1 VIVITROL ® A Brief Clinical Overview VIV 784A. 2 Presentation Overview Achieving recovery from Alcohol Dependence –Combining medication with psychosocial

1

VIVITROL®

A 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℠

CortexRole:• Decision making• Thinking• Reasoning• Rationalizing

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

Comprehensive Alcohol Dependence Treatment

3

Limbic Region

Role:• Drive generation

CortexRole:• Decision making• Thinking• Reasoning• Rationalizing

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

– VIVITROL

Psychosocial Treatment and Medication

Comprehensive Alcohol Dependence Treatment

4

Medication-Assisted TreatmentA National Consensus

National Council on Alcoholismand Drug Dependence

US Dept of Health & Human Services

National Institute on AlcoholAbuse and Alcoholism

National Institutes of Health

Institute of MedicineOf the National Academies

NationalAssociation ofDrug CourtProfessionals

PLNDPPLNDPPhysicians and Lawyersfor National Drug Policy

National Quality Forum

Substance Abuse & Mental Health Services Administration

5

http://www.samhsa.gov/index.aspx

http://www.samhsa.gov/index.aspx

Nonadherence Undermines Recovery1

1. Pettinati HM, et al. J Addict Dis. 2000;19:71-83.

6

Oral Naltrexone Discontinuation Rates

• 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. 2004;55:221.2. Hermos JA, et al. Alcohol Clin Exp Res. 2004;28:1229-1235.3. Un H, Addiction Health Services Research Conference, Boston 20084. Kranzler HR, et al. Addiction. 2008:103(11):1801-1808.

US Department of

Health and Human Services/SAMHSA study (2004)1

US Department of

Health and Human Services/SAMHSA study (2004)1

Kranzler et al., Addiction 20084

7

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.

2006

1/month

VIVITROL®

(naltrexone forextended-release

injectable suspension)4

1951

30 tabs/month*(1 tab/day)

Antabuse®

(disulfiram)1

1994

30 tabs/month*(1 tab/day)

ReVia®

(naltrexone)2

2004

Campral®(acamprosate)3

180 tabs/month*(2 tabs, 3x/day)

8

1. VIVITROL Full Prescribing Information. Alkermes, Inc.2. Gromov, I., et al. AMERSA, Washington, DC, November 8, 2007.

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)

9

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.

VIVITROL[full prescribing information]. Cambridge, MA: Alkermes, Inc; May 2009. 10

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.



• 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.



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.


• 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.


• 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.


Opioid Receptors and Alcohol Dependence

1.Gianoulakis C. Alcohol Health Res World. 1998;22:202-210.

2. Woodward JJ. Principles of Addiction Medicine. 3rd ed. 2003:101-118.

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VIVITROL: A Targeted Approach

1. VIVITROL full Prescribing Information. Alkermes, Inc. 2. Oswald LM, et al. PhysiolBehav. 2004;81:339-358.3.Kenna GA, et al. Am J Health Syst Pharm. 2004;61:2272-2279.4.Gianoulakis C. Alcohol Health Res World. 1998;22:202-210.

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

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VIVITROL Microspheres1,2

• Elimination: polymer eventually metabolized

and eliminated as CO2 and H2O

HydrationHydration DiffusionDiffusion ErosionErosion

1. Dean RL. Front Biosci. 2005;10:643-655.2. Data on file. Alkermes, Inc.

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1. Dunbar JL, et al. Alcohol Clin Exp Res. 2006;30:480-490.

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

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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. 2006;30(3):480-49020

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

1. Dean RL. Front Biosci. 2005;10:643-655.2. NIAAA. 2007. NIH publication 07-3769.

“…addressing patient adherence systematically will

maximize the effectiveness of these medications.”2

–Updated NIAAA Clinician’s Guide

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Phase III Safety & Efficacy TrialRandomized, double-blind, placebo-controlled study1-3

1.Garbutt JC, et al. JAMA. 2005;293:1617-1625.2.Volpicelli JR, et al. Combining Medication and Psychosocial Treatments

for Addictions: The BRENDA Approach. 2001.3. Data on file. Alkermes, Inc.

• No oral naltrexone lead-in

624 DSM-IV alcohol-dependent patients randomizedReceived 24-weeks treatment

including 12 sessions of standardized counselingMulticenter: 24 outpatient sites

Placebo Microspheresn=209

XR-NTX 190 mg n=210

VIVITROL n=205

134 received all 6 injections

64%


63%


65%

899 assessed for eligibility

128 completed trial

61%

124 completed trial

60%

126 completed trial

60%

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VIVITROL Provided Rapid Results

When VIVITROL was added to counseling*…Reductions were rapid1

1. Ciraulo D et al. J Clin Psychiatry. 2008;69(2):190-195. 2. VIVITROL Full Prescribing Information. Cambridge, MA. Alkermes, Inc.; 2008.

• 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

*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.

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Counseling* with PLACEBO (n=209)

Counseling* with VIVITROL (n=205)

VIVITROL Significantly Reduces Drinking Days1,2

.

• 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

Reductions were substantial1†

1. O’Malley SS et al. J ClinPsychopharmacol. 2007;27(5):507-512.

2. Drug and Alcohol Services Information System. The DASIS report: discharges from detoxification: 2000. http://oas.samhsa.gov/2K4/detoxDischarges/detoxDischarges.pdf. Published July 9, 2004. Accessed January 23, 2008.

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Counseling with VIVITROL (n=28)

Counseling with PLACEBO

(n=28)

Baseline(n=56)

1. O’Malley SS, et al. J ClinPsychopharm. 2007;27:507-512.

VIVITROL Sustained Abstinence1

VIVITROL prolonged initial abstinenceVIVITROL prolonged initial abstinence

VIVITROL maintained 6-month abstinenceVIVITROL maintained 6-month abstinence

32%32%

11%11%

Nearly three times as many patients remained abstinent

Nearly three times as many patients remained abstinent

• 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.

Counseling with VIVITROL (n=28)

Counseling with PLACEBO (n=28)

25

VIVITROL Sustained Reduction in Heavy Drinking

Data on file. Alkermes, Inc.

Among patients receiving VIVITROL or placebo in the 6-month trial

VIVITROL (n=205)

Patients continuing on VIVITROL (n=115)

Placebo ( n=209)

Patients switching from placebo to VIVITROL (n=60)

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VIVITROL Reduced Holiday Drinking1

1. Lapham. J Subst Abuse Treat. 2009;36:1. 2. Rosenbloom DL. J Subst Abuse Treat. 2009;36(1):7.

Med

ian

% D

rin

kin

g D

ays

• 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.

n=27

“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)

27

• 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

Summary of Efficacy Results1,2

1. O’Malley SS, et al. J ClinPsychopharmacol. 2007;27:507-512. 2. VIVITROL Full Prescribing Information. Alkermes, Inc.

In clients who were abstinent during the week before treatment initiation, VIVITROL and counseling, as compared to placebo and counseling, provided:

28

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

1.VIVITROL Full Prescribing Information. Alkermes, Inc.2.Garbutt JC, et al. JAMA. 2005;293:1617-1625.29

Most Common Adverse Events

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

Occurring in >10% of patients

*Injection site reaction (ISR) included tenderness, induration, pain, and pruritus. The dropout rate due to ISR was 3%.

VIVITROL Full Prescribing Information. Alkermes, Inc. 30

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. 2005;293:1617-1625.2. VIVITROL Full Prescribing Information. Alkermes, Inc.31

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.

32

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.

Epidermis

Dermis

Adipose

Muscle

33

Introducing…

Connecting people with care in recovery. 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

34

Offering patients a free start on the path to recovery

Connecting customers to reimbursement and distribution services

Providing confidential, supportive help for patients during recovery

Specializing in supporting continuity of therapy for VIVITROL patients transitioning between settings of care

An integrated network of providers supporting VIVITROL assisted recovery

Enhancing knowledge of VIVITROL assisted recovery and offering tools to aid in treatment

www.vivitrol.com1-800-VIVITROL (1-800-848-4876)

35

http://www.vivitrol.com/

VIVITROL Carton Components

36

APPENDIX

37

After the flood, Noah plants a vineyard, makes wine and gets drunk. (Genesis 9:21)

Proverbs 23:29 (~1,000 BC)Proverbs 23:29 (~1,000 BC)

Alcohol Dependence: An Ancient Problem

“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.”

38

“Consider adding medication wheneveryou are treating someone with active

alcohol dependence.”

National Institute on AlcoholAbuse and Alcoholism

National Institutes of Health

National Institute on Alcohol Abuse and Alcoholism. Helping Patients Who Drink Too Much: A Clinician’s Guide. Available at: http://pubs.niaaa.nih.gov/publications/Practitioner/CliniciansGuide2005/clinicians_guide.htm.May 2007 reprint. Accessed May 5, 2008.

Medication-Assisted Treatment:A National Consensus

39

“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


40

Substance Abuse & Mental HealthServices Administration

U.S. Department of Health and Human Services

“A combination of medication and behavioral therapies is

most 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.


41

“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/sudexesummary.pdf.Accessed May 5, 2008.


National Quality Forum

42

“[There is] a spectrum of evidence-based pharmacologic & psychosocial treatments … Naltrexone [shows] efficacy in treating

[alcohol dependence].”

Institute of Medicineof the National Academies

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.


43

“Integrate biological, psychosocial,and pharmacological approaches.

All are helpful and necessary.”

National Council on Alcoholismand Drug Dependence

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.


44

Alcoholics Anonymous(AA) and Use of Medication

Alcoholics Anonymous World Service, Inc. The AA Member – Medications and Other Drugs. 1984.

• Alcoholics Anonymous published a booklet for AA members (1984)

• Booklet supports appropriately prescribed medications

• Booklet is being updated to address new medications

45

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

Provides psychosocial treatment

Assesses appropriateness of medication for patient

Administers medication

46

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 Risperdal®Consta®†

* 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.47

Pharmacokinetics

• Minimal accumulation (<15%) 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.48

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

VIVITROL Prolongs Abstinence1,2

1. Garbutt JC, et al. JAMA. 2005;293:1617-1625.2. Data on file. Alkermes, Inc..

VIVITROL prolonged initial abstinenceVIVITROL prolonged initial abstinence

VIVITROL maintained 6-month abstinenceVIVITROL maintained 6-month abstinence

41%41%

17%17%

More than twice as many patients remained abstinent

More than twice as many patients remained abstinent

(n=17)

49

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.

50

Documents

1 VIVITROL ® A Brief Clinical Overview VIV 784A. 2 Presentation Overview Achieving recovery from Alcohol Dependence –Combining medication with psychosocial