CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`201655Orig1s000
`
`
`REMS
`
`
`
`
`
`

`

`Initial REMS Approval: 12/2011
`
`
`NDA 201655
`
`OPANA® ER (Oxymorphone Hydrochloride Extended-Release Tablets)
`
`
`
`Opioid Analgesic
`
`ENDO Pharmaceuticals Inc.
`100 Endo Boulevard
`Chadds Ford, PA 19317
`Telephone: (800) 462-3636
`
`RISK EVALUATION AND MITIGATION STRATEGY (REMS)
`
`
`I.
`
`GOAL(S):
`
`The goals of the OPANA ER REMS are:
`
`
`1. To inform patients and healthcare professionals about the potential for abuse, misuse,
`overdose and addiction associated with the use of OPANA ER
`
`
`
`2. To inform patients and healthcare professionals about the safe use of OPANA ER
`
`
`
`
`
`
`
`
`
`II.
`
`REMS ELEMENTS
`
`
`A. Medication Guide
`
`A Medication Guide will be dispensed with each OPANA ER prescription in accordance
`with 21 CFR 208.24.
`
`The Medication Guide is part of the REMS and is appended.
`
`
`
`B.
`
`Elements to Assure Safe Use
`
`
`1. Healthcare professionals (HCP) who prescribe OPANA ER will receive training.
`
`
`
`
`
` CONFIDENTIAL
`
`Endo Pharmaceuticals Inc.
`
`Page 1
`
`Reference ID: 3056370
`
`

`

`Initial REMS Approval: 12/2011
`
`
`
`a. Endo will ensure that training will be provided to HCPs who prescribe
`OPANA ER. Endo will ensure that each prescriber will be provided with the
`OPANA ER REMS educational material.
`
`
`b. The OPANA ER REMS training includes the following:
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3056370
`
`
`iv.
`
`
`Proper patient selection
`i.
`
`ii. Appropriate OPANA ER dosing and administration
`
`iii. General opioid use including information about opioid abuse and how to
`identify patients who are at risk for addiction
`The risks of abuse, misuse, overdose, and addiction from exposure to
`
`opioids, including OPANA ER
`
`
`v. Risks of OPANA ER, including:
`
`1. The risk of overdose caused by exposure to an essentially immediate-
`release form of oxymorphone by consuming broken, chewed, crushed
`or dissolved OPANA ER tablets
`
`2. The risk of addiction from exposure to OPANA ER
`Information to counsel patients on the need to store opioid analgesics
`
`safely out of the reach of children and household acquaintances
`
`The importance of providing each patient with a Medication Guide,
`instructing the patient to read the Medication Guide and assisting the
`patient in understanding the content.
`
`
`vi.
`
`
`vii.
`
`
`c. Endo will ensure that at least 3 weeks prior to first availability of OPANA ER
`
`to healthcare professionals, a Dear Healthcare Professional letter will be
`mailed to HCPs experienced in treating chronic pain with opioid agonists,
`including pain specialists and primary care physicians. This letter is designed
`to convey and reinforce the risks of abuse, misuse, overdose, and addiction of
`OPANA ER, as well as the need to complete the OPANA ER REMS
`prescriber training. The letter will be available on the OPANA ER REMS
`website (www.OPANAERrems.com) for 1 year from the date of mailing.
`
`
`
`d. The Dear Healthcare Professional letter mailing will include the following
`
`materials:
`
`
`i. Full Prescribing Information
`
`ii. Medication Guide
`
`iii. OPANA ER Healthcare Professional (HCP) Training Guide
`
`iv. OPANA ER REMS Education Confirmation Form
`
` CONFIDENTIAL
`
`Endo Pharmaceuticals Inc.
`
`Page 2
`
`

`

`Initial REMS Approval: 12/2011
`
`
`
`
`
`
`e. Additional copies of the printed REMS materials will be available for
`download via the OPANA ER website (www.OPANAERrems.com) or by
`calling Endo’s toll-free phone number 1-800-462-3636.
`
`f. Endo will maintain a list of all prescribers who have completed the OPANA
`ER REMS training.
`
`Prescribers will be re-trained every two years or following substantial changes to the
`OPANA ER REMS. Substantial changes may include changed to the OPANA ER Full
`Prescribing Information or to the Medication Guide that require substantial modification
`of the REMS educational materials.
`
`
`The following materials are part of the REMS and are appended:
`
`• Medication Guide
`
`
`• Dear Healthcare Professional letter
`
`
`• OPANA ER Healthcare Professional (HCP) Training Guide
`
`
`• OPANA ER REMS Website
`
`
`• OPANA ER REMS Education Confirmation Form
`
`
`
`C.
`
`Implementation System
`
`Because OPANA ER can be approved without the Elements to Assure Safe Use
`described under FDCA 505-1(f)(3)(B), (C), and (D) of the Act, an Implementation
`System is not required.
`
`
`D.
`
`Timetable for Submission of Assessments
`
`Endo will submit REMS assessments to the FDA every 6 months for the first year from
`
`the date of approval of the REMS and annually thereafter. To facilitate inclusion of as
`much information as possible while allowing reasonable time to prepare the submission,
`the reporting interval covered by each assessment will conclude no earlier than 60 days
`before the submission date for that assessment time interval. Endo will submit each
`assessment so that it will be received by the FDA before or on the due date.
`
`
`
`
`
`CONFIDENTIAL
`
`Endo Pharmaceuticals Inc.
`
`Page 3
`
`Reference ID: 3056370
`
`

`

`Initial REMS Approval: 12/2011
`
`
`DEAR HEALTHCARE PROFESSIONAL LETTER
`
`
`
`
`
`
`CONFIDENTIAL
`Endo Pharmaceuticals Inc.
`
`
`Page 12
`
`Reference ID: 3056370
`
`
`

`

`Initial REMS Approval: 12/2011
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` [COMPANY OR OPANA ER LOGO]
`
`
`[DATE]
`
`Dear Prescriber:
`
`The purpose of this communication is to notify you that a Risk Evaluation and Mitigation
`Strategy (REMS) has been instituted for OPANA® ER (oxymorphone HCl extended-
`
` release tablets). This REMS is required by the U.S Food and Drug Administration
`(FDA) to ensure that the benefits of OPANA ER outweigh the potential risks of abuse,
`misuse, overdose and addiction.
`
`OPANA ER is a Schedule II controlled substance that contains oxymorphone, an opioid
`agonist, indicated for the relief of moderate to severe pain in patients requiring
`continuous around the clock opioid treatment for an extended period of time.
`
`OPANA ER is NOT intended for use as “prn” (as needed) analgesic. OPANA ER is not
`indicated for treating acute or postoperative pain, mild pain, or pain that is not expected
`to persist for an extended period of time. Physicians should individualize treatment,
`moving from parenteral to oral analgesics as appropriate.
`
`OPANA ER is contraindicated in patients who have:
`
`• known hypersensitivity to any of its components or the active ingredient,
`
`oxymorphone or with known hypersensitivity to morphine analogs such as
`
`codeine
`
`
`• significant respiratory depression
`
`• acute or severe bronchial asthma, or hypercarbia (in unmonitored settings, or the
`absence of resuscitative equipment)
`
`
`• or are suspected of having paralytic ileus
`
`
`• moderate and severe hepatic impairment
`
`
`Endo Pharmaceuticals has developed an FDA approved OPANA ER REMS educational
`program. The educational program components include Prescribing Information, the
`Medication Guide, and a Healthcare Professional Training Guide.
`
`It is important that you read and understand the content of the educational material prior
`to prescribing OPANA ER. These materials are enclosed and are available online at
`www.OPANAERrems.com.
`
`
`
`
`
`CONFIDENTIAL
`Endo Pharmaceuticals Inc.
`
`
`Page 13
`
`Reference ID: 3056370
`
`

`

`Initial REMS Approval: 12/2011
`
`
`
`Also enclosed is an Education Confirmation Form. Please fill out the form to confirm
`that you have read the REMS Education Materials for OPANA ER and understand
`the major risks associated with OPANA ER and how to appropriately select and
`educate patients to whom OPANA ER is prescribed. Please answer the questions
`to verify your understanding of the information contained in the REMS Education
`Materials for OPANA ER. Completion of the questions in the form does not affect your
`ability to prescribe OPANA ER. You may also complete the form online at
`www.OPANAERrems.com or via fax at 1-877-637-2039.
`
`It is also important that you discuss the risks of OPANA ER with your patients and their
`caregivers. Encourage them to read the Medication Guide (see enclosed copy) that
`provides important information on the safe and effective use of OPANA ER. The
`Medication Guide will be provided to patients with each prescription.
`Additional copies of the Medication Guide are available by download from
`www.OPANAERrems.com or by contacting our Call Center at 1-800-462-3636.
`Please report all suspected adverse events associated with the use of
`OPANA ER to 1-800-462-3636.
`Adverse event information may also be reported to the FDA MedWatch
`Reporting System by phone at 1-800-FDA-1088 (1-800-332-1088) or by
`mail using Form 3500 at
`www.fda.gov/medwatch.
`
`Refer to the full Prescribing Information, with the boxed warning, for detailed safety
`information for OPANA ER. Educational information on OPANA ER is available at
`
` www.OPANAERrems.com.
`
`Sincerely,
`[NAME]
`[TITLE]
`
`Enclosures:
`OPANA ER Medication Guide
`OPANA ER Prescribing Information
`
`
`
`
`
`
` CONFIDENTIAL
`
`Endo Pharmaceuticals Inc.
`
`
`
` Page 14
`
`Reference ID: 3056370
`
`

`

`Initial REMS Approval: 12/2011
`
`
`OPANA ER Healthcare Professional Training Guide
`OPANA ER Education Confirmation Form
`
`This letter was approved by the Food and Drug Administration as part of the OPANA
`
`ER REMS.
`
`
`
`
`
`
`
`CONFIDENTIAL
`
`Endo Pharmaceuticals Inc.
`
`Page 15
`
`
`Reference ID: 3056370
`
`

`

`Initial REMS Approval: 12/2011
`
`OPANA ER HEALTHCARE PROFESSIONAL (HCP) TRAINING GUIDE
`
`
`
`
`
`CONFIDENTIAL
`
`Endo Pharmaceuticals Inc.
`
`
`Page 16
`
`
`
`Reference ID: 3056370
`
`
`

`

`Initial REMS Approval: 12/2011
`
`
`HEALTHCARE PROFESSIONAL TRAINING GUIDE
`
`
`
`
`Cover
`(HEADLINE)
`
`
`
`
`Healthcare Professional Training Guide
`(Subhead)
`[COMPANY OR OPANA ER LOGO]
`
`
`
`PRESCRIBING OPANA® ER - CII
`
`
`
`
`
`
`CONFIDENTIAL
`
`Endo Pharmaceuticals Inc.
`
`Page 17
`
`
`Reference ID: 3056370
`
`

`

`Initial REMS Approval: 12/2011
`
`
`
`Page 2
`(HEADLINE)
`
`(Box
`
`Warning)
`
`
`
`IMPORTANT SAFETY INFORMATION
`
`
`
`POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER
`WARNING:
`
`PATIENT SELECTION AND LIMITATIONS OF USE
`
`
`
`Potential for Abuse
`
`OPANA® ER contains oxymorphone, which is a morphine-like opioid
`
`agonist and a Schedule II controlled substance, with an abuse liability
`
`similar to other opioid analgesics.
`
`Oxymorphone can be abused in a manner similar to other opioid agonists,
`legal or illicit. This should be considered when prescribing or dispensing
`OPANA® ER in situations where the physician or pharmacist is concerned
`
`
`about an increased risk of misuse, abuse, or diversion.
`
`
`Proper Patient Selection
`
`OPANA® ER is an extended-release oral formulation of oxymorphone
`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.
`
`
`Limitations of Use
`
`OPANA® ER is NOT intended for use as an as needed analgesic.
`
`OPANA® ER tablets are to be swallowed whole and are not to be cut,
`
`broken, chewed, dissolved, or crushed. Taking cut, broken, chewed,
`dissolved, or crushed OPANA® ER tablets leads to rapid release and
`absorption of a potentially fatal dose of oxymorphone.
`
`Patients must not consume alcoholic beverages, or prescription or non­
`prescription medications containing alcohol, while on OPANA® ER therapy.
`
`The co-ingestion of alcohol with OPANA® ER may result in increased
`
`plasma levels and a potentially fatal overdose of oxymorphone.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3056370
`
`
`CONFIDENTIAL
`Endo Pharmaceuticals Inc.
`
`
`Page 18
`
`

`

`Initial REMS Approval: 12/2011
`
`
`
`
`
`
`Page 3
`
`
`(HEADLINE)
`
`(Copy)
`
`
`
`INTRODUCTION
`
`This Risk Evaluation and Mitigation Strategy (REMS) has been created to
`educate prescribers, patients, and caregivers about the potential risks associated
`with OPANA ER, which are reflected in the goals of the REMS.
`
`1:
`
`
`2:
`
`To inform patients and healthcare professionals about the
`potential for abuse, misuse, overdose and addiction associated
`with the use of OPANA ER.
`
`To inform patients and healthcare professionals about the safe
`use of OPANA ER.
`
`The purpose of this training guide is to provide prescribers with important safety
`information about OPANA ER so they can prescribe and counsel patients
`appropriately about the potential risks of OPANA ER abuse, misuse, overdose
`and addiction. Refer to the full Prescribing Information for complete safety
`information for OPANA ER.
`
`
`You should individualize treatment in every case using a progressive plan of pain
`
`management such as that outlined by the World Health Organization, the
`Federation of State Medical Boards Model Policy, and the American Pain
`Society. Healthcare providers should follow appropriate pain management
`principles of careful assessment and ongoing monitoring.
`
`In addition, patients and their caregivers must be told to carefully read the
`OPANA® ER Medication Guide. This Medication Guide contains important
`information to ensure the safe and appropriate use of OPANA ER, and to help
`prevent abuse, misuse, addiction and overdose.
`
`Finally, it is critical that you counsel patients and their caregivers about the need
`to store OPANA ER out of the reach of children, household visitors and pets, in a
`safe and secure place. This will help reduce the risk of an accidental overdose,
`which may result in death.
`
`
`
`Following your review of the enclosed information, please complete and
`
`return to Endo Pharmaceuticals the Education Confirmation Form to verify
`
`your understanding of the information contained in the REMS Education
`Materials. The REMS materials and Education Confirmation Form can be
`obtained online at www.OPANAERrems.com or by calling 1-800-462-3636.
`Completion of the form and questions does not affect your ability to prescribe
`OPANA ER.
`
`
`CONFIDENTIAL
`
`Endo Pharmaceuticals Inc.
`
`Page 19
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3056370
`
`

`

`Initial REMS Approval: 12/2011
`
`
`Page 4
`
`(HEADLINE)
`
`(Copy)
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`
`Risks of Overdose
`
`Risk of Respiratory Depression
`
`Interaction with Alcohol and other CNS Depressants
`
`Additional Side Effects
`
`Risks of Abuse, Misuse, and Addiction
`
`Addictive Disorder vs. Physical Dependence
`
`Screening for Patients at Risk for Opioid Abuse or Addiction
`
`Proper Patient Selection
`
`Appropriate Dosing and Administration
`
`
`
`Starting Therapy
`
`Individualizing Dosage
`
`Continuing Therapy
`
`Stopping Therapy
`
`What You Need To Tell Patients about OPANA® ER
`
`References
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`CONFIDENTIAL
`Endo Pharmaceuticals Inc.
`
`
`Page 20
`
`Reference ID: 3056370
`
`

`

`Initial REMS Approval: 12/2011
`
`
`Page 5
`
`(HEADLINE)
`(Copy)
`
`
`
`(Subhead)
`
`
`
`
`(Subhead)
`
`
`(Copy)
`
`
`
`
`
`(Subhead)
`
` (Copy)
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3056370
`
`RISKS OF OVERDOSE WITH OPANA® ER
`
`Instruct patients against the use by individuals other than the patient for whom
`you have prescribed OPANA ER, as such inappropriate use may have severe
`
`medical consequences, including death.
`
`Following is important information about overdose risks with OPANA ER. Refer
`to the full Prescribing Information for complete information about OPANA ER
`overdose.
`
`
`Risk of Overdose from Intact Tablets
`
`Any person who has not developed tolerance to the respiratory depressant or
`sedating effects of OPANA ER is at risk for overdose from exposure to
`inappropriate doses of OPANA ER, especially with concomitant exposure to
`drugs that depress respiratory drive or consciousness, whether there is a
`
`legitimate need for an analgesic or not.
`
`
`Risk of Overdose from Alteration of Tablets
`
`
`OPANA ER tablets must be swallowed whole and must not be cut, broken,
`
`
`chewed, dissolved, or crushed. Taking cut, broken, chewed, dissolved, or
`crushed OPANA ER tablets leads to rapid release and absorption of a
`potentially fatal dose of oxymorphone.
`
`The risk of a fatal overdose is even greater when OPANA ER is abused together
`with alcohol, prescription and non-prescription medications containing alcohol,
`
`including other opioids, and other CNS depressants. The co-ingestion of alcohol
`with OPANA ER may result in increased plasma levels and potentially fatal
`
`overdose of oxymorphone.
`
`Risk of Overdose from Higher Doses
`
`
`
`
`Patients can overdose by taking just one dose of OPANA ER.
`
`Acute overdosage with OPANA ER is characterized by respiratory depression (a
`
`decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration,
`cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle
`flaccidity, cold and clammy skin, constricted pupils and sometimes bradycardia
`
`and hypotension. In some cases, apnea, circulatory collapse, cardiac arrest and
`
`death may occur.
`
`OPANA ER may cause miosis, even in total darkness. Pinpoint pupils are a sign
`
`of opioid overdose but are not pathognomonic (e.g., pontine lesions of
`hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis
`rather than miosis may be seen with hypoxia in overdose situations
`
`
`CONFIDENTIAL
`
`Endo Pharmaceuticals Inc.
`
`Page 21
`
`
`
`

`

`Initial REMS Approval: 12/2011
`
`Page 6
`
`
`(HEADLINE)
`
`(Copy)
`
`Risk of Respiratory Depression
`
`
`Respiratory depression is the chief hazard associated with OPANA ER and can
`
`result in death.
`
`Respiratory depression is a potential problem in elderly or debilitated patients as
`well as in those suffering from conditions accompanied by hypoxia or
`hypercapnia when even moderate therapeutic doses may dangerously decrease
`pulmonary ventilation.
`
`Administer OPANA ER with extreme caution to patients with conditions
`accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such
`as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe
`obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression or
`coma. In these patients, even usual therapeutic doses of oxymorphone may
`decrease respiratory drive while simultaneously increasing airway resistance to
`the point of apnea. Consider alternative non-opioid analgesics and use OPANA
`ER only under careful medical supervision at the lowest effective dose in such
`patients.
`
`Interactions with Alcohol and other CNS Depressants
`
`
`Patients receiving other opioid analgesics, general anesthetics, phenothiazines
`
`or other tranquilizers, sedatives, hypnotics, or other CNS depressants (including
`
`alcohol) concomitantly with oxymorphone may experience respiratory
`depression, hypotension, profound sedation, coma and death. Avoid concurrent
`use of alcohol and OPANA ER.
`
`ADDITIONAL SIDE EFFECTS
`
`
`Adverse reactions reported in placebo-controlled clinical trials with incidence >=
`2% receiving oxymorphone hydrochloride extended-release tablets include
`nausea, constipation, dizziness, somnolence, vomiting, pruritus, headache,
`sweating, increased dry mouth, sedation, diarrhea, insomnia, fatigue, appetite
`decreased and abdominal pain.
`
`The common (>=1% to <10%) adverse drug reactions reported at least once by
`patients treated with oxymorphone hydrochloride extended-release tablets in the
`clinical trials include eye disorders, gastrointestinal disorders, general disorders
`and administration site conditions, nervous system disorders, psychiatric
`disorders, respiratory, thoracic and mediastinal disorders and vascular disorders.
`
`Refer to the full Prescribing Information, Warnings and Precautions and Adverse
`
`Reactions sections for a comprehensive list of adverse events for oxymorphone
`
`
`hydrochloride extended-release tablets.
`
`
`CONFIDENTIAL
`
`Endo Pharmaceuticals Inc.
`
`Page 22
`
`
`
`
`
`Page 7
`
`
`(HEADLINE)
`
`(Copy)
`
`
`
`Page 8
`
`(HEADLINE)
`
`(Copy)
`
`
`
`
`
`
`
`Reference ID: 3056370
`
`

`

`Initial REMS Approval: 12/2011
`
`
`
`
`Page 9
`
`(HEADLINE)
`
`(Subhead)
`
`(Copy)
`
`
`RISKS OF ABUSE, MISUSE, AND ADDICTION
`
`
`
`
`OPANA ER has an Abuse Liability Similar to Morphine
`
`OPANA ER contains oxymorphone, a mu agonist and a Schedule II controlled
`substance with an abuse liability similar to morphine and other opioids.
`
`Oxymorphone can be abused and is subject to criminal diversion.
`
`
`All patients treated with OPANA ER and other opioids require careful monitoring
`
`for signs of abuse and addiction, since use of opioid analgesic products carries
`
`the risk of addiction even under appropriate medical use. Addiction is a primary,
`chronic, neurobiologic disease, with genetic, psychosocial, and environmental
`factors influencing its development and manifestations. Addiction is characterized
`by one or more of the following: impaired control over drug use, compulsive use,
`use for non-medical purposes, and continued use despite harm. Drug addiction is
`a treatable disease, utilizing a multidisciplinary approach, but relapse is common.
`
`"Drug seeking" behavior is very common to addicts and drug abusers. Drug-
`seeking tactics include emergency calls or visits near the end of office hours,
`
`refusal to undergo appropriate examination, testing or referral, repeated claims of
`loss of prescriptions, tampering with prescriptions and reluctance to provide prior
`medical records or contact information for other treating physician(s). “Doctor
`shopping” (visiting multiple prescribers) to obtain additional prescriptions is
`common among drug abusers and people suffering from untreated addiction.
`Preoccupation with achieving adequate pain relief can be appropriate behavior in
`a patient with poor pain control.
`
`OPANA ER is intended for oral use only. Abuse of OPANA ER poses a risk of
`overdose and death. This risk is increased with concurrent abuse of OPANA ER
`with alcohol and other substances. Parenteral drug abuse is commonly
`associated with transmission of infectious disease such as hepatitis and HIV.
`
`Proper assessment of the patient, proper prescribing practices, periodic re-
`evaluation of therapy, and proper dispensing and storage are appropriate
`measures that help to limit abuse of opioid drugs.
`
`
`Addiction to OPANA ER is Possible
`
`There is a potential for drug addiction to develop following exposure to OPANA
`
`ER, even during appropriate medical use.
`
`People who have abused prescription medications in the past may have a higher
`
`chance of abusing or developing addiction again when treated with OPANA ER.
`
`
`Behaviors that suggest drug abuse exist on a continuum, and pain-relief seeking
`behavior can be mistaken for drug-seeking behavior. All patients treated with
`
`OPANA ER require careful monitoring for signs of addiction and drug abuse.
`
`
`CONFIDENTIAL
`Endo Pharmaceuticals Inc.
`
`
`Page 23
`
`
`
`(Subhead)
`
`(Copy)
`
`
`
`
`
`
`
`
`Reference ID: 3056370
`
`

`

`Initial REMS Approval: 12/2011
`
`
`
`Page 10
`
`(HEADLINE)
`
`(Copy)
`
`ADDICTIVE DISORDER VS. PHYSICAL DEPENDENCE
`
`
`It is important to differentiate between a person with an addiction disorder and a
`patient with pain who is adherent to therapy and has developed a physical
`
`dependence on opioid analgesic medications.
`
`
`(Subhead)
`
`
`
`
`
`
`
`
`
`
`(Subhead)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3056370
`
`Patients With Addiction Disorders:1
`
`• Suffer from a chronic, neurobiologic disease with genetic, psychosocial,
`
`and environmental components
`
`• Seek a drug in order to quickly affect the “reward center” of their brains
`
`
`• Crave drugs and use them compulsively
`
`
`
`• Continue abuse despite negative, even life-threatening, physical, mental,
`
`and/or social consequences
`
`
`• These persons often develop physical dependence to the substances
`
`they are abusing and are, therefore, at risk for signs and symptoms of
`withdrawal syndrome upon exposure to an antagonist (in the case of
`physical dependence on an opioid or benzodiazepine), significant
`reduction in dose or abrupt cessation of administration of the drug
`
`
`Patients With Physical Dependence Who Do Not Have an Addiction Disorder:1
`
`• Experience a normal response to the ongoing use of certain medicines,
`
`including opioids
`
`• Want sufficient medicine to reach opioid receptors to induce analgesia
`
`
`• Take medicines to relieve pain—not to satisfy a craving for a psychic
`
`effect or to stave off withdrawal syndrome
`
`• Can generally discontinue their medicine with mild to no withdrawal
`
`
`syndrome once their symptoms are gone by gradually tapering the
`
`dosage according to their doctor’s orders
`
`
`
`
`
`
`CONFIDENTIAL
`Endo Pharmaceuticals Inc.
`
`
`Page 24
`
`
`

`

`Initial REMS Approval: 12/2011
`
`
`
`Pages 11
`(HEADLINE)
`
`(Copy)
`
`SCREENING FOR PATIENTS AT RISK FOR OPIOID ABUSE OR ADDICTION
`
`
`Patients should be assessed for their clinical risks for opioid abuse or addiction
`prior to being prescribed an opioid, and all patients receiving opioids should be
`routinely monitored for signs of misuse, abuse and addiction.
`
`
` Patient/Family History
`
`Persons at increased risk for opioid abuse include those with a personal or family
`
`history of substance use disorder (including drug or alcohol abuse or addiction)
`or mental illness (eg, major depression).
`
`
`
`Participation or recommended participation in drug abuse treatment programs
`should be determined. Patients who have undergone opioid detoxification in the
`past are at higher risk for re-emergence of substance use disorders.
`
`
`
`
`Screening Tests and Physical Appearance
`
`Many drug abuse screening tests have been developed for use in clinical
`practice, including the CAGE and CAGE-AID Questionnaire, the Addiction
`Behaviors Checklist, the Opioid Risk Tool, The Brief MAST, and the Two-Item
`Conjoint Screening (TICS) for Alcohol & Other Drug Problems.2,3
`
`
`Physical screening may reveal signs of possible drug abuse. Initial screening
`clues may include unkempt appearance, ill-fitting clothes suggestive of weight
`loss/gain, sniffles, watery eyes, cough, nausea; lethargy, drowsiness, and
`nodding. Careful examination of skin may reveal marks caused by repeated
`injections.4
`
`
`While these signs might suggest abuse, they should not be the only criteria for
`determining whether opioid abuse has occurred.
`
`CONFIDENTIAL
`
`Endo Pharmaceuticals Inc.
`
`Page 25
`
`
`
`(Subhead)
`
`(Copy)
`
`
`
`
`
`(Subhead)
`
`(Copy)
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3056370
`
`

`

`Initial REMS Approval: 12/2011
`
`
`(Subhead)
`
`(Copy)
`
`
`
`
` Laboratory Tests
`
`
`
`
`
`
`
`
`Laboratory signs that may suggest substance abuse include elevated mean
`corpuscular volume (MCV) and abnormal liver enzymes.2,3
`
`Urine drug testing may yield unexpected results. The use of this technology
`
`requires understanding of specificity and sensitivity of the particular analytic
`method employed. Some point-of-care urine tests for “opioids” or “opiates” do
`not, for example, detect semisynthetic or synthetic opioid analgesics.2,5
`
`
`All laboratory markers are nonspecific for alcohol or drug use and should be
`
`viewed as screens, not as diagnostic criteria.
`
`(Subhead)
`
`
`
`
` Other Signs
`
`(Copy)
`
`
`
`Page 12
`
`(HEADLINE)
`
`
`(Subhead)
`
`(Copy)
`
`
`
`
`
`
`
`
`
`
`Signs of compulsive drug use include covertly obtaining prescription medications
`from more than one physician, referred to as “Doctor Shopping,” concurrent
`abuse of related illicit drugs, altering or forging prescriptions, and repeated
`unsanctioned dose escalations despite warnings.
`
`Other signs of compulsive drug use may be more subtle, including frequent visits
`to emergency rooms, and hoarding of drugs obtained from routine prescriptions.
`
`
`SCREENING FOR PATIENTS AT RISK FOR OPIOID ABUSE OR ADDICTION
`(CONT’D)
`
`
`
`When You Suspect Addiction or Drug Abuse
`
`Following are some suggestions about what to do if you suspect a patient is
`addicted to, or abusing OPANA ER:6
`
`
`
`• Remember, a person abusing drugs or affected by addictive disorder is
`in need of treatment for that disorder and any concomitant medical or
`mental conditions they have, although self-administered opioid
`analgesics may not be indicated
`
`
`• Refer the patient to an addiction specialist or substance use treatment
`center, if warranted
`
`If you are not the primary care physician, always consult a patient’s
`regular physician before initiating treatment with an opioid analgesic
`
`
`•
`
`
`• Contact authorities if you are threatened in any way
`
`
`CONFIDENTIAL
`Endo Pharmaceuticals Inc.
`
`
`Page 26
`
`Reference ID: 3056370
`
`

`

`Initial REMS Approval: 12/2011
`
`
`
`Pages 13
`(HEADLINE)
`
`(Bold Copy)
`
`PROPER PATIENT SELECTION
`
`
`Careful patient selection is key to initiating the appropriate use of OPANA
`ER. The decision to use this opioid must balance the potential benefits
`with the risks of OPANA ER treatment. The following points should be
`reviewed when considering treatment for your patients.
`
`
`Who May Be Appropriate for Treatment with OPANA ER
`
`OPANA ER is indicated for the management of moderate to severe pain when a
`continuous, around-the-clock analgesic is needed for an extended period of time.
`
`As used here, “moderate to severe” pain does not include commonplace and
`
`ordinary aches and pains, pulled muscles, cramps, sprains, or similar discomfort.
`OPANA ER is not intended for use as an as needed analgesic.
`
`OPANA ER is not intended for use as an as-needed analgesic.
`
`OPANA ER is not indicated for pain in the immediate post-operative period if the
`pain is mild, or not expected to persist for an extended period of time.
`
`OPANA ER is only indicated for post-operative use if the patient is already
`
`receiving the drug prior to surgery or if the post-operative pain is expected to be
`moderate or severe and persist for an extended period of time. Physicians
`
`should individualize treatment, moving from parenteral to oral analgesics as
`
`appropriate. (See American Pain Society guidelines).
`
`Please see full Prescribing Information (PI) including boxed warning.
`
`PROPER PATIENT SELECTION (CONT’D)
`
`
`
`
`
`Some Patients Should Never Receive OPANA ER
`
`For some patients, the risks associated with OPANA ER therapy outweigh any
`potential benefits, and therefore, its use is contraindicated in such patient
`populations.
`
`OPANA ER is contraindicated in:
`
`
`• Patients who have significant respiratory depression
`
`
`• Patients who have or are suspected of having paralytic ileus
`
`• Patients who have acute or severe bronchial asthma, or hypercarbia
`
`• Patients with moderate and severe hepatic impairment
`
`• Patients with known hypersensitivity to any of OPANA ER’s components or
`the active ingredient, oxymophone, or with known hypersensitivity to
`morphine analogs such as codeine.
`
`The safety and effectiveness of OPANA ER has not been established in pediatric
`patients below the age of 18 years.
`
`
`CONFIDENTIAL
`Endo Pharmaceuticals Inc.
`
`
`Page 27
`
`
`(Subhead)
`
`(Copy)
`
`
`
`
`
`
`Page 14
`(HEADLINE)
`
`(Subhead)
`
`(Copy)
`
`
`
`
`
`
`
`
`
`Reference ID: 3056370
`
`
`

`

`Initial REMS Approval: 12/2011
`
`(Subhead)
`
`
`Assess for Risks of Opioid Abuse or Addiction before Starting Treatment With
`OPANA ER
`
`Patients should be assessed for risks of opioid abuse or addiction before they
`start treatment with OPANA ER. In addition to a complete medical history, a
`detailed history of alcohol and other substance use in the patient and family is
`important to establish before initiating treatment with OPANA ER.2
`
`
`(Copy)
`
`
`(Copy)
`
`
`
`
`
`
`
`
`
`Reference ID: 3056370
`
`Persons at increased risk for opioid abuse include those with a personal or family
`history of substance use disorders (including drug or alcohol abuse or addiction)
`
`or mental illness (eg, major depression).2
`
`
`Documentation and maintenance of careful prescribing and treatment records is
`
`essential for supporting the evaluation, the reason for OPANA ER prescribing,
`the overall pain management plan, and any consultations received.2
`
`Documentation should include:
`
`
`
`• Strength and quantity of the OPANA ER prescribed
`
`• Dose and frequency of administration
`
`• Timeliness of requests for another prescription
`
`Initial and ongoing assessment of patients’ pain
`•
`
`• Proper prescribing practices
`
`• Periodic reevaluation of all therapy prescribed or recommended,
`including progress toward established treatment goals.
`
`CONFIDENTIAL
`
`Endo Pharmaceuticals Inc.
`
`Page 28
`
`
`

`

`Initial REMS Approval: 12/2011
`
`
`
`Pages 15
`(HEADLINE)
`
`(Copy)
`
`
`
`APPROPRIATE DOSING AND ADMINISTRATION
`
`
`
`(Subhead)
`
`(Copy)
`
`
`
`
`Initial doses should be low, especially in patients