`
`
`
`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)
`
`
`---------------------DOSAGE FORMS AND STRENGTHS-------------------
`
`Extended-Release Tablets, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30
`
`
`mg, and 40 mg
`
`------------------------------CONTRAINDICATIONS---------------------------
`
`Significant respiratory depression (4)
`
`
`Acute or severe bronchial asthma (4)
`
`
`Known or suspected paralytic ileus (4)
`
`
`
`Hypersensitivity to oxymorphone (4)
`
`
` Moderate or severe hepatic impairment (4)
`
`
`------------------------WARNINGS AND PRECAUTIONS--------------------
`See Boxed WARNINGS
`
`Elderly, cachectic, and debilitated patients, and patients with chronic
`
`
`pulmonary disease: Monitor closely because of increased risk of
`
`respiratory depression. (5.5, 5.6)
`
`Interaction with CNS depressants: Consider dose reduction of one or
`
`both drugs because of additive effects. (5.7, 7.2)
`Hypotensive effect: Monitor during dose initiation and titration. (5.9)
`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. (5.10)
`
`Respiratory depression: Increased risk in elderly, debilitated patients,
`and those suffering from conditions accompanied by hypoxia,
`hypercapnia, or decreased respiratory reserve. (5.2)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`-----------------------------ADVERSE REACTIONS-----------------------------
`Adverse reactions in ≥2% of 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.
`
`
`------------------------------DRUG INTERACTIONS---------------------------­
`
`CNS depressants: Increased risk of respiratory depression,
`
`
`hypotension, profound sedation, coma or death. 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)
`
`
`------------------------USE IN SPECIFIC POPULATIONS--------------------
`
` Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`
` Nursing mothers: Closely monitor infants of nursing women receiving
`
`OPANA ER. (8.3)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`Medication Guide
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`WARNING: ABUSE POTENTIAL, LIFE-THREATENING
`
`RESPIRATORY DEPRESSION, ACCIDENTAL EXPOSURE, and
`
`
`
`INTERACTION WITH ALCOHOL
`
`
`See full prescribing information for complete boxed warning.
`
` OPANA ER contains oxymorphone, a Schedule II controlled
`substance. Monitor for signs of misuse, abuse, and addiction
`
`during OPANA ER therapy. (5.1, 9)
`
`Fatal respiratory depression may occur, with highest risk at
`initiation and with dose increases. Instruct patients on proper
`
`administration of OPANA ER tablets to reduce the risk. (5.2)
`
`Accidental ingestion of OPANA ER can result in fatal overdose
`of oxymorphone, especially in children. (5.3)
`
`
`
`Instruct patients not to consume alcoholic beverages or use
`prescription or non-prescription products containing alcohol
`while taking OPANA ER because of the risk of increased, and
`potentially fatal, plasma oxymorphone levels. (5.4)
`
`
`
`
`-----------------------------RECENT MAJOR CHANGES--------------------
`Boxed Warning
`
`
`
`
`07/2012
`Indications and Usage (1)
`07/2012
`
`
`
`Dosage and Administration (2)
`07/2012
`
`
`
`
`
`
`
`Contraindications (4)
`07/2012
`
`Warnings and Precautions (5)
`07/2012
`
`
`
`
`
`----------------------------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)
`
`Limitations of Use
`
`
`• OPANA ER is not for use:
`
` As an as-needed (prn) analgesic (1)
`
` For pain that is mild or not expected to persist for an extended period
`of time (1)
`
` For acute pain (1)
`
`
` For postoperative pain, unless the patient is already receiving chronic
`opioid therapy prior to surgery, or if the postoperative pain is expected
`
`
`to be moderate to severe and persist for an extended period of time (1)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`---------------------DOSAGE AND ADMINISTRATION-------------------­
`
`
`Individualize dosing based on patient’s prior analgesic treatment
`
`experience, and titrate as needed to provide adequate analgesia and
`
`minimize adverse reactions. (2.1, 2.2,)
`
`Administer on an empty stomach, at least 1 hour prior to or 2
`
`
`hours after eating. (2.1)
`
`Instruct patients to swallow OPANA ER tablets intact. (2.4)
`Do not abruptly discontinue OPANA ER in a physically dependent
`patient. (2.3, 5.13)
`Reduce the dose of OPANA ER in patients with mild hepatic
`
`
`impairment and patients with renal impairment. (2.5, 2.6)
`
`
`
`
`
`Revised: 07/2012
`________________________________________________________________________________________________________________________________________
`
`3
`DOSAGE FORMS AND STRENGTHS
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`4
`CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`WARNING: ABUSE POTENTIAL, LIFE-THREATENING
`
`5.1 Abuse Potential
`RESPIRATORY DEPRESSION, ACCIDENTAL EXPOSURE, and
`
`
`
`5.2 Life Threatening Respiratory Depression
`
`INTERACTION WITH ALCOHOL
`
`
`5.3 Accidental Exposure
`
`
`5.4
`Interaction with Alcohol
`Boxed Warning
`
`
`5.5 Elderly, Cachectic, and Debilitated Patients
`1
`INDICATIONS AND USAGE
`
`
`5.6 Use in Patients with Chronic Pulmonary Disease
`2
`DOSAGE AND ADMINISTRATION
`
`
`
`5.7
`Interactions with CNS Depressants and Illicit Drugs
`Initial Dosing
`2.1
`
`
`5.8 Use in Patients with Hepatic Impairment
`2.2 Titration and Maintenance of Therapy
`
`
`
`5.9 Hypotensive Effect
`2.3 Discontinuation of OPANA ER
`
`
`
`5.10 Use in Patients with Head Injury or Increased Intracranial
`2.4 Administration of OPANA ER
`
`
`Pressure
`2.5 Patients with Hepatic Impairment
`
`
`5.11 Use in Patients with Gastrointestinal Conditions
`2.6 Patients with Renal Impairment
`
`5.12
` Use in Patients with Convulsive or Seizure Disorders
`
`2.7 Geriatric Patients
`
`
`
`Reference ID: 3154914
`
`
`
`1
`
`

`

`
`6
`
`
`7
`
`5.13 Avoidance of Withdrawal
`
`
`5.14 Driving and Operating Machinery
`
`
`
`ADVERSE REACTIONS
`
`6.1 Clinical Trial Experience
`
`6.2 Post-marketing Experience
`DRUG INTERACTIONS
`7.1 Alcohol
`7.2 CNS Depressants
`7.3 Mixed Agonist/Antagonist Opioid Analgesics
`
`7.4 Cimetidine
`7.5 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
`
`
`8.8 Neonatal Withdrawal Syndrome
`
`_________________________________________________________________________________________________________________________________
`
`
`9
`
`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
`
`
`*Sections or subsections omitted from the full prescribing
`information are not listed.
`
`
`
`8
`
`
`
`
`Reference ID: 3154914
`
`
`
`
`
`
` 2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`
`
`
`WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION,
`
`ACCIDENTAL EXPOSURE, and INTERACTION WITH ALCOHOL
`
`
`
`Abuse Potential
`
`OPANA ER contains oxymorphone, an opioid agonist and Schedule II controlled substance with an abuse
`
`liability similar to other opioid agonists, legal or illicit [see Warnings and Precautions (5.1)]. Assess each
`
`
`
`patient’s risk for opioid abuse or addiction prior to prescribing OPANA ER. The risk for opioid abuse is
`
`
`
`increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse
`
`or addiction) or mental illness (e.g., major depressive disorder). Routinely monitor all patients receiving
`
`
`OPANA ER for signs of misuse, abuse, and addiction during treatment [see Drug Abuse and Dependence
`
`(9)].
`
`
`Life-threatening Respiratory Depression
`Respiratory depression, including fatal cases, may occur with use of OPANA ER, even when the drug has
`
`been used as recommended and not misused or abused [see Warnings and Precautions (5.2)]. Proper dosing
`
`
`and titration are essential and OPANA ER should only be prescribed by healthcare professionals who are
`
`knowledgeable in the use of potent opioids for the management of chronic pain. Monitor for respiratory
`depression, especially during initiation of OPANA ER or following a dose increase. Instruct patients to
`
`
`
`
`
`
`
`swallow OPANA ER tablets whole. Crushing, dissolving, or chewing OPANA ER can cause rapid release
`
`
`and absorption of a potentially fatal dose of oxymorphone.
`
`
`Accidental Exposure
`
`
`Accidental ingestion of OPANA ER, especially in children, can result in a fatal overdose of oxymorphone
`[see Warnings and Precautions (5.3)].
`
`
`Interaction with Alcohol
`
`The co-ingestion of alcohol with OPANA ER may result in an increase of plasma levels and potentially fatal
`overdose of oxymorphone [see Warnings and Precautions (5.4)]. Instruct patients not to consume alcoholic
`
`
`beverages or use prescription or non-prescription products that contain alcohol while on OPANA ER.
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`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 (prn) analgesic
`
`
`
`For pain that is mild or not expected to persist for an extended period of time
`
`
`
`For acute pain
`
`
`
`
`
`For postoperative pain unless the patient is already receiving chronic opioid therapy prior to
`
`
`surgery or if the postoperative pain is expected to be moderate to severe and persist for an
`extended period of time.
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Initial Dosing
`
`
`
`Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment
`
`experience. 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)].
`
`Consider the following factors when selecting an initial dose of OPANA ER:
`
`
`
`Total daily dose, potency, and any prior opioid the patient has been taking previously;
`
`
`Reliability of the relative potency estimate used to calculate the equivalent dose of oxymorphone needed
`
`(Note: potency estimates may vary with the route of administration);
`
`
`
`Patient's degree of opioid experience and opioid tolerance;
`
`
`
` General condition and medical status of the patient;
`
`
`Concurrent medication;
`
`
`Type and severity of the patient's pain.
`
`
`
`
`Reference ID: 3154914
`
`
`
`
`
`
`
` 3
`
`

`

`
`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 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.
`
`
`
`Use of OPANA ER as the First Opioid Analgesic
`
`Initiate Opana ER therapy with the 5 mg tablet twice daily (at 12-hour intervals). Adjust the dose of OPANA ER in
`
`increments of 5-10 mg every 12 hours every 3 to 7 days.
`
`
`
`
`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
`
`
`While there are useful tables of oral and parenteral equivalents, there is substantial inter-patient variability in the
`
`
`relative potency of different opioid drugs and formulations. As such, it is safer to underestimate a patient’s 24-hour
`
`
`oral oxymorphone dose and provide rescue medication (e.g. immediate-release oxymorphone) than to overestimate
`
`
`
`the 24-hour oral oxymorphone dose and manage an adverse reaction. Consider the following general points:
`
`
`
`
`
`
`
`
`In a Phase 3 clinical trial with an open-label titration period, patients were converted from their prior opioid to
`
`OPANA ER using the following table as a guide for the initial OPANA ER dose.
`
`
`
`
`
`
`  The table is not a table of equianalgesic doses.
`
`  The conversion ratios in this table are only to be used for the conversion from oral therapy with one of
`
`the listed opioid analgesics to OPANA ER.
`
`
`  Do not use this table 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.
`
`
`
`
`For example, a patient receiving oxycodone at a total daily dose of 40 mg would then be converted to a total daily
`
`
`dose of 20 mg of oxymorphone (40 mg x 0.5), dosed as OPANA ER 10 mg twice daily.
`
`
`
`
`
`CONVERSION RATIOS TO OPANA ER
`
`Total Daily Oral Dose
`
`
`10 mg
`
`
`20 mg
`20 mg
`
`
`20 mg
`
`
`30 mg
`
`
`
`Opioid
`Oxymorphone
`Hydrocodone
`Oxycodone
`
`Methadone
`Morphine
`
`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. During chronic therapy, especially for non-cancer-related pain (or pain associated
`with other terminal illnesses), 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
`
`Oral
`
`Conversion Ratio
`1
`0.5
`0.5
`0.5
`0.333
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3154914
`
`
`
`
`
`
`
` 4
`
`

`

`
`
`
`
` 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 dosage adjustment or rescue medication with a small dose
` of an immediate-release medication (e.g. immediate-release oxymorphone).
`
`
`During chronic, around-the-clock opioid therapy, especially for non-cancer pain syndromes, reassess the continued
`
`
`
` need for around-the-clock opioid therapy periodically (e.g., every 6 to 12 months) as appropriate.
` If signs of excessive opioid-related adverse reactions are observed, the next 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 (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, round, film-coated, biconcave extended-release tablet debossed with an “E” on one
`side and a “5” on the other side.
`
`The 7.5 mg dosage form is a gray, round, film-coated, biconcave extended-release tablet debossed with an “E” on
`
`one side and a “7 ½” on the other side.
`
`
`The 10 mg dosage form is a light orange, round, film-coated, biconcave extended-release tablet debossed with an
`
`
`
`
`“E” on one side and a “10” on the other side.
`
`The 15 mg dosage form is a white, round, film-coated, biconcave extended-release tablet debossed with an “E” on
`
`one side and a “15” on the other side.
`
`The 20 mg dosage form is a light green, round, film-coated, biconcave extended-release tablet debossed with an “E”
`
`
`
`on one side and a “20” on the other side.
`
`
`
`
`
`
`
`
`Reference ID: 3154914
`
`
`
`
`
`
`
` 5
`
`

`

`The 30 mg dosage form is a red, round, film-coated, biconcave extended-release tablet debossed with an “E” on one
`side and a “30” on the other side.
`
`The 40 mg dosage form is a light yellow to pale yellow, round, film-coated, biconcave extended-release tablet
`
`
`
`debossed with an “E” on one side and a “40” on the other side.
`
`
`
`
`4 CONTRAINDICATIONS
`
`OPANA ER is contraindicated in patients with:
`
`
`
`Significant respiratory depression
`
`
`
` Acute or severe bronchial asthma or hypercarbia
`
` Known or suspected paralytic ileus
`
`
` Moderate and severe hepatic impairment [see Clinical Pharmacology (12.3), Warnings and Precautions
`
`
`
`(5.8)].
`
` 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 Abuse Potential
`OPANA ER contains oxymorphone, an opioid agonist and a Schedule II controlled substance. Oxymorphone can be
`
`abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists 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 in situations where there is concern about increased risks of misuse, abuse, or diversion.
`
`
`Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain.
`
`
`Assess each patient’s risk for opioid abuse or addiction prior to prescribing OPANA ER. The risk for opioid abuse
`
`
`
`is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or
`addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with
`
`modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse,
`
`abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction
`
`
`because these drugs carry a risk for addiction even under appropriate medical use.
`
`Misuse or abuse of OPANA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the
`
`uncontrolled delivery of the opioid and pose a significant risk that could result in overdose and death [see
`Overdosage (10)].
`
`
`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.
`
`
`
`5.2 Life Threatening Respiratory Depression
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`Respiratory depression is the primary risk of OPANA ER. Respiratory depression, if not immediately recognized
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`and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a
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`reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing
`(deep breaths separated by abnormally long pauses). Carbon dioxide (CO2) retention from opioid-induced
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`respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may
`include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical
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`status [see Overdosage (10)].
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`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. Instruct patients
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`against use by individuals other than the patient for whom OPANA ER was prescribed and to keep OPANA ER out
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`of the reach of children, as such inappropriate use may result in fatal respiratory depression.
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`To reduce the risk of respiratory depression, proper dosing and titration of OPANA ER are essential [see Dosage
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`and Administration (2.1, 2.2)]. Overestimating the OPANA ER dose when converting patients from another opioid
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`product can result in fatal overdose with the first dose. Respiratory depression has also been reported with use of
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`modified-release opioids when used as recommended and not misused or abused.
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`Reference ID: 3154914
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` 6
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` To further reduce the risk of respiratory depression, consider the following:
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` • Proper dosing and titration are essential and OPANA ER should only be prescribed by healthcare professionals
`
` who are knowledgeable in the use of potent opioids for the management of chronic pain.
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`• Instruct patients to swallow OPANA ER tablets intact. The tablets are not to be crushed, dissolved, or chewed.
` The resulting oxymorphone dose may be fatal, particularly in opioid-naïve individuals.
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` • OPANA ER is contraindicated in patients with respiratory depression and in patients with conditions that
` increase the risk of life-threatening respiratory depression [see Contraindications (4)].
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`5.3 Accidental Exposure
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`Accidental consumption of OPANA ER, especially in children, can result in a fatal overdose of oxymorphone.
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`5.4 Interaction with Alcohol
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`The co-ingestion of alcohol with OPANA ER can result in an increase of oxymorphone plasma levels and
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`potentially fatal overdose of oxymorphone. Instruct patients not to consume alcoholic beverages or use prescription
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`or non-prescription products containing alcohol while on OPANA ER therapy [see Clinical Pharmacology (12.3)].
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`5.5 Elderly, Cachectic, and Debilitated Patients
`Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered
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`pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance compared to younger, healthier
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`patients. Therefore, monitor such patients closely, particularly when initiating and titrating OPANA ER and when
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`OPANA ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)].
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`5.6 Use in Patients with Chronic Pulmonary Disease
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`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
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`respiratory depression, particularly when initiating therapy and titrating with OPANA ER, as in these patients, even
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`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.
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`5.7 Interactions with CNS Depressants and Illicit Drugs
`Hypotension, profound sedation, coma, or respiratory depression may result if OPANA ER is used concomitantly
`
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`with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering
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`the use of OPANA ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and
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`the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally,
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`consider the patient’s use, if any, of alcohol or illicit drugs that cause CNS depression. If OPANA ER therapy is to
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`be initiated in a patient taking a CNS depressant, start with a lower OPANA ER dose than usual and monitor
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`patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS
`depressant [see Drug Interactions (7.2)].
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`5.8 Use in Patients with Hepatic Impairment
`A study of OPANA ER in patients with hepatic disease indicated greater plasma concentrations than those with
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`normal hepatic function [see Clinical Pharmacology (12.3)]. OPANA ER is contraindicated in patients with
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`moderate or severe hepatic impairment. In patients with mild hepatic impairment reduce the starting dose to the
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`lowest dose and monitor for signs of respiratory and central nervous system depression [see Dosage and
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`Administration (2.5)].
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`5.9 Hypotensive Effect
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`OPANA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients.
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`There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a
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`reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general
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`anesthetics) [see Drug Interactions (7.2)]. Monitor these patients for signs of hypotension after initiating or titrating
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`the dose of OPANA ER. In patients with circulatory shock, OPANA ER may cause vasodilation that can further
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`reduce cardiac output and blood pressure. Avoid the use of OPANA ER in patients with circulatory shock.
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`5.10 Use in Patients with Head Injury or Increased Intracranial Pressure
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`Monitor patients taking OPANA ER who may be susceptible to the intracranial effects of CO2 retention (e.g., those
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`with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression,
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`particularly when initiating therapy with OPANA ER. OPANA ER may reduce respiratory drive, and the resultant
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`Reference ID: 3154914
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`CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient
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` with a head injury. Avoid the use of OPANA ER in patients with impaired consciousness or coma.
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`5.11 Use in Patients with Gastrointestinal Conditions
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`OPANA ER is contraindicated in patients with paralytic ileus. Avoid the use of OPANA ER in patients with other
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`GI obstruction.
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`The oxymorphone in OPANA ER may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract
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`disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase.
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`5.12 Use in Patients with Convulsive or Seizure Disorders
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`The oxymorphone in OPANA ER may aggravate convulsions in patients with convulsive disorders, and may induce
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`or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened
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`seizure control during OPANA ER therapy.
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`5.13 Avoidance of Withdrawal
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`Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients
`
`who have received or are receiving a course of therapy with an opioid agonist analgesic, including OPANA ER. In
`these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate
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`withdrawal symptoms.
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`When discontinuing OPANA ER, gradually taper the dose [see Dosage and Administration (2.3)]. Do not abruptly
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`discontinue OPANA ER.
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`5.14 Driving and Operating Machinery
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`OPANA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as
`driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are
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`tolerant to the effects of OPANA ER and know how they will react to the medication.
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`6 ADVERSE REACTIONS
`The following serious adverse reactions are discussed elsewhere in the labeling:
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` Respiratory Depression [see Warnings and Precautions (5.2)]
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` Chronic Pulmonary Disease [see Warnings and Precautions (5.6)]
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` Head Injuries and Increased Intracranial Pressure [see Warnings and Precautions (5.10)]
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`Interactions with Other CNS Depressants [see Warnings and Precautions (5.7)]
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`
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` Hypotensive Effect [see Warnings and Precautions (5.9)]
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` Gastrointestinal Effects [see Warnings and Precautions (5.11)]
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` Seizures [see Warnings and Precautions (5.12)]
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`6.1 Clinical Trial Experience
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical
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`trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates
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`observed in clinical practice.
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`The safety of oxymorphone hydrochloride extended-release tablets was evaluated in a total of 2011 patients in open-
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`label and controlled clinical trials. The clinical trials enrolled of patients with moderate to severe chronic non­
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`malignant pain, cancer pain, and post surgical p