CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`201655Orig1s000
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`LABELING
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`------------------------WARNINGS AND PRECAUTIONS----------------------
`See Boxed WARNINGS
` Respiratory depression: Increased risk in elderly, debilitated patients, and
`those suffering from conditions accompanied by hypoxia, hypercapnia, or
`decreased respiratory reserve. (5.2)
` Misuse, abuse, and diversion: OPANA ER is an opioid agonist and a
`Schedule II controlled substance with an abuse liability similar to morphine.
`(5.3)
` CNS effects: Additive CNS-depressive effects when used in conjunction
`with alcohol, other opioids, or illicit drugs. (5.4)
` Head Injury: Effects may be markedly exaggerated. Administer OPANA ER
`with extreme caution. (5.5)
` Hypotensive effect: Increased risk with compromised ability to maintain
`blood pressure. Administer with caution to patients in circulatory shock.
`(5.6)
` Mild hepatic impairment: Use with caution and at lower doses due to higher
`plasma concentrations than in patients with normal hepatic function. (5.7)
` Prolonged gastric obstruction: May occur in patients with gastrointestinal
`obstruction. (5.9)
` Sphincter of Oddi: Administer with caution in patients with biliary tract
`disease. (5.11)
` Impaired mental/physical abilities: Caution must be used with potentially
`hazardous activities (5.12)
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`-------------------------------ADVERSE REACTIONS------------------------------
`Adverse reactions in ≥2% of oxymorphone ER-treated patients in placebo-
`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.
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`----------------------------------DRUG INTERACTIONS---------------------------
` CNS depressants: Increased risk of respiratory depression, hypotension,
`profound sedation, coma or death when combined with OPANA ER. When
`combined therapy with CNS depressant is contemplated, the dose of one or
`both agents should be reduced. (7.2)
` Mixed agonist/antagonist opioids (i.e., pentazocine, nalbuphine, and
`butorphanol): May reduce analgesic effect and/or precipitate withdrawal
`symptoms. (7 3)
` Cimetidine: Combination use with OPANA ER may precipitate confusion,
`disorientation, respiratory depression, apnea, seizures. (7.4)
` Anticholinergics: Concurrent use with OPANA ER may result in urinary
`retention and/or severe constipation, which may lead to paralytic ileus. (7.5)
` Monoamine oxidase inhibitors (MAOIs): Potentiate the action of opioids.
`OPANA ER should not be used in patients taking MAOIs or within 14 days
`of stopping such treatment. (7.6)
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`-------------------------USE IN SPECIFIC POPULATIONS----------------------
` Pregnancy: Based on animal data, may cause fetal harm. (8.1)
` Geriatric Patients – OPANA ER should be used with caution in elderly
`patients. (8.5)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA –
`approved Medication Guide
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` Revised: 12/2011
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`WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER
`PATIENT SELECTION AND LIMITATIONS OF USE
`See full prescribing information for complete boxed warning.
` OPANA ER contains oxymorphone which is an opioid agonist and a
`Schedule II controlled substance with an abuse liability similar to other
`opioid analgesics. (9)
` 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. (9)
` OPANA ER is NOT intended for use as an as needed analgesic. (1)
` OPANA ER tablets are to be swallowed whole and are not to be cut,
`broken, chewed, dissolved, or crushed as this leads to rapid release and
`absorption of a potentially fatal dose of oxymorphone. (2)
` Patients must not consume alcoholic beverages, prescription or non-
`prescription medications containing alcohol. Co-ingestion of alcohol with
`OPANA ER may result in a potentially fatal overdose of oxymorphone. (2)
`
`-------------------------------INDICATIONS AND USAGE-------------------------------
` OPANA ER is 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. (1)
` Not intended for use as an as needed analgesic. Not indicated in the immediate
`post-operative period or if the pain is mild or not expected to persist for an
`extended period of time. (1)
`-------------------------DOSAGE AND ADMINISTRATION--------------------------
` Administer on an empty stomach, at least 1 hour prior to or 2 hours after
`eating. (2.2)
` Symmetrical, every 12 h dosing is appropriate for the majority of patients. (2.1)
` Opioid-Naïve Patients: Initiate treatment with 5 mg every 12 hours. (2.2)
` Opioid-Experienced Patients: Ratios as a guide to convert only from other
`opioids to OPANA ER. (2.2)
` Individualize treatment; titrate to effective and tolerable dose. (2.1)
` Don’t stop abruptly (9.3); taper gradually to stop treatment. (2.8)
` OPANA ER tablets should be taken one tablet at a time, with enough water
`to ensure complete swallowing immediately after placing in the mouth (2.1,
`17)
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`-------------------------DOSAGE FORMS AND STRENGTHS-----------------------
` Extended-Release Tablets, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, and 40
`mg (3)
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`---------------------------------CONTRAINDICATIONS---------------------------------
` Known hypersensitivity to oxymorphone, any other ingredients in OPANA ER,
`or morphine analogs. (4)
` Respiratory depression (4)
` Acute or severe bronchial asthma or hypercarbia (4)
` Paralytic ileus (4)
` Moderate or severe hepatic impairment (4)
`
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`________________________________________________________________________________________________________________________________________
`5.3 Misuse, Abuse and Diversion of Opioids
`FULL PRESCRIBING INFORMATION: CONTENTS*
`5.4
`Interactions with Alcohol and other CNS Depressants
`BOXED WARNING
`1
`5.5 Use in Patients with Head Injury and Increased Intracranial Pressure
`INDICATIONS AND USAGE
`2
`5.6 Hypotensive Effect
`DOSAGE AND ADMINISTRATION
`5.7 Hepatic Impairment
`2.1 Safe Administration Instructions
`5.8 Special Risk Groups
`2.2
`Initiating Therapy with OPANA ER
`5.9 Gastrointestinal Effects
`2.3 Patients with Hepatic Impairment
`5.10 Ambulatory Surgery and Post Operative Use
`2.4 Patients with Renal Impairment
`5.11 Use in Pancreatic/Billiary Tract Disease
`2 5 Use with Central Nervous System Depressants
`5.12 Driving and Operating Machinery
`2.6 Geriatric Patients
`2.7 Maintenance of Therapy
`ADVERSE REACTIONS
`6.1 Clinical Trial Experience
`2.8 Cessation of Therapy
`3
`DRUG INTERACTIONS
`DOSAGE FORMS AND STRENGTHS
`4
`7.1 Drug-Drug Interactions
`CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`7.2 Use with CNS Depressants
`7.3
`5 1
`Interactions with Mixed Agonist/Antagonist Opioid Analgesics
`Information Essential for Safe Administration
`5 2 Respiratory Depression
`7.4 Cimetidine
`
`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, CII
`Initial U.S. Approval: 1959
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`Reference ID: 3071831
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`8
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`7 5 Anticholinergics
`7.6 MAO Inhibitors
`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
`10.1 Symptoms
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`9
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`10.2 Treatment
`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
`14.1 12-Week Study in Opioid-Naïve Patients with Low Back Pain
`14.2 12-Week Study in Opioid-Experienced Patients with Low Back Pain
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
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`*Sections or subsections omitted from the full prescribing information are not
`listed.
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`Reference ID: 3071831
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`FULL PRESCRIBING INFORMATION
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`WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER 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. (9)
`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. (9.2)
`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. (1)
`Limitations of Use
`OPANA ER is NOT intended for use as an as needed analgesic. (1)
`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. (2)
`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. (2)
`
` 1
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`INDICATIONS AND USAGE
`OPANA ER is indicated for the relief of moderate to severe pain in patients requiring continuous, around-
`the-clock opioid treatment for an extended period of time.
`
`Limitations of Usage
`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).
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Safe Administration Instructions
`OPANA ER tablets must 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.
`
`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)].
`
`OPANA ER must be taken on an empty stomach, at least one hour prior to or two hours after eating
`[see Clinical Pharmacology (12.3)].
`
`While symmetric (same dose AM and PM), around-the-clock, every 12 hours dosing is appropriate for the
`majority of patients, some patients may benefit from asymmetric (different dose given in AM than in PM)
`dosing, tailored to their pain pattern. It is usually appropriate to treat a patient with only one extended-
`release opioid for around-the-clock therapy.
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`Selection of patients for treatment with OPANA ER should be governed by the same principles that apply
`to the use of other extended-release opioid analgesics [see Indications and Usage (1)]. Physicians should
`individualize treatment in every case, using non-opioid analgesics, opioids on an as needed basis,
`combination products, and chronic opioid therapy in a progressive plan of pain management such as
`outlined by the World Health Organization, the American Pain Society and the Federation of State Medical
`Boards Model Guidelines. Healthcare professionals should follow appropriate pain management principles
`of careful assessment and ongoing monitoring [see Boxed Warning].
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`2.2 Initiating Therapy with OPANA ER
`It is necessary to adjust the dosing regimen for each patient individually, taking into account the patient’s
`prior analgesic treatment experience. In the selection of the initial dose of OPANA ER, attention should be
`given to the following:
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`
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`total daily dose, potency and specific characteristics of the opioid the patient has been taking
`previously;
`relative potency estimate used to calculate the equivalent oxymorphone dose needed;
`patient’s degree of opioid tolerance;
`age, general condition, and medical status of the patient;
`concurrent non-opioid analgesics and other medications;
`type and severity of the patient’s pain;
`balance between pain control and adverse experiences;
`risk factors for abuse or addiction, including a prior history of abuse or addiction.
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`Once therapy is initiated, frequently assess pain relief and other opioid effects. Base the titration of the total
`daily OPANA ER dose upon the amount of supplemental opioid utilization, severity of the patient’s pain,
`and the patient’s ability to tolerate the opioid. Titrate dose to generally mild or no pain with the regular use
`of no more than two doses of supplemental analgesia, i.e. “rescue,” per 24 hours, and tolerable side effects.
`Patients who experience breakthrough pain may require dosage adjustment.
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`If signs of excessive opioid-related adverse experiences are observed, the next dose may be reduced. If this
`adjustment leads to inadequate analgesia, a supplemental dose of immediate-release opioid, or a non-
`opioid analgesic may be administered. Adjust dosing to obtain an appropriate balance between pain relief
`and opioid-related adverse experiences. If significant adverse events occur before the therapeutic goal of
`mild or no pain is achieved, the events should be treated aggressively. If adverse events are adequately
`managed, continue upward titration to an acceptable level of pain control.
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`During periods of changing analgesic requirements, including initial titration, frequent contact is
`recommended between physician, other members of the healthcare team, the patient and the
`caregiver/family. Advise patients and caregivers/family members of the potential adverse reactions.
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`The dosing recommendations below, therefore, can only be considered as suggested approaches to what is
`actually a series of clinical decisions over time in the management of the pain of each individual patient.
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`Titrate dose to adequate pain relief (generally mild or no pain).
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`Opioid-Naïve Patients
`The initial dose for patients who are not opioid-experienced and who are being initiated on chronic around-
`the-clock opioid therapy with OPANA ER is 5 mg every 12 hours. Thereafter, titrate the dose individually
`at increments of 5-10 mg every 12 hours every 3-7 days, to a level that provides adequate analgesia and
`tolerable side effects under the close supervision of the prescribing physician.
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`Opioid-Experienced Patients
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`Reference ID: 3071831
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`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.
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`Conversion from Parenteral Oxymorphone to OPANA ER
`Given OPANA ER’s absolute oral bioavailability of approximately 10%, patients receiving parenteral
`oxymorphone may be converted 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.
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`Conversion from Other Oral Opioids to OPANA ER
`For conversion from other opioids to OPANA ER, physicians and other healthcare professionals are
`advised to refer to published relative potency information, keeping in mind that conversion ratios are only
`approximate.
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`The following table provides approximate equivalent doses, which may be used as a guideline for
`conversion. The conversion ratios and approximate equivalent doses in this conversion table are only
`to be used for the conversion from current opioid therapy to OPANA ER.
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`In general, it is safest to start the OPANA ER therapy by administering 50% of the calculated total
`daily dose, calculated below, of OPANA ER (see conversion ratio table below) in 2 divided doses,
`every 12 hours. Gradually adjust the initial dose of OPANA ER until adequate pain relief and
`acceptable side effects have been achieved.
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`Calculating the total daily dose of OPANA ER:
`
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`Step 1 Calculate the total daily dose of the opioid.
`Step 2 Multiply the total daily dose for the opioid by the conversion ratio in Table 1 to
`calculate the total daily oxymorphone dose.
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`Table 1: Oral Opioid Conversion Ratios to OPANA ER
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`Oral Opioid
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`Oxymorphone
`Hydrocodone
`Oxycodone
`Methadone a
`Morphine
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`Oral Conversion
`Ratio
`1
`0.5
`0.5
`0.5
`0.333
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`Step 3
`Step 4
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`Adjust the total daily dose of oxymorphone for the individual patient.
`Divide the total daily oxymorphone dose in half to determine the OPANA ER dose to be
`administered every 12 hours.
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` For patients on a regimen of mixed opioids, calculate the approximate oral oxymorphone dose for
`each opioid, sum the totals, and divide in half to estimate the total daily oxymorphone dose.
` The dose of OPANA ER can be gradually adjusted, preferably at increments of 10 mg every 12
`hours every 3-7 days, until adequate pain relief and acceptable side effects have been achieved
`[see Dosage and Administration (2.1)].
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`aIt is extremely important to monitor all patients closely when converting from methadone to
`other opioid agonists including OPANA ER. 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
`accumulates in the plasma.
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`No dose adjustment for CYP 3A4 or 2C9 mediated drug-drug interactions is required [see Clinical
`Pharmacology (12.3)].
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`2.3 Patients with Hepatic Impairment
`Start patients with mild hepatic impairment with the lowest dose and titrated slowly while carefully
`monitoring side effects. OPANA ER is contraindicated in patients with moderate or severe hepatic
`impairment [Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)]
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`2.4 Patients with Renal Impairment
`There are 57% and 65% increases in oxymorphone bioavailability in patients with moderate and severe
`renal impairment, respectively [see Clinical Pharmacology (12.3)]. Accordingly, in patients with
`creatinine clearance rates less than 50 mL/min, start OPANA ER with the lowest dose and titrate slowly
`while carefully monitoring side effects.
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`2.5 Use with Central Nervous System Depressants
`In patients who are concurrently receiving other central nervous system (CNS) depressants including
`sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol, start OPANA ER at
`1/3 to 1/2 of the usual dose because respiratory depression, hypotension, and profound sedation, coma or
`death may result [see Warnings and Precautions (5.4) and Drug Interactions (7.2)].
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`Although no specific interaction between oxymorphone and monoamine oxidase inhibitors has been
`observed, OPANA ER is not recommended for use in patients who have received MAO inhibitors within
`14 days [see Drug Interactions (7.6)].
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`2.6 Geriatrics Patients
`The steady-state plasma concentrations of oxymorphone are approximately 40% higher in elderly subjects
`than in young subjects. Exercise caution in the selection of the starting dose of OPANA ER for an elderly
`patient by starting at the low end of the dosing range and slowly titrating to adequate analgesia [see
`Clinical Pharmacology (12.3) and Use in Specific Populations (8.5)].
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`2.7 Maintenance of Therapy
`During chronic therapy with OPANA ER, periodically reassess the continued need for around-the-clock
`opioid therapy. Continue to assess patients for their clinical risks for opioid abuse, addiction, or diversion
`particularly with high-dose formulations. If patients need to titrate while on maintenance therapy, follow
`the same method outlined in Initiating Therapy with OPANA ER.
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`2. 8 Cessation of Therapy
`When the patient no longer requires therapy with OPANA ER tablets, gradually taper doses to prevent
`signs and symptoms of withdrawal in the physically dependent patient.
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`DOSAGE FORMS AND STRENGTHS
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`The 5 mg dosage form is a pink, round, film-coated, biconvex extended-release tablet debossed with an “E”
`on one side and a “5” on the other side.
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`The 7.5 mg dosage form is a gray, round, film-coated, biconvex extended-release tablet debossed with an
`“E” on one side and a “7 ½” on the other side.
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`The 10 mg dosage form is a light orange, round, film-coated, biconvex extended-release tablet debossed
`with an “E” on one side and a “10” on the other side.
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`The 15 mg dosage form is a white, round, film-coated, biconvex extended-release tablet debossed with an
`“E” on one side and a “15” on the other side.
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`The 20 mg dosage form is a light green, round, film-coated, biconvex extended-release tablet debossed
`with an “E” on one side and a “20” on the other side.
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`The 30 mg dosage form is a red, round, film-coated, biconvex extended-release tablet debossed with an “E”
`on one side and a “30” on the other side.
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`The 40 mg dosage form is a light yellow to pale yellow, round, film-coated, biconvex extended-release
`tablet debossed with an “E” on one side and a “40” on the other side.
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`4 CONTRAINDICATIONS
`OPANA ER is contraindicated in patients who have:
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`known hypersensitivity to any of its components or the active ingredient, oxymorphone or with
`known hypersensitivity to morphine analogs such as codeine.
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`significant respiratory depression
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`acute or severe bronchial asthma or hypercarbia
`
`or are suspected of having paralytic ileus
` moderate and severe hepatic impairment [see Clinical Pharmacology (12.3), Warnings and
`Precautions (5.7)].
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`5 WARNINGS AND PRECAUTIONS
`5.1 Information Essential for Safe Administration
`OPANA ER tablets are to be swallowed whole, and are not to be cut, broken, chewed, crushed or
`dissolved. Taking cut, broken, chewed, dissolved, or crushed OPANA ER tablets could lead to the
`rapid release and absorption of a potentially fatal dose of oxymorphone [see Boxed Warning].
`
`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 [see
`Pharmacokinetics (12.3)].
`
`Instruct patients against use by individuals other than the patient for whom OPANA ER was
`prescribed, as such inappropriate use may have severe medical consequences, including death.
`
`5.2 Respiratory Depression
`Respiratory depression is the chief hazard of OPANA ER. 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.
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`5.3 Misuse, Abuse and Diversion of Opioids
`OPANA ER contains oxymorphone, a mu opioid agonist and a Schedule II controlled substance with an
`abuse liability similar to morphine. Opioid agonists are sought by drug abusers and people with addiction
`disorders and are subject to criminal diversion.
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`Reference ID: 3071831
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`Oxymorphone can be abused in a manner similar to other opioid agonists, legal or illicit. This issue should
`be considered when prescribing or dispensing oxymorphone in situations where the physician or pharmacist
`is concerned about an increased risk of misuse, abuse, or diversion.
`
`OPANA ER tablets may be abused by crushing, chewing, snorting or injecting the product. These practices
`will result in the less controlled delivery of the opioid and pose a significant risk to the abuser that could
`result in overdose and death [see Drug Abuse and Dependence (9)].
`
`OPANA ER may be targeted for theft and diversion. Healthcare professionals should contact their State
`Medical Board, State Board of Pharmacy, or State Control Board for information on how to detect or
`prevent diversion of this product, and security requirements for storing and handling of OPANA ER.
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`Healthcare professionals should advise patients to store OPANA ER in a secure place, preferably locked
`and out of the reach of children and other non-caregivers.
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`Concerns about abuse, misuse, diversion and addiction should not prevent the proper management of pain.
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`5.4 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 [see Drug Interactions
`(7.2)]. Avoid concurrent use of alcohol and OPANA ER [see Pharmacokinetics (12.3)].
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`5.5 Use in Patients with Head Injury and Increased Intracranial Pressure
`In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the
`possible respiratory depressant effects of opioid analgesics and their potential to elevate cerebrospinal fluid
`pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated.
`Furthermore, opioid analgesics can produce effects on papillary response and consciousness, which may
`obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.
`
`Administer OPANA ER with extreme caution to patients who may be particularly susceptible to the
`intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure or
`impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury and should
`be used only if clinically warranted.
`
`5.6 Hypotensive Effect
`OPANA ER may cause severe hypotension in a patient whose ability to maintain blood pressure has been
`compromised by a depleted blood volume, or after concurrent administration with drugs such as
`phenothiazines or other agents that compromise vasomotor tone. Administer OPANA ER with caution to
`patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output
`and blood pressure.
`
`5.7 Hepatic Impairment
`A study of oxymorphone hydrochloride extended-release tablets in patients with hepatic disease indicated
`greater plasma concentrations than those with normal hepatic function [see Clinical Pharmacology (12)].
`Use OPANA ER with caution in patients with mild impairment, starting with the lowest dose and titrating
`slowly while carefully monitoring for side effects [see Dosage and Administration (2.3)]. OPANA ER is
`contraindicated in patients with moderate or severe hepatic impairment.
`
`5.8 Special Risk Groups
`Use OPANA ER with caution in the following conditions: adrenocortical insufficiency (e.g., Addison's
`disease), prostatic hypertrophy or urethral stricture, severe impairment of pulmonary or renal function, and
`toxic psychosis.
`
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`Reference ID: 3071831
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`Opioids may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate
`seizures in some clinical settings.
`
`5.9 Gastrointestinal Effects
`OPANA ER decreases bowel motility. Opioids diminish propulsive peristaltic waves in the gastrointestinal
`tract. Monitor for decreased bowel motility in post-operative patients receiving opioids. The administration
`of
`OPANA ER may obscure the diagnosis or clinical course in patients with acute abdominal conditions.
`OPANA ER is contraindicated in patients with paralytic ileus.
`
`5.10 Ambulatory Surgery and Post-Operative Use
`OPANA ER is not indicated for pre-emptive analgesia (administration pre-operatively for the management
`of post-operative pain).
`
`OPANA ER is only indicated for postoperative use in the patient if the patient is already receiving the drug
`prior to surgery or if the postoperative pain is expected to be moderate to 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).
`
`Patients who are already receiving OPANA ER as part of ongoing analgesic therapy may be safely
`continued on the drug if appropriate dosage adjustments are made considering the procedure, other drugs
`given, and the temporary changes in physiology caused by the surgical intervention.
`
`5.11 Use in Pancreatic/Biliary Tract Disease
`OPANA ER, like other opioids, may cause spasm of the sphincter of Oddi and should be used with caution
`in patients with biliary tract disease, including acute pancreatitis.
`
`5.12 Driving and Operating Machinery
`Opioid analgesics, including OPANA ER, may impair the mental and physical abilities needed to perform
`potentially hazardous activities such as driving a car or operating machinery.
`
` 6
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` ADVERSE REACTIONS
`The following serious adverse reactions are discussed elsewhere in the labeling:
` Respiratory depression [see Warnings and Precautions (5.2)]
` Misuse and abuse [see Warning and Precautions (5.3) and Drug Abuse and Dependence (9)]
` CNS depressant effects [see Warnings and Precautions (5.4)]
`
`
`6.1 Clinical Trial Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
`the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
`may not reflect the rates observed in clinical practice.
`
`The safety of oxymorphone hydrochloride extended-release tablets was evaluated in a total of 2011 patients
`in controlled clinical trials. The clinical trials consisted of patients with moderate to severe chronic non-
`malignant pain, cancer pain, and post surgical pain.
`
`Tables 1 and 2 list the most frequently occurring adverse reactions (in at least 5% of patients) from the
`placebo-controlled trials in patients with low back pain.
`
`Table 1:Treatment-Emergent Adverse Events Reported in 5% of Patients
`During the Open-Label Titration Period and Double-Blind Treatment Period by Preferred
`Term —Number (%) of Treated Patients (12-Week Study In Opioid-Naïve Patients with Low
`Back Pain)
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`Reference ID: 3071831
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`Table 2. Treatment-Emergent Adverse Events Reported in 5% of Patients
`During the Open-Label Titration Period and Double-Blind Treatment Period by Preferred Term —
`Number (%) of Treated Patients (12-Week