Len 7 rannazzisi

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


  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


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


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)


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)”


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. 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


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


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


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


Most commonly prescribed prescription medicine?

Hydrocodone/acetaminophen



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:


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



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


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.


  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


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


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


43376-‐230-‐10 100 ct bo^les

40 mg Dark brown and white opaque


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


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)


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


Dosing Data for Clinically Employed Opioid Analgesics

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th edition


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


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)


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


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


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


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


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


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


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


  Clinical tools

Pharmacist IniIaIves   Pharmacist brochure


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


Concerns

Aôrney Generals from 28 States sent a leêr to FDA Commissioner regarding the approval of ZohydroTM ER

The leêr 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


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


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


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


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


Len 7 rannazzisi

Health & Medicine

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