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12/10/2013
1
Recent FDA Labeling Changes for Extended-Release and Long-Acting
Opioids: Clinical Implications
December 11, 2013
A webinar brought to you by the American Medical Association
Sharon Hertz, M.D. , Deputy Director,
Division of Anesthesia, Analgesia, and
Addiction Products, CDER/FDA
Learning Objectives
At the conclusion of this activity, participants should be able
to:
• To understand the background underlying the ER/LA
opioid analgesic labeling changes
• Identify the recent changes to the ER/LA opioid analgesic
labeling
• To understand the intent of the new indication for ER/LA
opioid analgesics
3
12/10/2013
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Agenda
• Background of the problems with extended-release
and long-acting (ER/LA) opioids leading to the ER/LA
risk evaluation and mitigation strategy (REMS)
• Most Recent ER/LA labeling changes
• Clinical implications of the labeling changes
The Background
• Greater emphasis on managing pain (2001-2010 Decade of Pain Control and Research - The 106th U.S. Congress passed H.R. 3244 and President Clinton signed this bill into law. Title VI, Sec. 1603).
• Use of opioid analgesics has nearly doubled over the last decade.
• Use of ER/LA opioids increased proportionately greater than immediate-release opioids.
The Background
• There is a spectrum of behaviors contributing to these
problems including inappropriate prescribing such as
improper dosing, patient selection, and patient counseling.
• Inappropriate patient behaviors are also contributing to
the problem
– improper use, storage, and disposal of prescription drug
opioid products.
• http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/D
rugs/AnestheticAndLifeSupportDrugsAdvisoryCommittee/UCM217510.pdf
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7
Total number of prescriptions dispensed for ER/LA and IR opioids
from U.S. outpatient retail pharmacies, Year 2000 - 2009SDI, Vector One®: National. Extracted June 2010.
164.8 171.3 174.8 179.9188.6
199.9211.1
223.9
11.6 12.7 14.7 16.0 17.4 19.4 21.3 22.9 22.99.3
233.8 234.0
0.0
50.0
100.0
150.0
200.0
250.0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Years
TR
x (m
ilio
ns)
ER Opioids
IR Opioids
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Total number of unique patients receiving a dispensed
prescription for a ER/LA opioid product from U.S. outpatient retail
pharmacies, Years 2002 – 2009SDI, Total Patient Tracker. Extracted June 2010.
2.70
3.16 3.083.24
3.493.70
3.95 3.83
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
Uniq
ue P
atie
nts
(mill
ions)
2002 2003 2004 2005 2006 2007 2008 2009
Years
Unique Patients*
Who are the patients and who are the prescribers?
• ER/LA 0pioids are prescribed predominantly for musculoskeletal pain/ connective tissue disorders and headache/nerve pain
• Immediate-release opioids are prescribed predominantly for musculoskeletal pain/ connective tissue disorders and fractures/sprains/contusions,/injuries, and diseases of the respiratory tract.
• Pain in the US is managed primarily by primary care physicians.
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Diagnoses Associated with Selected Opioid Analgesics,
January 2007-November 2011, Cumulative
Hydrocodone Combination
Oxycodone Combination
Oxycodone ER
Morphine ER
Oxymorphone ER
Hydromorphone ER
N= 2,850,000 N= 1,406,000 N= 13,385,000 N= 2,618,000 N= 1,410,000 N= 183,000Diseases of the Musculoskeletal System and Connective Tissue (710-739) 25% 20% 59% 68% 63% 64%Disease of Respiratory System (462-493) 21% 2% 0% 0% 0% 0%
Fractures, Sprains, Contusions, Injuries (800-999) 19% 26% 6% 3% 5% 9%
Follow up examinations 10% 14% 6% 4% 6% 5%
Headaches and Nerve Pain (337-359) 3% 4% 17% 15% 14% 4%
Fever and General Symptoms (780-789) 3% 4% 2% 2% 5% 7%
Neoplasms (140-239) 2% 0% 7% 4% 4% 8%
Disease of Genitourinary System (592-626) 2% 22% 0% 0% 1% 0%
Bacterial, Viral and Parasitic Infections (001-138) 1% 0% 1% 0% 1% 0%
All others 13% 7% 2% 2% 3% 3%Source: Encuity Research TreatmentAnswers™ , Extracted January, November 2012
11
Total number of prescriptions dispensed in the U.S. by top 10
prescribing specialties for IR and ER/LA opioids, Year 2009SDI: Vector One®: National. Extracted June 2010.
IR Opoid Prescribers
Others, 20.2%PM&R, 2.7%
ANES, 3.2%
NP, 3.5%
PA, 4.0%
Unspec, 4.5%
EM, 4.7%
ORTH SURG, 7.4%
Dentists, 7.7%
IM, 15.4%
GP/FM/DO, 26.7%
ER/LA Opioid Prescribers
GP/FM/DO, 27.0%
IM, 16.8%
ANES, 13.8%PM&R, 9.3%
NP, 5.7%
UNSPEC, 4.9%
PA, 4.3%
NEURO, 2.8%
ORTH SURG, 1.9%
HEM, 1.7%
Others, 11.8%
A Major Public Health Problem Arises
• Along with the increase in use of opioid analgesics, has been an increase in problems associated with opioids –overdose, death, misuse, abuse, and addiction.
• Overdose and death - not limited to misuse and abuse, occurring in patients as well
• Drug overdose deaths have been increasing rapidly and are predominantly opioid overdose deaths
• Opioid overdose deaths are predominantly prescription opioids
– Majority of these deaths involve another CNS depressant – e.g. benzodiazepines, alcohol
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Drug overdose death rates continue to increase
US, 1980-2010
NCHS Data Brief, December, 2011, Updated with 2009 and 2010 mortality data
0
5
10
15
20
25
19
80
19
81
19
82
19
83
19
84
19
85
19
86
19
87
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19
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20
00
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01
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20
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20
09
20
10
Ra
te p
er
10
0,0
00
po
pu
lati
on
Year
Motor Vehicle Traffic Crashes Drug Overdose
14
Prescription drugs primary driver of overdose deaths, top 15 drugs or drug classes, US 2010
Jones et al Pharmaceutical overdose deaths, United States, 2010. JAMA 2013 and CDC/NCHS NVSS MCOD 2010.
0
2,000
4,000
6,000
8,000
10,000
12,000
14,000
16,000
18,000
Nu
mb
er
of
De
ath
s
Drug or Drug Class
15
Opioid and benzodiazepine trends different than
heroin and cocaine, US, 1999-2010
CDC/NCHS National Vital Statistics System, CDC Wonder. Updated with 2010 mortality.
0
2,000
4,000
6,000
8,000
10,000
12,000
14,000
16,000
18,000
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Nu
mb
er
of
De
ath
s
Year
Opioids Heroin Cocaine Benzodiazepines
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A Major Public Health Problem Arises
• Nonmedical use of opioids has been on the rise
• The most common source of opioids for nonmedical use is from a friend or relative who gets the drug from a single physician
17
NSDUH: Nonmedical Use of Pain Relievers
• The proportion of the US population aged ≥12 years of age ever using prescription pain relievers non-medically has more than doubled in 10 years:
• Increase in incidence (initiates) of non-medical prescription pain relievers use over the years:
1990 2005
627,000 2.2 million
1998 2001 2008
5.8% 9.8% 13.6%
Includes all pain reliever formulations; Source: NSDUH, SAMHSA
18
NSDUH: Where Pain Relievers Were Obtained
for Most Recent Nonmedical Use among Past
Year Users
Totals may not sum to 100% because of rounding or because suppressed estimates are not shown.1 Other category includes: “Wrote Fake Prescription,” “Stole from Doctor’s Office/Clinic/Hospital/Pharmacy,” and “Some Other Way.”
Source: SAMHSA, NSDUH, 2006
Bought/Took from Friend/Relative
14.8%
Drug Dealer/Stranger
3.9%
Bought on Internet
0.1% Other 1
4.9%
Free from Friend/Relative
7.3%
Bought/Took fromFriend/Relative
4.9%
OneDoctor80.7%
Drug Dealer/Stranger
1.6%Other 1
2.2%Source: Where Respondent Obtained
Source: Where Friend/Relative Obtained
One Doctor19.1%
More than One Doctor
1.6%
Free from Friend/Relative
55.7%
More than One Doctor3.3%
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A Major Public Health Problem Arises
• Harm from ER/LA opioids is disproportionately greater than from immediate-release opioids when corrected for the number of prescriptions
20
0
20000
40000
60000
80000
100000
2004 2005 2006 2007 2008
Hydrocodone Oxycodone IR Oxycodone ER Fentanyl Transdermal
Hydromorphone Methadone Morphine ER
DAWN: Number AllMA-Related ED Visitsby Year and Release Type, 2004-2008
Source: DAWN 2004-2008, SAMHSA
AllMA = All Misuse and Abuse-Related ED Visits with Illegal Drugs or Alcohol Present
21
AllMA Ratio: Number of AllMA ED Visits per
10,000 Retail Prescriptions 2004 – 2008
*Source: SDI Vector One®: National (VONA). Extracted June, 2010
AllMA Ratios 2004 2005 2006 2007 2008
IROxycodone IR 8.8 10.4 10.8 12.2 14.3
Hydrocodone 4.7 5.2 5.8 6.4 8.4
ER/LAOxycodone ER 53.2 59.0 68.3 74.2 106.8
Fentanyl Transdermal 24.4 27.1 34.4 31.9 39.7
Hydromorphone 40.5 40.6 53.1 62.3 70.1
Morphine ER 17.1 7.6 13.5 14.0 12.7
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FDA response
• Work to maintain access for patients who need opioid
medications while trying to curb inappropriate
prescribing, misuse, and abuse
• Develop REMS for ER/LA opioid analgesics
FDA Amendments Act (FDAAA) of 2007 Title IX
• Authority to require risk evaluation and mitigation
strategies (REMS) under section 505-1
– A risk management plan that uses risk minimization
strategies beyond approved professional labeling to
manage serious risks associated with a drug.
• REMS are enforceable
– Failure to comply can lead to:
• Issue a warning letter
• Initiate a seizure, injunction, or other proceeding
• Impose civil monetary penalties
ER/LA Opioid Analgesics REMS Goals
• Help address the significant increase in inappropriate
prescribing, misuse and abuse of these products over the
past decade.
• Minimize the burden on the healthcare system of having
all these products with a different REMS.
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ER/LA Opioid Analgesics in ER/LA REMS
AVINZA (morphine sulfate) extended-release capsules
BUTRANS (buprenorphine) Transdermal System for transdermal administration
DOLOPHINE (methadone hydrochloride) tablets and its generic equivalents
METHADONE ORAL SOLUTION and ORAL CONCENTRATE and its generic equivalents
DURAGESIC (Fentanyl Transdermal System) for transdermal administration and its generic equivalents
EMBEDA (morphine sulfate and naltrexone hydrochloride) extended-release capsules
EXALGO (hydromorphone HCL) extended-release tablets
KADIAN (morphine sulfate) extended-release capsules and its generic equivalent
MS CONTIN (morphine sulfate) controlled release tablets and its generic equivalents
NUCYNTA ER (tapentadol) extended-release oral tablets
OPANA ER (oxymorphone hydrochloride) extended-release tablets and its generic equivalents
OXYCONTIN (oxycodone hydrochloride controlled-release) tablets
ZOHYDRO (hydrocodone extended-release) tablets
REMS Elements
• Medication Guide
• Patient Counseling Document
• Elements to Assure Safe Use
– Training for healthcare providers who prescribe ER/LA opioid analgesics
• Timetable for Submission of Assessments
ER/LA Opioid Analgesics REMS
Medication Guide
• Communicates essential information to patients
• Not intended to replace patient counseling
• Aids patients in use of medication at home
• Has both common content applicable to all ER/LA opioids and product specific information necessary for safe and effective use of the drug.
D R
A F
T
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ER/LA Opioid Analgesics
Patient Counseling Document
ER/LA Opioid Analgesics REMS
Prescriber Education
• CE training will be provided through accredited CE activities supported by independent educational grants from ER/LA opioid analgesic manufacturers.
• FDA developed the core messages (FDA Blueprint) to be communicated to prescribers.
• No mandatory requirement for education as a precondition to prescribing the medication to patients.
• The core REMS prescriber education to be about three hours in length.
• Content is not exhaustive nor a substitute for a more comprehensive pain management course.
• A list of REMS-compliant CE courses offered by accredited CE providers will be posted at www.ER-LA-opioidREMS.com when it becomes available.
FDA Blueprint* for Prescriber Education
for ER/LA Opioid Analgesics
I. Why Prescriber Education is Important
II. Assessing Patients for Treatment with ER/LA OpioidAnalgesic Therapy
III. Initiating Therapy, Modifying Dosing, and Discontinuing Use of ER/LA Opioid Analgesics
IV. Managing Therapy with ER/LA Opioid Analgesics
V. Counseling Patients and Caregivers about the Safe Use of ER/LA Opioid Analgesics
VI. General Drug Information for ER/LA Opioid Analgesics
VII. Specific Drug Information for ER/LA Opioid Analgesics
* http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM277916.pdf
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ER/LA Opioid Analgesics REMS- Milestones
• REMS approved July 9, 2012
• Labeling for all of the products in the
REMS updated and harmonized for important risk
information
• REMS-compliant CE courses offered by accredited CE
providers became available March 1, 2013
http://www.er-la-opioidrems.com/IwgUI/rems/training.action
Latest Labeling Update
• While REMS training is underway, problems remain
• Labeling is one of FDA’s primary communication tools
• September 10, 2013 - letter issued to all sponsors of ER/LA opioid products
– Clarify and streamline existing language
– Consistent with Patient Labeling Rule format
– New warnings
– Modified indication
• Emphasis on helping prescribers weigh risk and benefit when making decision to prescribe opioids
• Language is NOT YET FINALIZED
Boxed Warning
ADDICTION, ABUSE, AND MISUSE
• Tradename exposes patients and other users to the risks of
opioid addiction, abuse, and misuse which can lead to
overdose and death. Assess each patient’s risk prior to
prescribing Tradename, and monitor all patients regularly
for the development of these syndromes [see Warnings and
Precautions (5.1)].
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Boxed Warning
LIFE-THREATENING RESPIRATORY DEPRESSION
• Serious, life-threatening, or fatal respiratory depression may
occur with use of Tradename. Monitor for respiratory
depression, especially during initiation of Tradename or
following a dose increase. Instruct patients to swallow
Tradename tablets whole; crushing, chewing, or dissolving
Tradename tablets can cause rapid release and absorption of
a potentially fatal dose of (active opioid) [see Warnings and
Precautions (5.2)].
Boxed Warning
ACCIDENTAL EXPOSURE
• Accidental consumption of even one dose of Tradename,
especially by children, can result in a fatal overdose of
(active opioid) [see Warnings and Precautions (5.2)].
Boxed Warning
NEONATAL OPIOID WITHDRAWAL SYNDROME
• New warning added
• For patients who require opioid therapy while pregnant, be
aware that infants may require treatment for neonatal
opioid withdrawal syndrome. Prolonged maternal use of
Tradename during pregnancy can result in neonatal opioid
withdrawal syndrome, which may be life-threatening and
requires management according to protocols developed by
neonatology experts [see Warnings and Precautions (5.3)].
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Boxed Warning
INTERACTION WITH ALCOHOL
For some products:
• The co-ingestion of alcohol with Tradename may result in
increased plasma levels and a potentially fatal overdose of
(active opioid). Instruct patients not to consume alcoholic
beverages, or use prescription or non-prescription products
that contain alcohol, while on Tradename [see Clinical
Pharmacology (12.3)].
Section 2 – Dosage and Administration
Streamlined and clarified:
2.1 Initial Dosing
• Focus on the individual
• Initiate the dosing regimen for each patient individually,
taking into account the patient's prior analgesic treatment
experience and risk factors for addiction, abuse, and misuse
[see Warnings and Precautions (5.1)]. Monitor patients
closely for respiratory depression, especially within the first
24-72 hours of initiating therapy with Tradename [see
Warnings and Precautions (5.2)].
Section 2 – Dosage and Administration
Streamlined and clarified:
2.1 Initial Dosing
• Distinction between dose conversion tables included in
labeling and equianalgesic tables removed from labeling
• Methadone separated out due to drug specific issues
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5 WARNINGS AND PRECAUTIONS
5.1 Addiction, Abuse, and Misuse (Replaces
subsection “Abuse Potential”)
• Tradename contains (active opioid), a Schedule II controlled
substance. As an opioid, Tradename exposes users to the
risks of addiction, abuse, and misuse [see Drug Abuse and
Dependence (9)]. As modified-release products such as
Tradename deliver the opioid over an extended period of
time, there is a greater risk for overdose and death due to
the larger amount of (active opioid) present.
5.1 Addiction, Abuse, and Misuse (Replaces
subsection “Abuse Potential”)
• Although the risk of addiction in any individual is unknown,
it can occur in patients appropriately prescribed Tradename
and in those who obtain the drug illicitly. Addiction can
occur at recommended doses and if the drug is misused or
abused.
5.1 Addiction, Abuse, and Misuse (Replaces
subsection “Abuse Potential”)• Assess each patient’s risk for opioid addiction, abuse, or
misuse
• Monitor all patients for the development of these behaviors
or conditions.
• Risks are increased in patients with a personal or family
history of substance abuse (including drug or alcohol
addiction or abuse) or mental illness (e.g., major
depression).
• These risks should not prevent the prescribing … but use in
such patients necessitates intensive counseling about the
risks and proper use of Tradename along with intensive
monitoring for signs of addiction, abuse, and misuse.
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Section 1 INDICATIONS AND USAGE
New Indication:
Tradename is indicated for the management of pain severe
enough to require daily, around-the-clock, long-term opioid
treatment and for which alternative treatment options are
inadequate.
Section 1 INDICATIONS AND USAGE
New Indication:
Limitations of Use
• Because of the risks of addiction, abuse, and misuse with
opioids, even at recommended doses, and because of the
greater risks of overdose and death with extended-release
opioid formulations, reserve Tradename for use in patients
for whom alternative treatment options (e.g., non-opioid
analgesics or immediate-release opioids) are ineffective, not
tolerated, or would be otherwise inadequate to provide
sufficient management of pain.
• Tradename is not indicated as an as-needed (prn) analgesic.
Additional Changes to Warnings and Precautions
• 5.2 Life-threatening Respiratory Depression (Now
incorporates subsection “Accidental Exposure”)
• 5.3 Neonatal Opioid Withdrawal Syndrome (New)
.
• 5.4 Interactions with Central Nervous System
Depressants (Replaces subsections “Interactions with CNS
Depressants and Illicit Drugs” and “Interactions with
Alcohol”)
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17 Patient Counseling
Updates to:
• Addiction, Abuse, and Misuse
• Life-threatening Respiratory Depression
• Accidental Consumption
• Neonatal Opioid Withdrawal Syndrome
• Interactions with Alcohol and other CNS Depressants
Mostly unchanged
• Important Administration Instructions, Hypotension, Driving
or Operating Heavy Machinery, Constipation, Anaphylaxis,
Pregnancy
Summary
• There is a public health crisis due to prescription opioid
abuse, misuse and addiction, overdose and death
• FDA has used the tools of the ER/LA Opioid REMS and
updated product labeling to address the problems
associated with prescriptions opioids while attempting to
maintain access for patients in need of these medications.
• Prescribers are in a key position to positively impact this
problem
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