HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`OPANA® ER safely and effectively. See full prescribing information for
`OPANA® ER.
`OPANA® ER (oxymorphone hydrochloride) extended-release tablets,
`for oral use, CII
`Initial U.S. Approval: 1959
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-
`THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL
`INGESTION; NEONATAL OPIOID WITHDRAWAL
`SYNDROME; and INTERACTION WITH ALCOHOL
`See full prescribing information for complete boxed warning.
`(cid:120) OPANA ER exposes users to risks of addiction, abuse, and
`misuse, which can lead to overdose and death. Assess each
`patient’s risk before prescribing, and monitor regularly for
`development of these behaviors or conditions. (5.1)
`Serious life-threatening or fatal respiratory depression may
`occur. Monitor closely, especially upon initiation or following a
`dose increase. Instruct patients to swallow OPANA ER tablets
`whole to avoid exposure to a potentially fatal dose of
`oxymorphone. (5.2)
`Accidental ingestion of OPANA ER, especially in children, can
`result in fatal overdose of oxymorphone. (5.2)
`Prolonged use of OPANA ER during pregnancy can result in
`neonatal opioid withdrawal syndrome, which may be life-
`threatening if not recognized and treated. If opioid use is
`required for a prolonged period in a pregnant woman, advise
`the patient of the risk of neonatal opioid withdrawal syndrome
`and ensure that appropriate treatment will be available (5.3).
`Instruct patients not to consume alcohol or any product
`containing alcohol while taking OPANA ER because co-
`ingestion can result in fatal plasma oxymorphone levels. (5.4)
`-------------------------------RECENT MAJOR CHANGES----------------------
`Boxed Warning
`4/2014
`Indications and Usage (1)
`4/2014
`Dosage and Administration (2)
`4/2014
`Warnings and Precautions (5)
`4/2014
`
`(cid:120)
`
`----------------------------INDICATIONS AND USAGE--------------------------
`OPANA ER is an opioid agonist indicated for the management of pain
`severe enough to require daily, around-the-clock, long-term opioid treatment
`and for which alternative treatment options are inadequate. (1)
`Limitations of Use
`(cid:120) Because of the risks of addiction, abuse, and misuse with opioids,
`even at recommended doses, and because of the greater risks of
`overdose and death with extended-release opioid formulations,
`reserve OPANA ER for use in patients for whom alternative treatment
`options (e.g., non-opioid analgesics or immediate-release opioids) are
`ineffective, not tolerated, or would be otherwise inadequate to provide
`sufficient management of pain. (1)
`(cid:120) OPANA ER is not indicated as an as-needed (prn) analgesic. (1)
`
`(cid:120) Administer on an empty stomach, at least 1 hour prior to or 2 hours
`after eating. (2.1)
`(cid:120) Do not abruptly discontinue OPANA ER in a physically dependent
`patient. (2.3, 5.13)
`(cid:120) Instruct patients to swallow OPANA ER tablets intact. (2.4)
`(cid:120) Reduce the dose of OPANA ER in patients with mild hepatic
`impairment and patients with renal impairment. (2.5, 2.6)
`
`---------------------DOSAGE FORMS AND STRENGTHS-------------------
`Extended-release tablets: 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, and
`40 mg
`------------------------------CONTRAINDICATIONS---------------------------
`(cid:120) Significant respiratory depression (4)
`(cid:120) Acute or severe bronchial asthma (4)
`(cid:120) Known or suspected paralytic ileus (4)
`(cid:120) Hypersensitivity to oxymorphone (4)
`(cid:120) Moderate or severe hepatic impairment (4)
`
`------------------------WARNINGS AND PRECAUTIONS--------------------
`See Boxed WARNINGS
`
`(cid:120) Interaction with CNS depressants: Concomitant use may cause profound
`sedation, respiratory depression, and death. If coadministration is
`required, consider dose reduction of one or both drugs because of
`additive pharmacological effects. (5.4, 7.2)
`(cid:120) Elderly, cachectic, and debilitated patients and those with chronic
`pulmonary disease: Monitor closely because of increased risk for life-
`threatening respiratory depression. (5.5, 5.6)
`(cid:120) Hypotensive effect: Monitor during dose initiation and titration. (5.8)
`(cid:120) Patients with head injury or increased intracranial pressure: Monitor for
`sedation and respiratory depression. Avoid use of OPANA ER in
`patients with impaired consciousness or coma susceptible to intracranial
`effects of CO2 retention. (5.9)
`
`-----------------------------ADVERSE REACTIONS-----------------------------
`(cid:36)(cid:71)(cid:89)(cid:72)(cid:85)(cid:86)(cid:72)(cid:3)(cid:85)(cid:72)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:76)(cid:81)(cid:3)(cid:149)(cid:21)(cid:8)(cid:3)(cid:82)(cid:73)(cid:3)(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86)(cid:3)(cid:76)(cid:81)(cid:3)(cid:83)(cid:79)(cid:68)(cid:70)(cid:72)(cid:69)(cid:82)-controlled trials: nausea,
`constipation, dizziness, somnolence, vomiting, pruritus, headache, sweating
`increased, dry mouth, sedation, diarrhea, insomnia, fatigue, appetite
`decreased, and abdominal pain. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Endo
`Pharmaceuticals Inc. at 1-800-462-3636 or FDA at 1-800 FDA-1088 or
`www.fda.gov/medwatch.
`------------------------------DRUG INTERACTIONS----------------------------
`(cid:120) Mixed agonist/antagonist and partial agonist opioid analgesics: Avoid
`use with OPANA ER because they may reduce analgesic effect of
`OPANA ER or precipitate withdrawal symptoms. (7.3)
`
`------------------------USE IN SPECIFIC POPULATIONS--------------------
`(cid:120) Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`(cid:120) Nursing mothers: Closely monitor infants of nursing women receiving
`OPANA ER. (8.3)
`
`---------------------DOSAGE AND ADMINISTRATION--------------------
`(cid:120) For opioid-naïve and opioid non-tolerant patients, initiate with 5 mg
`tablets orally every 12 hours. (2.1)
`(cid:120) To convert to OPANA ER from another opioid, use available conversion
`factors to obtain estimated dose. (2.1)
`(cid:120) Dose can be increased every 3 to 7 days, using increments of 5 to 10 mg
`every 12 hours (i.e., 10 to 20 mg per day). (2.2)
`________________________________________________________________________________________________________________________________________
`
`See 17 for PATIENT COUNSELING INFORMATION and
`Medication Guide
`
`Revised: 04/2014
`
`Reference ID: 3490223
`
`1
`
`1
`
`ENDO - Ex. 2086
`Amneal v. Endo
`IPR2014-00360
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-
`THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL
`INGESTION; NEONATAL OPIOID WITHDRAWAL
`SYNDROME; and INTERACTION WITH ALCOHOL
`
`7
`
`8
`
`9
`
`6.2 Post-marketing Experience
`DRUG INTERACTIONS
`7.1 Alcohol
`7.2 CNS Depressants
`7.3 Mixed Agonist/Antagonist and partial Agonist Opioid
`Analgesics
`7.4 Muscle Relaxants
`7.5 Cimetidine
`7.6 Anticholinergics
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Labor and Delivery
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`8.7 Renal Impairment
`DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.2 Abuse
`9.3 Dependence
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`Boxed Warning
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Initial Dosing
`2.2 Titration and Maintenance of Therapy
`2.3 Discontinuation of OPANA ER
`2.4 Administration of OPANA ER
`2.5 Patients with Hepatic Impairment
`2.6 Patients with Renal Impairment
`2.7 Geriatric Patients
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Addiction, Abuse, and Misuse
`5.2 Life Threatening Respiratory Depression
`5.3 Neonatal Opioid Withdrawal Syndrome
`5.4
`Interaction with Central Nervous System Depressants
`5.5 Use in Elderly, Cachectic, and Debilitated Patients
`5.6 Use in Patients with Chronic Pulmonary Disease
`5.7 Use in Patients with Hepatic Impairment
`5.8 Hypotensive Effect
`5.9 Use in Patients with Head Injury or Increased Intracranial
`Pressure
`5.10 Use in Patients with Gastrointestinal Conditions
`5.11 Use in Patients with Convulsive or Seizure Disorders
`5.12 Avoidance of Withdrawal
`5.13 Driving and Operating Machinery
`ADVERSE REACTIONS
`6.1 Clinical Trial Experience
`_________________________________________________________________________________________________________________________________
`
`6
`
`*Sections or subsections omitted from the full prescribing
`information are not listed.
`
`Reference ID: 3490223
`
`2
`
`

`

`FULL PRESCRIBING INFORMATION
`
`WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION;
`ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and
`INTERACTION WITH ALCOHOL
`
`Addiction, Abuse, and Misuse
`OPANA ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to
`overdose and death. Assess each patient’s risk prior to prescribing OPANA ER, and monitor all patients regularly
`for the development of these behaviors or conditions [see Warnings and Precautions (5.1)].
`
`Life-threatening Respiratory Depression
`Serious, life-threatening, or fatal respiratory depression may occur with use of OPANA ER. Monitor for respiratory
`depression, especially during initiation of OPANA ER or following a dose increase. Instruct patients to swallow
`OPANA ER tablets whole; crushing, chewing, or dissolving OPANA ER tablets can cause rapid release and
`absorption of a potentially fatal dose of oxymorphone [see Warnings and Precautions (5.2)].
`
`Accidental Ingestion
`Accidental ingestion of even one dose of OPANA ER, especially by children, can result in a fatal overdose of
`oxymorphone [see Warnings and Precautions (5.2)].
`
`Neonatal Opioid Withdrawal Syndrome
`Prolonged use of OPANA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be
`life-threatening if not recognized and treated, and requires management according to protocols developed by
`neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the
`risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings
`and Precautions (5.3)].
`
`Interaction with Alcohol
`Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain
`alcohol while taking OPANA ER. The co-ingestion of alcohol with OPANA ER may result in increased plasma levels
`and a potentially fatal overdose of oxymorphone [see Warnings and Precautions (5.4)].
`
`INDICATIONS AND USAGE
`1
`OPANA ER is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and
`for which alternative treatment options are inadequate.
`
`Limitations of Usage
`(cid:120) Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks
`of overdose and death with extended-release opioid formulations, reserve OPANA ER for use in patients for whom alternative
`treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be
`otherwise inadequate to provide sufficient management of pain.
`(cid:120) OPANA ER is not indicated as an as-needed (prn) analgesic.
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Initial Dosing
`To avoid medication errors, prescribers and pharmacists must be aware that oxymorphone is available as both immediate-release 5 mg
`and 10 mg tablets and extended-release 5 mg and 10 mg tablets [see Dosage Forms and Strengths].
`
`OPANA ER should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the
`management of chronic pain.
`
`Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk
`factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression,
`especially within the first 24-72 hours of initiating therapy with OPANA ER [see Warnings and Precautions (5.2)].
`
`OPANA ER tablets must be taken whole, one tablet at a time, with enough water to ensure complete swallowing immediately after
`placing in the mouth [see Patient Counseling Information (17)]. Crushing, chewing, or dissolving OPANA ER tablets will result in
`uncontrolled delivery of oxymorphone and can lead to overdose or death [see Warnings and Precautions (5.2)].
`
`OPANA ER is administered at a frequency of twice daily (every 12 hours). Administer on an empty stomach, at least 1 hour prior to
`or 2 hours after eating.
`
`Reference ID: 3490223
`
`3
`
`

`

`Use of OPANA ER as the First Opioid Analgesic
`Initiate treatment with OPANA ER with the 5 mg tablet orally every 12-hours.
`
`Use of OPANA ER in Patients who are not Opioid Tolerant
`The starting dose for patients who are not opioid tolerant is OPANA ER 5 mg orally every 12 hours. Patients who are opioid tolerant
`are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral
`oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid.
`
`Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.
`
`Conversion from OPANA to OPANA ER
`Patients receiving OPANA may be converted to OPANA ER by administering half the patient's total daily oral OPANA dose as
`OPANA ER, every 12 hours.
`
`Conversion from Parenteral Oxymorphone to OPANA ER
`The absolute oral bioavailability of OPANA ER is approximately 10%. Convert patients receiving parenteral oxymorphone to
`OPANA ER by administering 10 times the patient's total daily parenteral oxymorphone dose as OPANA ER in two equally divided
`doses (e.g., [IV dose x 10] divided by 2). Due to patient variability with regards to opioid analgesic response, upon conversion
`monitor patients closely to evaluate for adequate analgesia and side effects.
`
`Conversion from Other Oral Opioids to OPANA ER
`Discontinue all other around-the-clock opioid drugs when OPANA ER therapy is initiated.
`
`While there are useful tables of opioid equivalents readily available, there is substantial inter- patient variability in the relative potency
`of different opioid drugs and products. As such, it is preferable to underestimate a patient’s 24-hour oral oxymorphone requirements
`and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral oxymorphone requirements
`which could result in adverse reactions. In an OPANA ER clinical trial with an open-label titration period, patients were converted
`from their prior opioid to OPANA ER using Table 1 as a guide for the initial OPANA ER dose.
`Consider the following when using the information in Table 1:
`(cid:120) This is not a table of equianalgesic doses.
`(cid:120) The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to OPANA ER.
`(cid:120) This table cannot be used to convert from OPANA ER to another opioid. Doing so will result in an over-estimation of the dose
`of the new opioid and may result in fatal overdose.
`
`CONVERSION FACTORS TO OPANA ER
`Prior Oral Opioid
`Approximate Oral
`Conversion Factor
`1
`0.5
`0.5
`0.5
`0.333
`
`Oxymorphone
`Hydrocodone
`Oxycodone
`Methadone
`Morphine
`
`To calculate the estimated OPANA ER dose using Table 1:
`
`(cid:120) For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the
`conversion factor to calculate the approximate oral (active opioid) daily dose.
`(cid:120) For patients on a regimen of more than one opioid, calculate the approximate oral (active opioid) dose for each opioid and sum
`the totals to obtain the approximate total (active opioid) daily dose.
`(cid:120) For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in
`the conversion
`
`Always round the dose down, if necessary, to the appropriate OPANA ER strength(s) available.
`
`Reference ID: 3490223
`
`4
`
`

`

`Example conversion from a single opioid to OPANA ER:
`
`Step 1: Sum the total daily dose of the opioid oxycodone 20 mg BID
`20 mg former opioid 2 times daily = 40 mg total daily dose of former opioid
`
`Step 2: Calculate the approximate equivalent dose of oral (active opioid) based on the total daily dose of the current opioid using
`Table 1
`40 mg total daily dose of former opioid x 0.5 mg Conversion Factor = 20 mg of oral (active opioid) daily
`
`Step 3: Calculate the approximate starting dose of OPANA ER to be given every 12 hours. Round down, if necessary, to the
`appropriate OPANA ER TABLETS strengths available.
`10 mg OPANA ER every 12 hours
`
`Conversion from Methadone to OPANA ER
`Close monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between
`methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and
`can accumulate in the plasma.
`
`2.2 Titration and Maintenance of Therapy
`Individually titrate OPANA ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate
`patients receiving OPANA ER to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as
`monitoring for the development of addiction, abuse, and misuse. Frequent communication is important among the prescriber, other
`members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including
`initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.
`
`If the level of pain increases, attempt to identify the source of increased pain, while adjusting the OPANA ER dose to decrease the
`level of pain. Because steady-state plasma concentrations are approximated within 3 days, OPANA ER dosage adjustments, preferably
`at increments of 5-10 mg every 12 hours, may be done every 3 to 7 days.
`Patients who experience breakthrough pain may require a dose increase of OPANA ER, or may need rescue medication with an
`appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source
`of increased pain before increasing OPANA ER dose.
`If unacceptable opioid-related adverse reactions are observed, the subsequent dose may be reduced. Adjust the dose to obtain an
`appropriate balance between management of pain and opioid-related adverse reactions.
`
`2.3 Discontinuation of OPANA ER
`When a patient no longer requires therapy with OPANA ER, use a gradual downward titration of the dose every two to four days, to
`prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue OPANA ER.
`2.4 Administration of OPANA ER
`Instruct patients to swallow OPANA ER tablets intact. The tablets are not to be crushed, dissolved, or chewed due to the risk of rapid
`release and absorption of a potentially fatal dose of oxymorphone [see Warnings and Precautions (5.2)]. Administer on an empty
`stomach, at least 1 hour prior to or 2 hours after eating.
`
`2.5 Patients with Hepatic Impairment
`OPANA ER is contraindicated in patients with moderate or severe hepatic impairment.
`
`In opioid-naïve patients with mild hepatic impairment, initiate treatment with the 5 mg dose. For patients on prior opioid therapy, start
`OPANA ER at 50% lower than the starting dose for a patient with normal hepatic function on prior opioids and titrate slowly.
`
`Monitor patients closely for signs of respiratory or central nervous system depression [see Warnings and Precautions (5.2), Use in
`Specific Populations (8.6) and Clinical Pharmacology (12.3)].
`
`2.6 Patients with Renal Impairment
`In patients with creatinine clearance rates less than 50 mL/min, start OPANA ER in the opioid-naïve patient with the 5 mg dose. For
`patients on prior opioid therapy, start OPANA ER at 50% lower than the starting dose for a patient with normal renal function on prior
`opioids and titrate slowly. Monitor patients closely for signs of respiratory or central nervous system depression [see Warnings and
`Precautions (5.2), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
`
`2.7 Geriatric Patients
`The steady-state plasma concentrations of oxymorphone are approximately 40% higher in elderly subjects than in young subjects.
`Initiate dosing with OPANA ER in patients 65 years of age and over using the 5 mg dose and monitor closely for signs of respiratory
`and central nervous system depression when initiating and titrating OPANA ER to adequate analgesia [see Warnings and Precautions
`
`Reference ID: 3490223
`
`5
`
`

`

`(5.2), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. For patients on prior opioid therapy, start OPANA ER at
`50% lower than the starting dose for a younger patient on prior opioids and titrate slowly.
`
`3 DOSAGE FORMS AND STRENGTHS
`The 5 mg dosage form is a pink, octagon shape, film coated, convex extended-release tablets debossed with “5” on one side and plain
`on the other.
`
`The 7.5 mg dosage form is a gray, octagon shape, film coated, convex extended-release tablets debossed with “7 ½” on one side and
`plain on the other.
`
`The 10 mg dosage form is a light orange, octagon shape, film coated, convex extended-release tablets debossed with “10” on one side
`and plain on the other.
`
`The 15 mg dosage form is a white, octagon shape, film coated, convex extended-release tablets debossed with “15” on one side and
`plain on the other.
`
`The 20 mg dosage form is a light green, octagon shape, film coated, convex extended-release tablets debossed with “20” on one side
`and plain on the other.
`
`The 30 mg dosage form is a red, octagon shape, film coated, convex extended-release tablets debossed with “30” on one side and plain
`on the other.
`
`The 40 mg dosage form is a yellow, octagon shape, film coated, convex extended-release tablets debossed with “40” on one side and
`plain on the other.
`
`4 CONTRAINDICATIONS
`OPANA ER is contraindicated in patients with:
`
`Significant respiratory depression
`(cid:131)
`(cid:131) Acute or severe bronchial asthma or hypercarbia
`(cid:131) Known or suspected paralytic ileus
`(cid:131) Moderate and severe hepatic impairment [see Clinical Pharmacology (12.3), Warnings and Precautions (5.7)].
`(cid:131) Hypersensitivity (e.g. anaphylaxis) to oxymorphone, any other ingredients in OPANA ER, or to morphine analogs such as
`codeine [see Adverse Reactions (6.1)].
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Addiction, Abuse, and Misuse
`OPANA ER contains oxymorphone, a Schedule II controlled substance. As an opioid, OPANA ER exposes users to the risks of
`addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. As modified-release products such as OPANA ER deliver the
`opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of oxymorphone
`present.
`
`Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OPANA ER and in those
`who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.
`
`Assess each patient’s risk for opioid abuse or addiction, abuse, or misuse prior to prescribing OPANA ER, and monitor all patients
`receiving OPANA ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family
`history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for
`these risks should not, however, prevent the prescribing of OPANA ER for the proper management of pain in any given patient.
`Patients at increased risk may be prescribed modified-release opioid formulations such as OPANA ER, but use in such patients
`necessitates intensive counseling about the risks and proper use of OPANA ER along with intensive monitoring for signs of addiction,
`abuse, and misuse.
`
`Abuse, or misuse of OPANA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled
`delivery of the oxymorphone and can result in overdose and death [see Overdosage (10)].
`
`Opioid agonists such as OPANA ER are sought by drug abusers and people with addiction disorders and are subject to criminal
`diversion. Consider these risks when prescribing or dispensing OPANA ER. Strategies to reduce these risks include prescribing the
`drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling
`Information (17)] . Contact local state professional licensing board or state controlled substances authority for information on how to
`prevent and detect abuse or diversion of this product.
`
`Reference ID: 3490223
`
`6
`
`

`

`5.2 Life Threatening Respiratory Depression
`Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as
`recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and
`death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists,
`depending on the patient’s clinical status [see Overdosage (10)] . Carbon dioxide (CO2) retention from opioid-induced respiratory
`depression can exacerbate the sedating effects of opioids.
`
`While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of OPANA ER, the risk is greatest
`during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating
`therapy with OPANA ER and following dose increases.
`
`To reduce the risk of respiratory depression, proper dosing and titration of OPANA ER are essential [see Dosage and Administration
`(2.1, 2.2)]. Overestimating the OPANA ER dose when converting patients from another opioid product can result in fatal overdose
`with the first dose.
`
`Accidental ingestion of even one dose of OPANA ER, especially by children, can result in respiratory depression and death due to an
`overdose of oxymorphone.
`
`5.3 Neonatal Opioid Withdrawal Syndrome
`Prolonged use of OPANA ER during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome,
`unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according
`to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient
`of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
`
`Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor,
`vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on
`the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.
`
`5.4 Interactions with Central Nervous System Depressants
`Patients must not consume alcoholic beverages or prescription or non-prescription products 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 [see Clinical Pharmacology (12.3)] .
`
`Hypotension, profound sedation, coma, respiratory depression, and death may result if OPANA ER is used concomitantly with alcohol
`or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).
`
`When considering the use of OPANA ER in a patient taking a CNS depressant, assess the duration use of the CNS depressant and the
`patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of
`alcohol or illicit drugs that cause CNS depression. If the decision to begin OPANA ER is made, start with OPANA ER 5 mg every 12
`hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS
`depressant [see Drug Interactions (7.2)] .
`
`5.5 Use in Elderly, Cachectic, and Debilitated Patients
`Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered
`pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when
`initiating and titrating OPANA ER and when OPANA ER is given concomitantly with other drugs that depress respiration [see
`Warnings and Precautions (5.2)].
`
`5.6 Use in Patients with Chronic Pulmonary Disease
`Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially
`decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly
`when initiating therapy and titrating with OPANA ER, as in these patients, even usual therapeutic doses of OPANA ER may decrease
`respiratory drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in
`these patients if possible.
`
`5.7 Use in Patients with Hepatic Impairment
`A study of OPANA ER in patients with hepatic disease indicated greater plasma concentrations than those with normal hepatic
`function [see Clinical Pharmacology (12.3)]. OPANA ER is contraindicated in patients with moderate or severe hepatic impairment.
`In patients with mild hepatic impairment reduce the starting dose to the lowest dose and monitor for signs of respiratory and central
`nervous system depression [see Dosage and Administration (2.5)].
`
`Reference ID: 3490223
`
`7
`
`

`

`5.8 Hypotensive Effect
`OPANA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an
`increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or
`concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions (7.2)].
`Monitor these patients for signs of hypotension after initiating or titrating the dose of OPANA ER. In patients with circulatory shock,
`OPANA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of OPANA ER in
`patients with circulatory shock.
`
`5.9 Use in Patients with Head Injury or Increased Intracranial Pressure
`Monitor patients taking OPANA ER who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of
`increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy
`with OPANA ER. OPANA ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial
`pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of OPANA ER in patients with
`impaired consciousness or coma.
`
`5.10 Use in Patients with Gastrointestinal Conditions
`OPANA ER is contraindicated in patients with paralytic ileus. Avoid the use of OPANA ER in patients with other GI obstruction.
`
`The oxymorphone in OPANA ER may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including
`acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase.
`
`5.11 Use in Patients with Convulsive or Seizure Disorders
`The oxymorphone in OPANA ER may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate
`seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during OPANA
`ER therapy.
`
`5.12 Avoidance of Withdrawal