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					History of Modified-Release
       Morphine and
     Opioid/Antagonist
       Combinations
                   Ellen Fields, M.D., M.P.H.
                     Medical Team Leader
                            DAARP


Anesthetic and Life Support Drugs and Drug Safety and Risk
Management Advisory Committees, November 14, 2008
    Overview of Presentation
• Modified Release Morphine Products
  – Important labeling changes

• Approved opioid/antagonist
  combination products




   Anesthetic and Life Support Drugs and Drug Safety and Risk
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   Management Advisory Committees, November 14, 2008
     Modified-Release Morphine
              Products
• MS CONTIN

• Oramorph SR

• Kadian

• Avinza

   Anesthetic and Life Support Drugs and Drug Safety and Risk
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   Management Advisory Committees, November 14, 2008
• Schedule II

• Indication: Management of moderate-to
  severe pain when a continuous around-
  the-clock opioid analgesic is needed for an
  extended period of time

• Extended-release opioid formulations
  provide for improved compliance,
  convenience for the patient and longer
  pain relief than immediate-release
  products

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    Management Advisory Committees, November 14, 2008
                              MS CONTIN
•   Approved May 1987
•   Priority review
•   Strengths: 15mg, 30mg, 60mg, 100mg, 200mg
•   Dosing: Q12 hours
•   Major labeling changes
     – May 2003: Box Warning added
        • Restricted 100mg and 200mg to opioid
          tolerant patients
        • Abuse liability, not prn, not to be broken,
          chewed, crushed, dissolved
     – May 2007: strengthens language throughout
       the label regarding abuse, misuse and
       diversion

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      Management Advisory Committees, November 14, 2008
       *100 mg and 200 mg are for use in opioid-tolerant patients only
WARNING:
MS CONTIN contains morphine sulfate, an opioid agonist and a Schedule II controlled
substance, with an abuse liability similar to other opioid analgesics.
Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. This
should be considered when prescribing or dispensing MS CONTIN in situations where the
physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
MS CONTIN Tablets are a controlled-release oral formulation of morphine sulfate indicated
for the management of moderate to severe pain when a continuous, around-the-clock opioid
analgesic is needed for an extended period of time.
MS CONTIN Tablets are NOT intended for use as a prn analgesic.
MS CONTIN 100 and 200 mg Tablets ARE FOR USE IN OPIOID-TOLERANT PATIENTS
ONLY. These tablet strengths may cause fatal respiratory depression when administered to
patients not previously exposed to opioids.
MS CONTIN TABLETS ARE TO BE SWALLOWED WHOLE AND ARE NOT TO BE
BROKEN, CHEWED, DISSOLVED, OR CRUSHED. TAKING BROKEN, CHEWED,
DISSOLVED, OR CRUSHED MS CONTIN TABLETS LEADS TO RAPID RELEASE AND
ABSORPTION OF A POTENTIALLY FATAL DOSE OF MORPHINE.



          Anesthetic and Life Support Drugs and Drug Safety and Risk
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          Management Advisory Committees, November 14, 2008
MS CONTIN contains morphine sulfate, an opioid agonist
and a Schedule II controlled substance, with an abuse
liability similar to other opioid analgesics.
Morphine can be abused in a manner similar to other opioid
agonists, legal or illicit. This should be considered when
prescribing or dispensing MS CONTIN in situations where
the physician or pharmacist is concerned about an increased
risk of misuse, abuse, or diversion




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      Management Advisory Committees, November 14, 2008
MS CONTIN Tablets are a controlled-release oral formulation of morphine
sulfate indicated for the management of moderate
to severe pain when a continuous, around-the-clock opioid analgesic is needed
for an extended period of time.
MS CONTIN Tablets are NOT intended for use as a prn analgesic.
MS CONTIN 100 and 200 mg Tablets ARE FOR USE IN OPIOID-
TOLERANT PATIENTS ONLY. These tablet strengths
may cause fatal respiratory depression when administered to patients not
previously exposed to opioids.




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         Management Advisory Committees, November 14, 2008
MS CONTIN tablets are to be swallowed whole and are
not to be broken, chewed, dissolved, or crushed. Taking
broken, chewed, dissolved, or crushed MS CONTIN
tablets leads to rapid release and absorption of a
potentially fatal dose of morphine.




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      Management Advisory Committees, November 14, 2008
                              Oramorph
• Approved August 1991
• Strengths:15mg, 30mg 60mg, and
  100mg tablets
• Dosing: every 8 to 12 hours.
• Label being updated




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   Management Advisory Committees, November 14, 2008
                                    Kadian
• Approved July 1996
• Initial strengths: 20mg, 50mg, and 100mg
  capsules
• Added strengths: 10mg, 30mg, 60mg,
  80mg, and 200mg capsules (2005)
• Dosing every 12 to 24 hours
• The capsules are to be swallowed whole
  or may be sprinkled on applesauce
• 2006: Box Warning added

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   Management Advisory Committees, November 14, 2008
KADIAN® capsules are to be swallowed whole or
the contents of the capsules sprinkled on apple
sauce. The pellets in the capsules are not to be
chewed, crushed, or dissolved due to the risk of
rapid release and absorption of a potentially fatal
dose of morphine




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      Management Advisory Committees, November 14, 2008
                                     Avinza
• Approved March 2002
• Strengths: 30mg, 60mg, 90mg, and 120mg
  capsules
• Dosing every 24 hours
• The capsules may be swallowed whole or
  sprinkled on applesauce.
• Maximum dose: 1600 mg/day
   – Related to an inactive ingredient
• 60mg, 90mg, 120mg for opioid-tolerant only
• October 2005: language added that alcohol
  compromises the controlled release properties of
  the formulation and causes it to act as an
  immediate release product (dose-dumping)

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    Management Advisory Committees, November 14, 2008
       Interaction with Alcohol
• 2004: Palladone (modified-release
  hydromorphone) dose-dumps in presence
  of alcohol in vivo and removed from
  market
• All modified-release opioids underwent in
  vitro dissolution studies with ETOH,
  followed by in vivo if needed
• 40% (all), 20%, 4% (Avinza and Kadian)
• Kadian: positive in vitro, negative in vivo
• Avinza: positive in vitro, not tested in vivo
• MS Contin, Oramorph: negative in vitro

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    Management Advisory Committees, November 14, 2008
                                     Avinza 30mg

                                     Avinza 30m g Capsules


                120.0
                100.0
% Dissolution




                 80.0
                 60.0
                 40.0
                 20.0
                  0.0
                        0    2   4     6   8   10   12   14   16   18   20   22   24
                                               Tim e (hour)


                            0%ETOH         4%ETOH        20%ETOH             40%ETOH



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Management Advisory Committees, November 14, 2008
     Standard Alcohol Language
          Pharmacodynamic Interaction
Tradename may be expected to have
additive effects when used in conjunction
with alcohol, other opioids, or illicit drugs
that cause central nervous system
depression because respiratory
depression, hypotension, and profound
sedation or coma may result

Tradename should not be taken with
alcohol or other CNS depressants….

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  Management Advisory Committees, November 14, 2008
Wording Added to Avinza Label
      Physico-chemical interaction
“Patients must not consume alcoholic
beverages while on Avinza therapy.
Additionally, patients must not use
prescription or non-prescription
medications containing alcohol while on
Avinza therapy. Consumption of alcohol
while taking Avinza may result in the rapid
release and absorption of a potentially
fatal dose of morphine.”

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  Management Advisory Committees, November 14, 2008
Opioid/Antagonist Combinations




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  Management Advisory Committees, November 14, 2008
                     21CFR300.50(a)
 “Two or more drugs may be combined
  in a single dosage form when each
  component makes a contribution to
  the claimed effect…”
• A special case of this rule is where a
  component is added…To minimize
  the potential for abuse of the
  principal active ingredient
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   Management Advisory Committees, November 14, 2008
                               Approved
• Talwin NX (pentazocine/naloxone)
• Suboxone (buprenorphine/naloxone)
• Naloxone HCl was added to both
  products in order to deter
  intravenous abuse of the drugs




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   Management Advisory Committees, November 14, 2008
                               Naloxone
• Pure opioid agonist
• Causes complete or partial reversal
  of opioid effects
• Administered IV
• Very limited systemic bioavailability
  by non-parenteral routes of
  administration


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   Management Advisory Committees, November 14, 2008
                               Talwin NX
• Talwin (pentazocine) was approved in 1967 for
  the relief of moderate-to-severe pain.
   – No known potential for abuse
   – Not-scheduled

• 1968: First reports of dependence, limited

• Late 1970’s: Increasing frequency of cases of
  abuse, diversion, overdose and death
   – T’s and Blues: Talwin and tripelennamine
     (antihistamine, blue tablet)
   – Intravenous abuse of crushed tablets
   – Substitute for heroin

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    Management Advisory Committees, November 14, 2008
• Efforts to mitigate abuse:
  – 1979: Schedule IV
  – Labeling changed to include
    postmarketing events of addiction

• 1982: Reformulated with naloxone
  (pentazocine 50mg/naloxone 0.5mg)
   – Marketed starting April 1983

• January 1983: Talwin removed from
  market
   – Reports of abuse declined during two
     years after withdrawal of Talwin from
     the market


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   Management Advisory Committees, November 14, 2008
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Management Advisory Committees, November 14, 2008
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Management Advisory Committees, November 14, 2008
           Scheduled 1979

                                            Removal of Talwin




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Management Advisory Committees, November 14, 2008
        Scheduled 1979




                                       Removal of Talwin




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Management Advisory Committees, November 14, 2008
 Possible Factors Contributing to
 the Decrease in Abuse of Talwin
• Scheduling of Talwin
• Removal of single entity Talwin from
  the market
• Introduction of Talwin NX
• Change in the availability of heroin




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   Management Advisory Committees, November 14, 2008
                              Suboxone
• Combination of buprenorphine HCl (a
  partial mu opioid agonist) and Naloxone
  HCl (a full opioid antagonist)
• Approved in October, 2002 for the
  treatment of opioid dependence, along
  with Subutex, which is buprenorphine HCl
  without the addition of Naloxone
• The two products are interchangeable in
  terms of the pharmacokinetics of
  buprenorphine

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   Management Advisory Committees, November 14, 2008
• Suboxone was designed to be administered
  sublingually
   – absorption of the Naloxone component
     caused no clinically significant effect although
     plasma levels were measurable

• In clinical pharmacology studies, if Suboxone
  was improperly administered via the intravenous
  route, the naloxone component would become
  available and block the euphoric effects of the
  opioid component or precipitate opioid
  withdrawal

• There have been no formal studies to assess the
  impact of Suboxone in terms of abuse

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    Management Advisory Committees, November 14, 2008
                   Suboxone Abuse
• Reports of abuse
   – Sublingual
   – Nasal inhalation
   – Injection

• Baltimore Sun, December 2007
   – Maine health department reported in August
     that misuse spread rapidly as more Suboxone
     was prescribed. Abusers of the drug "have
     figured out how to separate out the naloxone"
     to inject the buprenorphine….
   – In Massachusetts, …"A lot of people are
     injecting it. They're getting hooked on it."

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    Management Advisory Committees, November 14, 2008
                             Summary




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Management Advisory Committees, November 14, 2008
  Modified-Release Morphine

• Four approved products
• Highest doses for opioid-tolerant
  patients
• Box Warning
• One product has labeling regarding
  dose-dumping in alcohol

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   Management Advisory Committees, November 14, 2008
 Opioid-Antagonist Combinations
• Two approved products
   – Talwin NX and Suboxone
• Naloxone added to mitigate IV abuse
• Some evidence that introduction of Talwin
  NX led to decreased pentazocine abuse
   – Multifactorial
• No formal assessment of Suboxone
  impact on abuse
   – Multiple reports of IV and intranasal
     abuse

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   Management Advisory Committees, November 14, 2008

				
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