Office of Diversion Control
Concerns
A^orney Generals from 28 States sent a le^er to FDA Commissioner regarding the approval of ZohydroTM ER
The le^er requests FDA reconsider its approval or set a .meline for ZohydroTM ER to be reformulated to be abuse-‐deterrent while working with other federal agencies to impose restric.ons on how ZohydroTM ER can be marketed and prescribed
U.S. Drug Enforcement Administra.on Office of Diversion Control
Concerns
Recently a coali.on of more than 40 healthcare, consumer and addic.on treatment groups urged FDA to revoke approval of ZohydroTM ER
In a le^er to the Secretary of Health and Human Services, eight members of the United States Congress requested HHS to reconsider approval of ZohydroTM ER
U.S. Drug Enforcement Administra.on Office of Diversion Control
Potential methods of Diversion Medicine Cabinet
Friends
Street sales
Prescrip.on Fraud
Doctor Shopping
Burglary/Robbery
Rogue pain clinic – Rogue prac..oner
Rogue pharmacy
Hospital/medical staff U.S. Drug Enforcement Administra.on
Office of Diversion Control
Law Enforcement Action Plan for Zohydro™ (hydrocodone bitartrate ER)
Learn from our previous mistakes -‐ OxyCon.n™ (oxycodone ER)
Contact MEs and emergency room physicians to ensure they are educated on this product. Ensure that first responders are educated as well. Liaison with poison control centers
Educate students, teachers , guidance counselors , civic and community groups
Introduce yourself to local addic.on treatment providers and ask them to report recent trends they are observing
Request ARCOS and PDMP informa.on as appropriate.
Follow up all leads as quickly as possible concerning inappropriate health prac..oner prescribing
Work with DEA, pharmacy/medical boards and other LE agencies at the first hint of diversion and abuse in your area. Our ability to network and share resources will greatly assist in quickly iden.fying and shuQng down a threat U.S. Drug Enforcement Administra.on
Office of Diversion Control
Review Questions / Comments
Background on Zohydro™ ER
– Pharmacology – Indicated Use – Poten.al for Abuse – Toxicity
DEA’s Zohydro™ ER Ac.on Plan
Risk Evalua.on and Mi.ga.on Strategy (REMS)
What The Future Holds
U.S. Drug Enforcement Administra.on Office of Diversion Control
U.S. Drug Enforcement Administra.on Office of Diversion Control
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