VIVITROL

1
VIVITROLA Brief Clinical Overview
VIV 784A
2
Presentation Overview

• Achieving recovery from Alcohol Dependence
• Combining medication with psychosocial support
• National consensus on the addition of medication
  to psychosocial support
• Challenges of Current Therapies
• Nonadherence
• Relapse rates
• VIVITROL
• Mechanism of action
• Safety and efficacy
• Touchpoints? services

3
Comprehensive Alcohol Dependence Treatment

• Cortex
• Role
• Decision making
• Thinking
• Reasoning
• Rationalizing

• Psychosocial treatments
• 12-step fellowships
• Faith-based support

4
Comprehensive Alcohol Dependence Treatment

• Cortex
• Role
• Decision making
• Thinking
• Reasoning
• Rationalizing

• Psychosocial treatments
• 12-step fellowships
• Faith-based support

5
Medication-Assisted TreatmentA National Consensus
Substance Abuse Mental Health Services
Administration
US Dept of Health Human Services
NationalAssociation ofDrug CourtProfessionals
Institute of MedicineOf the National Academies
6
Nonadherence Undermines Recovery1
1. Pettinati HM, et al. J Addict Dis.
20001971-83.
7
Oral Naltrexone Discontinuation Rates
US Department of Health and Human
Services/SAMHSA study (2004)1
Kranzler et al., Addiction 20084

• Pharmacy claims for NTX-PO 1,4
• Guidelines recommend treatment from 3-6 months to
  2 years1
• The vast majority did not persist in refills for
  a reasonable course of treatment 1,4
• Both analyses show that approximately 50 failed
  to refill even beyond 30 days1,4
• Two additional independent studies obtained
  similar discontinuation rates2,3

• 1. Harris KM, et al. Psychiatr Serv. 200455221.
• 2. Hermos JA, et al. Alcohol Clin Exp Res.
  2004281229-1235.
• 3. Un H, Addiction Health Services Research
  Conference, Boston 2008
• 4. Kranzler HR, et al. Addiction.
  2008103(11)1801-1808.

8
Medications for Alcohol Dependence
1. Antabuse full Prescribing Information.
Odyssey Pharmaceuticals, Inc. 2. ReVia full
Prescribing Information. Duramed Pharmaceuticals,
Inc. 3.Campral full Prescribing Information.
Merck Santé s.a.s. 4.VIVITROLFull Prescribing
Information. Alkermes, Inc.
Based on a month with 30 days.
9
What is VIVITROL?

• VIVITROL is NOT1
• Addictive
• Aversive (e.g. disulfiram)
• Euphorigenic (i.e. pleasure producing)
• VIVITROL is1
• An opioid blocker (i.e. antagonist)
• Extended-release (30 days)
• Compatible with psychosocial treatments,
  antidepressants and Alcoholics Anonymous2
• Administered by a healthcare professional
  
• (use can be monitored)

• VIVITROL Full Prescribing Information. Alkermes,
  Inc.
• Gromov, I., et al. AMERSA, Washington, DC,
  November 8, 2007.

10
VIVITROL Indication

• VIVITROL is indicated for the treatment of
  alcohol dependence in patients who are able to
  abstain from alcohol in an outpatient setting
  prior to initiation of treatment with VIVITROL.
• Patients should not be actively drinking at the
  time of initial VIVITROL administration.
• Treatment with VIVITROL should be part of a
  comprehensive management program that includes
  psychosocial support.

VIVITROLfull prescribing information.
Cambridge, MA Alkermes, Inc May 2009.
11
Important Safety Information

• VIVITROL is contraindicated in patients receiving
  opioid analgesics or with current physiologic
  opioid dependence,patients in acute opiate
  withdrawal, any individual who has failed the
  naloxone challenge test or has a positive urine
  screen for opioids, or in patients who have
  previously exhibited hypersensitivity to
  naltrexone, PLG, carboxymethylcellulose or any
  other components of the diluent.
• VIVITROL patients must be opioid free for a
  minimum of 7-10 days before treatment.
• Attempts to overcome opioid blockade due to
  VIVITROL may result in a fatal overdose.
• In prior opioid users, use of opioids after
  discontinuing VIVITROL may result in a fatal
  overdose because patients may be more sensitive
  to lower doses of opioids.

VIVITROLfull prescribing information.
Cambridge, MA Alkermes, Inc May 2009.
12
Important Safety Information

• In an emergency situation in patients receiving
  VIVITROL, suggestions for pain management include
  regional analgesia or use of non-opioid
  analgesics.
• If opioid therapy is required as part of
  anesthesia or analgesia, such patients should be
  continuously monitored, in an anesthesia care
  setting, by persons not involved in the conduct
  of the surgical or diagnostic procedure.
• The opioid therapy must be provided by
  individuals specifically trained in the use of
  anesthetic drugs and the management of the
  respiratory effects of potent opioids,
  specifically the establishment and maintenance of
  a patent airway and assisted ventilation.
• Irrespective of the drug chosen to reverse the
  VIVITROL blockade, the patient should be
  monitored closely by appropriately trained
  personnel in a setting equipped and staffed for
  cardiopulmonary resuscitation.

VIVITROLfull prescribing information.
Cambridge, MA Alkermes, Inc May 2009.
13
Important Safety Information
Naltrexone has the capacity to cause
hepatocellular injury when given in excessive
doses. Naltrexone is contraindicated in acute
hepatitis or liver failure, and its use in
patients with active liver disease must be
carefully considered in light of its hepatotoxic
effects. The margin of separation between the
apparently safe dose of naltrexone and the dose
causing hepatic injury appears to be only
five-fold or less. VIVITROL does not appear to be
a hepatotoxin at the recommended doses. Patients
should be warned of the risk of hepatic injury
and advised to seek medical attention if they
experience symptoms of acute hepatitis. Use of
VIVITROL should be discontinued in the event of
symptoms and/or signs of acute hepatitis.
VIVITROLfull prescribing information.
Cambridge, MA Alkermes, Inc May 2009.
14
Important Safety Information

• VIVITROL is administered as an intramuscular
  gluteal injection. Inadvertent subcutaneous
  injection of VIVITROL may increase the likelihood
  of severe injection site reactions.
• VIVITROL must be injected using the customized
  needle provided in the carton. Because needle
  length may not be adequate due to body habitus,
  each patient should be assessed prior to each
  injection to assure that needle length is
  adequate for intramuscular administration.
• VIVITROL injection site reactions may be followed
  by pain, tenderness, induration, swelling,
  erythema, bruising or pruritus however, in some
  cases injection site reactions may be very
  severe.
• Injection site reactions not improving may
  require prompt medical attention, including in
  some cases surgical intervention.

VIVITROL full prescribing information.
Cambridge, MA Alkermes, Inc 2009.
VIVITROLfull prescribing information.
Cambridge, MA Alkermes, Inc May 2009.
15
Important Safety Information

• Consider the diagnosis of eosinophilic pneumonia
  if patients develop progressive dyspnea and
  hypoxemia.
• Alcohol dependent patients, including those
  taking VIVITROL, should be monitored for the
  development of depression or suicidal thoughts.
• Caution is recommended in administering VIVITROL
  to patients with moderate to severe renal
  impairment.
• The most common adverse events associated with
  VIVITROL in clinical trials were nausea,
  vomiting, headache, dizziness, asthenic
  conditions and injection site reactions.

VIVITROL full prescribing information.
Cambridge, MA Alkermes, Inc 2009.
VIVITROLfull prescribing information.
Cambridge, MA Alkermes, Inc May 2009.
16
Opioid Receptors and Alcohol Dependence

• 1.Gianoulakis C. Alcohol Health Res World.
  199822202-210.
• 2. Woodward JJ. Principles of Addiction Medicine.
  3rd ed. 2003101-118.

17
VIVITROL A Targeted Approach
The mechanism by which VIVITROL exerts its
effects in alcohol-dependent patients is not
entirely understood.

• 1. VIVITROL full Prescribing Information.
  Alkermes, Inc.
• 2. Oswald LM, et al. PhysiolBehav.
  200481339-358.
• 3.Kenna GA, et al. Am J Health Syst Pharm.
  2004612272-2279.
• 4.Gianoulakis C. Alcohol Health Res World.
  199822202-210.

18
VIVITROL Microspheres1,2

• Elimination polymer eventually metabolized and
  eliminated as CO2 and H2O

1. Dean RL. Front Biosci. 200510643-655. 2.
Data on file. Alkermes, Inc.
19
VIVITROL Provides aSustained-Release of
Medication
Mean steady-state naltrexone concentration
following monthly VIVITROL compared to daily oral
dosing1
VIVITROL IM Injection Oral naltrexone 50 mg
1. Dunbar JL, et al. Alcohol Clin Exp Res.
200630480-490.
20
Pharmacokinetics

• Reduced first-pass hepatic metabolism vs oral
  naltrexone1
• The cytochrome P450 system is not involved in
  naltrexone metabolism1
• No clinical drug interaction studies have been
  performed
• Lower total monthly dose
• 380mg of VIVITROL vs 1500mg of oral naltrexone1
• Total area-under-the-curve of VIVITROL
• is approximately 4-times that with oral
  naltrexone2

1. VIVITROL Full Prescribing Information. Alkermes,
   Inc.
2. Dunbar, JL. Et al. Alcohol and Clin Exp Res.
   200630(3)480-490

21
VIVITROL Eliminates DailyAdherence Decisions1

• VIVITROL utilizes a delivery system that
• Provides a month of medication in a single dose
• Adherence to any treatment program is essential
  for successful outcomes
• Administration by a healthcare provider
  ensuresthat the patient receives the medication
  as directed

addressing patient adherence systematically
will maximize the effectiveness of these
medications.2 Updated NIAAA Clinicians Guide
1. Dean RL. Front Biosci. 200510643-655. 2.
NIAAA. 2007. NIH publication 07-3769.
22
Phase III Safety Efficacy TrialRandomized,
double-blind, placebo-controlled study1-3
899 assessed for eligibility
624 DSM-IV alcohol-dependent patients
randomized Received 24-weeks treatment including
12 sessions of standardized counseling Multicenter
24 outpatient sites
Placebo Microspheres n209
XR-NTX 190 mg n210
VIVITROL n205
134 received all 6 injections
130 received all 6 injections
137 received all 6 injections
64
63
65
128 completed trial
124 completed trial
126 completed trial
61
60
60

• No oral naltrexone lead-in

1.Garbutt JC, et al. JAMA. 20052931617-1625. 2.V
olpicelli JR, et al. Combining Medication and
Psychosocial Treatments for Addictions The
BRENDA Approach. 2001. 3. Data on file. Alkermes,
Inc.
23
VIVITROL Provided Rapid Results
When VIVITROL was added to counseling Reductions
were rapid1

• Post hoc analysis of a randomized, double-blind,
  placebo-controlled study. Patients had 2 heavy
  drinking episodes/week during the month prior to
  screening. Inclusion did not require
  detoxification, abstinence or intent to abstain
  from alcohol1
• VIVITROL is indicated for the treatment of
  alcohol dependence in patients who are able to
  abstain from alcohol in an outpatient setting
  prior to initiation of
  treatment with VIVITROL. Patients should not be
  actively drinking at the
  time of initial VIVITROL administration2
• Approval of VIVITROL was based on a subset of
  patients who were able to abstain for 7 days
  prior to treatment initiation1

Counseling with PLACEBO (n209)
Counseling with VIVITROL (n205)
The counseling used with all subjects was
BRENDA, a low-intensity intervention designed to
facilitate direct feedback of alcohol-related
consequences. BRENDA consists of biopsychosocial
assessment, reporting the assessment to the
patient, an empathetic approach, identified and
stated patient needs, direct advice regarding
drinking behavior, and assessment of treatment
adherence.

1. Ciraulo D et al. J Clin Psychiatry.
   200869(2)190-195.
2. VIVITROL Full Prescribing Information.
   Cambridge, MA. Alkermes, Inc. 2008.

24
VIVITROL Significantly Reduces Drinking
Days1,2
Reductions were substantial1
Counseling with VIVITROL (n28)
Counseling with PLACEBO (n28)
Baseline (n56)

• According to the SAMHSA/CSAT, 4 days is the US
  norm (median duration) for detoxification2
• Approval of VIVITROL was based on a subset of
  patients who were able to abstain for 7 days
  prior to treatment initiation1
• These results are from a post hoc subgroup
  analysis of a 6-month, multicenter, double-blind,
  placebo-controlled clinical trial of alcohol
  dependent patients. This subset analysis
  evaluated patients who were abstinent for 4 or
  more days prior to treatment initiation1

• OMalley SS et al. J ClinPsychopharmacol.
  200727(5)507-512.
• Drug and Alcohol Services Information System. The
  DASIS report discharges from detoxification
  2000. http//oas.samhsa.gov/2K4/detoxDischarges/de
  toxDischarges.pdf. Published July 9, 2004.
  Accessed January 23, 2008.

.
25
VIVITROL Sustained Abstinence1
VIVITROL prolonged initial abstinence
Counseling with PLACEBO (n28)
Counseling with VIVITROL (n28)

• Results are from a post hoc subgroup analysis
  of a 6-month multicenter, double-blind,
• placebo controlled clinical trial of alcohol
  dependents who were abstinent for 4 or more days
• prior to treatment initiation.
• The approval of VIVITROL was based on a subset
  of patients who were able to
  
• abstain for 7 days prior to treatment
  initiation.

1. OMalley SS, et al. J ClinPsychopharm.
200727507-512.
26
VIVITROL Sustained Reduction in Heavy Drinking
Among patients receiving VIVITROL or placebo in
the 6-month trial
Patients continuing on VIVITROL (n115)
Placebo ( n209)
Patients switching from placebo to VIVITROL
(n60)
VIVITROL (n205)
Data on file. Alkermes, Inc.
27
VIVITROL Reduced Holiday Drinking1
The public health significance
of the findings by Lapham et al.
in this issue is huge.2 --David
Rosenbloom, Ph.D.
Boston University School of Public
Health (2009)
n27

• Results are from a post hoc subgroup analysis
  of a 6-month multicenter, double-blind,
• placebo controlled clinical trial of alcohol
  dependents who were abstinent for 4 or more days
• prior to treatment initiation.
• The approval of VIVITROL was based on a subset
  of patients who were able to
  
• abstain for 7 days prior to treatment
  initiation.

1. Lapham. J Subst Abuse Treat. 2009361.
2. Rosenbloom DL. J Subst Abuse Treat. 200936(1)7.

28
Summary of Efficacy Results1,2
In clients who were abstinent during the week
before treatment initiation, VIVITROL and
counseling, as compared to placebo and
counseling, provided

• Rapid results
• Substantial reduction in drinking days
• Prolonged initial abstinence
• Sustained continuous abstinence through the
  6-month study
• Sustained reduction in heavy drinking days
  through 18 months
• Substantial reduction in holiday drinking

1. OMalley SS, et al. J ClinPsychopharmacol.
200727507-512. 2. VIVITROL Full Prescribing
Information. Alkermes, Inc.
29
Safety Profile

• During clinical trials
• Treatment with extended-release naltrexone was
  generally well tolerated
• Safety profile is based on more than 900 patients
  
• Adverse events in the majority of patients were
  mild or moderate
• Discontinuation rates due to adverse events
• 9 in patients treated with VIVITROL
• 7 in patients treated with placebo
• The safety profile of patients treated with
  VIVITROL concomitantly with antidepressants was
  similar to that of patients taking VIVITROL
  without antidepressants1
• No significant increase in mean AST or ALT
  levels2

• VIVITROL Full Prescribing Information. Alkermes,
  Inc.
• Garbutt JC, et al. JAMA. 20052931617-1625.

30
Most Common Adverse Events
Occurring in gt10 of patients
VIVITROL Placebo
Injection site reaction 69 50
Nausea 33 11
Headache 25 18
Asthenic conditions 23 12
Anorexia, appetite decreased NOS, appetite disorder NOS 14 3
Vomiting 14 6
Insomnia, sleep disorder 14 12
Dizziness 13 4
Diarrhea 13 10
Anxiety 12 8
Abdominal pain 11 8
Pharyngitis 11 11
Injection site reaction (ISR) included
tenderness, induration, pain, and pruritus.
The dropout rate due to ISR was 3.
VIVITROL Full Prescribing Information. Alkermes,
Inc.
31
Serious Adverse Events

• In clinical trials, serious adverse events
  occurred at a rate similar to patients receiving
  placebo injections1
• 5.4 on VIVITROL vs 7.2 on placebo
• Most common serious adverse event (SAE) was
  inpatient hospitalization for detoxification
• Other SAEs seen on VIVITROL2
• 2 cases of pneumonia (one confirmed case of
  eosinophilic)
• 1 case of injection site induration requiring
  excision

1.Garbutt JC, et al. JAMA. 20052931617-1625. 2.
VIVITROL Full Prescribing Information. Alkermes,
Inc.
32
Emergency Pain Management

• VIVITROL antagonizes the effects of
  opioid-containing medications.Patients receiving
  VIVITROL may not benefit from opioid-containing
  medications.
• Patients should be advised to carry a patient
  alert card that informs medical personnel they
  are taking VIVITROL
• A suggested plan for pain management is
• Regional analgesia
• Use of non-opioid analgesics
• In an emergency situation requiring opioid
  analgesia, the amount of opioid required may be
  greater than usual and the resulting respiratory
  depression may be deeper and more prolonged
• Such patients should be continuously monitored in
  an anesthesia care setting by persons not
  involved in the conduct of the surgical or
  diagnostic procedure
• The opioid therapy must be provided by
  individuals specifically trained in the use of
  anesthetic drugs and the management of the
  respiratory effects of potent opioids,
  specifically the establishment and maintenance of
  a patent airway and assisted ventilation
• A rapidly acting opioid analgesic that minimizes
  the duration of respiratory depression is
  preferred
• Patients should be closely monitored by trained
  personnel in a setting
  equipped for cardiopulmonary resuscitation.

33
Dosage and Administration

• VIVITROL is given as an intramuscular (IM)
  gluteal injection every 4 weeks or once a month
• VIVITROL should not be given subcutaneously or in
  the adipose layer
• VIVITROL must not be administered intravenously
• VIVITROL should be administeredby a healthcare
  professional, into alternating buttocks each
  month
• VIVITROL should be injected into the upper outer
  quadrant of the buttock, deep into the muscle-not
  the adipose.

VIVITROL Full Prescribing Information.
Alkermes, Inc.
34
Introducing
Connecting people with care in recovery.

• A free service for patients and treatment
  providers
• designed to
• Promote long-term recovery
• Improve access to treatment
• Support continuity of care

35
Specializing in supporting continuity of therapy
for VIVITROL patients transitioning between
settings of care
Offering patients a free start on the path to
recovery
Connecting customers to reimbursement and
distribution services
An integrated network of providers supporting
VIVITROL assisted recovery
Enhancing knowledge of VIVITROL assisted recovery
and offering tools to aid in treatment
Providing confidential, supportive help for
patients during recovery
1-800-VIVITROL (1-800-848-4876)
www.vivitrol.com
36
VIVITROL Carton Components
37
APPENDIX
38
Alcohol Dependence An Ancient Problem
After the flood, Noah plants a vineyard, makes
wine and gets drunk. (Genesis 921)
Who hath woe? Who hath sorrow? Who is always
fighting?Who is always complaining? Who hath
wounds without cause?Who has bloodshot eyes?
They who tarry long at the wine when it
sparkles in the cup. Don't let the smooth taste
deceive you. For in the end it bites like a
poisonous serpent. And you will say, They hit
me, but I didn't feel it. Your eyes will see
strange visions and you will say strange
thoughts. Yet when you awaken, you seek it yet
again.
Proverbs 2329 (1,000 BC)
39
Medication-Assisted TreatmentA National
Consensus
Consider adding medication wheneveryou are
treating someone with active alcohol dependence.
National Institute on Alcohol Abuse and
Alcoholism. Helping Patients Who Drink Too Much
A Clinicians Guide. Available at
http//pubs.niaaa.nih.gov/publications/Practitione
r/CliniciansGuide2005/clinicians_guide.htm.May
2007 reprint. Accessed May 5, 2008.
40
Medication-Assisted TreatmentA National
Consensus
Patient nonadherence is a common problem with
all types of oral medications. In addition,
people with substance use disorders experience
fluctuations in their motivation for abstinence,
further affecting their compliance With
injectable naltrexone, one intramuscular
injection is effective for 4 weeks, reducing
opportunities for patients to cease their
medication.
U.S. Department of Health and Human Services,
Substance Abuse and Mental Health Services
Administration, Center for Substance Abuse
Treatment Advisory (Spring 2007) http//kap.samhsa
.gov/products/manuals/advisory/index.htm
41
Medication-Assisted TreatmentA National
Consensus
Substance Abuse Mental HealthServices
Administration
U.S. Department of Health and Human Services
A combination of medication and behavioral
therapies ismost successful.
Substance Abuse Mental Health Services
Administration, Division of Pharmacologic
Therapies. Medication-Assisted Treatment for
Substance Use Disorders. Available at
http//www.dpt.samhsa.gov. Accessed May 5, 2008.
42
Medication-Assisted TreatmentA National
Consensus
Pharmacotherapy should be available to all
adult patients diagnosed with alcohol dependence
and should be provided in addition to
psychosocial treatment/support.
National Quality Forum. 2007. National Voluntary
Consensus Standards for the Treatment of
Substance Use Conditions Evidence-Based
Treatment Practices. Available at
http//www.qualityforum.org/pdf/reports/sud/sudexe
summary.pdf.Accessed May 5, 2008.
43
Medication-Assisted TreatmentA National
Consensus
Institute of Medicineof the National Academies
There is a spectrum of evidence-based
pharmacologic psychosocial treatments
Naltrexone shows efficacy in treating alcohol
dependence.
Institute of Medicine of the National Academies.
Improving the Quality of Health Care for Mental
and Substance-Use Conditions Quality Chasm
Series. Committee on Crossing the Quality Chasm
Adaptation to Mental Health and Addictive
Disorders. Executive Summary. 2006. Available at
http//www.iom.edu/CMS/3809/19405/30836.aspx.
Accessed May 5, 2008.
44
Medication-Assisted TreatmentA National
Consensus
Integrate biological, psychosocial,and
pharmacological approaches.All are helpful and
necessary.
The National Council on Alcoholism and Drug
Dependence. Interviews with the Experts Robert
Morse, MD on the Use of Pharmacology in Addiction
Treatment. http//www.ncadd.org/facts/morse.html.
Accessed May 5, 2008.
45
Alcoholics Anonymous(AA) and Use of Medication

• Alcoholics Anonymous published a booklet for AA
  members (1984)
• Booklet supports appropriately prescribed
  medications
• Booklet is being updated to address new
  medications

Alcoholics Anonymous World Service, Inc. The AA
Member Medications and Other Drugs. 1984.
46
Typical Clinical Team Roles

• Counselor (psychosocial treatment provider)
• Provides psychosocial treatment
• Monitors response to medication
• Communicates patient status with treatment team
• Physician (prescriber/injector)
• Assesses appropriateness of medication for
  patient
• Monitors medical response to medication
• Communicates patient status with treatment team
• Nurse (injector)
• Administers medication
• Monitors medical response to medication
• Communicates patient status with treatment team

47
Development of VIVITROL

• Problem of nonadherence was well understood by
  19751
• NIAAA and NIDA awarded grants that led to
  development of Medisorb technology
• VIVITROL uses the Medisorb extended-release
  properties, first introduced in
  RisperdalConsta

Medisorb is a registered trademark of Alkermes,
Inc. Risperdal and Consta are registered
trademarks of Janssen Pharmaceutica. 1. NIDA
Monograph. Narcotic Antagonists The Search for
Long-Acting Preparations.
48
Pharmacokinetics

• Minimal accumulation (lt15) of naltrexone or
  6-?naltrexol upon repeat administration of
  VIVITROL
• Elimination
• Primarily via urine for naltrexone and its
  metabolites
• Minimal excretion of unchanged naltrexone
• Half-life 5 to 10 days (dependent on erosion of
  polymer)

VIVITROL Full Prescribing Information.
Alkermes, Inc.
49
VIVITROL Prolongs Abstinence1,2

• Among patients who were abstinent for 7
  days prior to treatment initiation

VIVITROL prolonged initial abstinence
(n17)
1. Garbutt JC, et al. JAMA. 20052931617-1625. 2
. Data on file. Alkermes, Inc. .
50
Subjects With Nausea by Month

• Mild in the majorityof reports
• Occurred in the first month in the majority of
  cases
• Median duration of a few days
• Trial dropout rate due to nausea was 2 in the
  VIVITROL group

Data on file. Alkermes, Inc.