History of Modified-Release Morphine and Opioid/Antagonist Combinations

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History of Modified-Release Morphine and
Opioid/Antagonist Combinations

• Ellen Fields, M.D., M.P.H.
• Medical Team Leader
• DAARP

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Overview of Presentation

• Modified Release Morphine Products
• Important labeling changes
• Approved opioid/antagonist combination products

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Modified-Release Morphine Products

• MS CONTIN
• Oramorph SR
• Kadian
• Avinza

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• 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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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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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.
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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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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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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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Oramorph

• Approved August 1991
• Strengths15mg, 30mg 60mg, and 100mg tablets
• Dosing every 8 to 12 hours.
• Label being updated

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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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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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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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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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Avinza 30mg
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Standard Alcohol LanguagePharmacodynamic
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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Wording Added to Avinza LabelPhysico-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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Opioid/Antagonist Combinations
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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 addedTo minimize the potential for abuse of
  the principal active ingredient

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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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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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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 1970s Increasing frequency of cases of
  abuse, diversion, overdose and death
• Ts and Blues Talwin and tripelennamine
  (antihistamine, blue tablet)
• Intravenous abuse of crushed tablets
• Substitute for heroin

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• 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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Scheduled 1979
Removal of Talwin
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Scheduled 1979
Removal of Talwin
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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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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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• 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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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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Summary
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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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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