OXYMORPHONE HYDROCHLORIDE

Oxymorphone Hydrochloride Extended-Release Tablets, USP are for oral use and contain oxymorphone, a semi-synthetic opioid analgesic. Oxymorphone Hydrochloride Extended-Release Tablets, USP are supplied in 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg and 40 mg tablet strengths for oral administration. The tablet strength describes the amount of oxymorphone hydrochloride per tablet. The tablets contain the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, hypromellose, xanthan gum, magnesium stearate, polyvinyl alcohol - partially hydrolyzed, polyethylene glycol, talc, and titanium dioxide. The 5 mg, 7.5 mg, 10 mg, 20 mg and 40 mg tablets contain FD&C Yellow No. 6 Aluminum Lake. In addition, the 5 mg tablets contain FD&C Blue No. 2 and D&C Red No. 27. The 7.5 mg tablets contain FD&C Blue No. 2 and FD&C Red No. 40. The 10 mg tablets contain FD&C Red No. 40. The 20 mg tablets contain D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1, and FD&C Blue No. 2. The 30 mg tablets contain Iron Oxide Yellow and Iron Oxide Black. The 40 mg tablets contain D&C Yellow No. 10 Aluminum Lake. The chemical name of oxymorphone hydrochloride is 4,5α-epoxy-3, 14-dihydroxy-17-methylmorphinan-6-one hydrochloride. Oxymorphone hydrochloride, USP is a white or slightly off-white, odorless powder, which is sparingly soluble in alcohol and ether, but freely soluble in water. The molecular weight of oxymorphone hydrochloride is 337.80. The pKa1 and pKa2 of oxymorphone at 37°C are 8.17 and 9.54, respectively. The octanol/aqueous partition coefficient at 37°C and pH 7.4 is 0.98. The structural formula for oxymorphone hydrochloride is as follows: Chemical Structure

Oxymorphone Hydrochloride Extended-Release Tablets are indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. Oxymorphone Hydrochloride Extended-Release Tablets are indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. ( 1 ) Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations, reserve Oxymorphone Hydrochloride Extended-Release Tablets 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 ) Oxymorphone Hydrochloride Extended-Release Tablets are not indicated as an as-needed (prn) analgesic. ( 1 ) Limitations of Usage: Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations [see Warnings and Precautions (5.1) ] , reserve Oxymorphone Hydrochloride Extended-Release Tablets 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. Oxymorphone Hydrochloride Extended-Release Tablets are not indicated as an as-needed (prn) analgesic.

Oxymorphone Hydrochloride Extended-Release Tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of Oxymorphone Hydrochloride Extended-Release Tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5 ) Administer on an empty stomach, at least 1 hour prior to or 2 hours after eating. ( 2.1 ) Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with Oxymorphone Hydrochloride Extended-Release Tablets. Consider prescribing naloxone based on the patient’s risk factors for overdose ( 2.2 , 5.1 , 5.2 , 5.3 ) . For opioid-naïve and opioid non-tolerant patients, initiate treatment with 5 mg tablets orally every 12 hours. ( 2.3 ) To convert to Oxymorphone Hydrochloride Extended-Release Tablets from another opioid, use available conversion factors to obtain estimated dose. ( 2.3 ) Dose can be increased every 3 to 7 days, using increments of 5 mg to 10 mg every 12 hours (i.e., 10 mg to 20 mg per day). (2.4 ) Do not abruptly discontinue Oxymorphone Hydrochloride Extended-Release Tablets in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5 , 5.15 ) Mild Hepatic Impairment: For opioid-naïve patients, initiate treatment with 5 mg and titrate slowly. For patients on prior opioid therapy, reduce starting dose by 50% and titrate slowly. Monitor for signs of respiratory and central nervous system depression. ( 2.6 ) Renal Impairment: For opioid-naïve patients, initiate treatment with 5 mg and titrate slowly. For patients on prior opioid therapy, reduce starting dose by 50% and titrate slowly. Monitor for signs of respiratory and central nervous system depression. ( 2.7 ) Geriatric Patients: Initiate dosing with 5 mg, titrate slowly, and monitor for signs of respiratory and central nervous system depression. ( 2.8 ) 2.1 Important Dosage and Administration Instructions Oxymorphone Hydrochloride Extended-Release Tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5) ] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Oxymorphone Hydrochloride Extended-Release Tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1) ] . Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Oxymorphone Hydrochloride Extended-Release Tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5) ] . Instruct patients to swallow Oxymorphone Hydrochloride Extended-Release Tablets whole [see Patient Counseling Information (17) ] . Crushing, chewing, or dissolving Oxymorphone Hydrochloride Extended-Release Tablets will result in uncontrolled delivery of oxymorphone and can lead to overdose or death [see Warnings and Precautions (5.3) ] . Administer on an empty stomach, at least 1 hour prior to or 2 hours after eating. Oxymorphone Hydrochloride Extended-Release Tablets are administered orally twice daily (every 12 hours). 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Oxymorphone Hydrochloride Extended-Release Tablets [see Warnings and Precautions (5.3) and Patient Counseling Information (17) ] . Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.1 , 5.3 , 5.5 ) ] . Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. 2.3 Initial Dosage Use of Oxymorphone Hydrochloride Extended-Release Tablets as the First Opioid Analgesic Initiate treatment with Oxymorphone Hydrochloride Extended-Release Tablets with the 5 mg tablet orally every 12-hours. Use of Oxymorphone Hydrochloride Extended-Release Tablets in Patients who are not Opioid Tolerant The starting dose for patients who are not opioid tolerant is Oxymorphone Hydrochloride Extended-Release Tablets 5 mg orally every 12 hours. Patients considered opioid tolerant are those taking, 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, 60 mg oral hydrocodone 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 Other Oral Opioids to Oxymorphone Hydrochloride Tablets to Oxymorphone Hydrochloride Extended-Release Tablets Patients receiving oxymorphone hydrochloride tablets may be converted to Oxymorphone Hydrochloride Extended-Release Tablets by administering half the patient's total daily oral oxymorphone hydrochloride tablets dose as Oxymorphone Hydrochloride Extended-Release Tablets, every 12 hours. Conversion from Parenteral Oxymorphone to Oxymorphone Hydrochloride Extended-Release Tablets The absolute oral bioavailability of Oxymorphone Hydrochloride Extended-Release Tablets are approximately 10%. Convert patients receiving parenteral oxymorphone to Oxymorphone Hydrochloride Extended-Release Tablets by administering 10 times the patient's total daily parenteral oxymorphone dose as Oxymorphone Hydrochloride Extended-Release Tablets in two equally divided doses (e.g., [Intravenous dose × 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 Opioids to Oxymorphone Hydrochloride Extended-Release Tablets When Oxymorphone Hydrochloride Extended-Release Tablets therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate. 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 Oxymorphone Hydrochloride Extended-Release Tablets clinical trial with an open-label titration period, patients were converted from their prior opioid to Oxymorphone Hydrochloride Extended-Release Tablets using Table 1 as a guide for the initial Oxymorphone Hydrochloride Extended-Release Tablets dose. Consider the following when using the information in the below Table1: This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to Oxymorphone Hydrochloride Extended-Release Tablets. This table cannot be used to convert from Oxymorphone Hydrochloride Extended-Release Tablets to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose. Table 1 CONVERSION FACTORS TO OXYMORPHONE HYDROCHLORIDE EXTENDED-RELEASE TABLETS Prior Oral Opioid Approximate Oral Conversion Factor Oxymorphone 1 Hydrocodone 0.5 Oxycodone 0.5 Methadone 0.5 Morphine 0.333 To calculate the estimated Oxymorphone Hydrochloride Extended-Release Tablet dose using the above table: 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. 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. 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 Oxymorphone Hydrochloride Extended-Release Tablet strength(s) available. Example conversion from a single opioid to Oxymorphone Hydrochloride Extended-Release Tablets: Step 1: Sum the total daily dose of the opioid oxycodone 20 mg twice daily 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 × 0.5 mg Conversion Factor = 20 mg of oral (active opioid) daily Step 3: Calculate the approximate starting dose of Oxymorphone Hydrochloride Extended-Release Tablets to be given every 12 hours. Round down, if necessary, to the appropriate Oxymorphone Hydrochloride Extended-Release Tablets strengths available. 10 mg Oxymorphone Hydrochloride Extended-Release Tablets every 12 hours Conversion from Methadone to Oxymorphone Hydrochloride Extended-Release Tablets 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. 2.4 Titration and Maintenance of Therapy Individually titrate Oxymorphone Hydrochloride Extended-Release Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Oxymorphone Hydrochloride Extended-Release Tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions as well as to reassess for the development of addiction, abuse, and misuse [see Warnings and Precautions (5.1, 5.15)] . 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 use of opioid therapy for an extended period of time, 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 Oxymorphone Hydrochloride Extended-Release Tablets dose to decrease the level of pain. Because steady-state plasma concentrations are approximated within 3 days, Oxymorphone Hydrochloride Extended-Release Tablets dosage adjustments, preferably at increments of 5 mg to 10 mg every 12 hours, may be done every 3 to 7 days. Patients who experience breakthrough pain may require a dose increase of Oxymorphone Hydrochloride Extended-Release Tablets, 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 Oxymorphone Hydrochloride Extended-Release Tablets dose. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), the subsequent dose may be reduced [see Warnings and Precautions (5)] . Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of Oxymorphone Hydrochloride Extended-Release Tablets Do not abruptly discontinue Oxymorphone Hydrochloride Extended-Release Tablets in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Oxymorphone Hydrochloride Extended-Release Tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including Oxymorphone Hydrochloride Extended-Release Tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Oxymorphone Hydrochloride Extended-Release Tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.14) and Drug Abuse and Dependence (9.3) ] . 2.6 Dosage Modification in Patients with Hepatic Impairment Oxymorphone Hydrochloride Extended-Release Tablets are 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 Oxymorphone Hydrochloride Extended-Release Tablets 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 (5.3) , Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. 2.7 Dosage Modification in Patients with Renal Impairment In patients with creatinine clearance rates less than 50 mL/min, start Oxymorphone Hydrochloride Extended-Release Tablets in the opioid-naïve patient with the 5 mg dose. For patients on prior opioid therapy, start Oxymorphone Hydrochloride Extended-Release Tablets 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 (5.3) , Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]. 2.8 Dosage Modification in Geriatric Patients The steady-state plasma concentrations of oxymorphone are higher in elderly subjects than in young subjects. Initiate dosing with Oxymorphone Hydrochloride Extended-Release Tablets 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 Oxymorphone Hydrochloride Extended-Release Tablets to adequate analgesia [see Warnings and Precautions (5.3) , Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ] . For patients on prior opioid therapy, start Oxymorphone Hydrochloride Extended-Release Tablets at 50% lower than the starting dose for a younger patient on prior opioids and titrate slowly.

Oxymorphone Hydrochloride Extended-Release Tablets are contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.3) ] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.6) ] Hypersensitivity (e.g. anaphylaxis) to oxymorphone, any other ingredients in Oxymorphone Hydrochloride Extended-Release Tablets [see Warnings and Precautions (5.7) , Adverse Reactions (6) ]. Moderate and severe hepatic impairment [see Warnings and Precautions (5.9) , Clinical Pharmacology (12.3) ] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.12) ] Significant respiratory depression ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment ( 4 ) Hypersensitivity to oxymorphone ( 4 ) Moderate or severe hepatic impairment ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 )

The following serious adverse reactions are discussed elsewhere in the labeling: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1) ] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 ) ] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3 ) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4) ] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.6) ] Anaphylaxis and Angioedema [see Warnings and Precautions (5.8 ) ] Adrenal Insufficiency [see Warnings and Precautions (5.9) ] Severe Hypotension [see Warnings and Precautions (5.11) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.13) ] Seizures [see Warnings and Precautions (5.14) ] Withdrawal [see Warnings and Precautions (5.15) ] 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 Impax Laboratories, Inc. at 1-800-934-6729 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 open-label and controlled clinical trials. The clinical trials enrolled of patients with moderate to severe chronic non-malignant pain, cancer pain, and post surgical pain. The most common serious adverse events reported with administration of Oxymorphone Hydrochloride Extended-Release Tablets were chest pain, pneumonia and vomiting. Tables 2 and 3 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 2: Treatment-Emergent Adverse Reactions 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) Open-Label Titration Period Double-Blind Treatment Period Oxymorphone Hydrochloride Extended-Release Tablets Oxymorphone Hydrochloride Extended-Release Tablets Placebo Preferred Term (N = 325) (N = 105) (N = 100) Constipation 26% 7% 1% Somnolence 19% 2% 0% Nausea 18% 11% 9% Dizziness 11% 5% 3% Headache 11% 4% 2% Pruritus 7% 3% 1% Table 3: Treatment-Emergent Adverse Reactions 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-Experienced Patients with Low Back Pain) Open-Label Titration Period Double-Blind Treatment Period Oxymorphone Hydrochloride Extended-Release Tablets Oxymorphone Hydrochloride Extended-Release Tablets Placebo Preferred Term (N = 250) (N = 70) (N = 72) Nausea 20% 3% 1% Constipation 12% 6% 1% Headache 12% 3% 0% Somnolence 11% 3% 0% Vomiting 9% 0% 1% Pruritus 8% 0% 0% Dizziness 6% 0% 0% The Table 4 lists adverse reactions that were reported in at least 2% of patients in placebo-controlled trials (N=5). Table 4: Adverse Reactions Reported in Placebo-Controlled Clinical Trials with Incidence ≥2% in Patients Receiving Oxymorphone Hydrochloride Extended-Release Tablets MedDRA Preferred Term Oxymorphone Hydrochloride Extended-Release Tablets (N=1,259) Placebo (N=461) Nausea 33% 13% Constipation 28% 13% Dizziness (Excl Vertigo) 18% 8% Somnolence 17% 2% Vomiting 16% 4% Pruritus 15% 8% Headache 12% 6% Sweating increased 9% 9% Dry mouth 6% < 1% Sedation 6% 8% Diarrhea 4% 6% Insomnia 4% 2% Fatigue 4% 1% Appetite decreased 3% < 1% Abdominal pain 3% 2% The common (≥1% to <10%) adverse drug reactions reported at least once by patients treated with Oxymorphone Hydrochloride Extended-Release Tablets in the clinical trials organized by MedDRA's (Medical Dictionary for Regulatory Activities) System Organ Class and not represented in Table 1 were: Eye disorders: vision blurred Gastrointestinal disorders: diarrhea, abdominal pain, dyspepsia General disorders and administration site conditions: dry mouth, appetite decreased, fatigue, lethargy, weakness, pyrexia, dehydration, weight decreased, edema Nervous system disorders: insomnia Psychiatric disorders: anxiety, confusion, disorientation, restlessness, nervousness, depression Respiratory, thoracic and mediastinal disorders: dyspnea Vascular disorders: flushing and hypertension Other less common adverse reactions known with opioid treatment that were seen <1% in the Oxymorphone Hydrochloride Extended-Release Tablet trials include the following: Bradycardia, palpitation, syncope, tachycardia, postural hypotension, miosis, abdominal distention, ileus, hot flashes, allergic reactions, hypersensitivity, urticaria, oxygen saturation decreased, central nervous system depression, depressed level of consciousness, agitation, dysphoria, euphoric mood, hallucination, mental status changes, difficult micturition, urinary retention, hypoxia, respiratory depression, respiratory distress, clamminess, dermatitis, hypotension. 6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of opioids. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous system disorder: amnesia, convulsion, memory impairment. Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Oxymorphone Hydrochloride Extended-Release Tablets. Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12) ] . Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.6) ] Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Table 5 includes clinically significant drug interactions with Oxymorphone Hydrochloride Extended-Release Tablets. Table 5: Clinically Significant Drug Interactions with Oxymorphone Hydrochloride Extended-Release Tablets Alcohol Clinical Impact: The concomitant use of alcohol with Oxymorphone Hydrochloride Extended-Release Tablets can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone. Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on Oxymorphone Hydrochloride Extended-Release Tablets therapy [see Clinical Pharmacology (12.3) ]. Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) and Warnings and Precautions (5.1 , 5.2 , 5.3) ]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Oxymorphone Hydrochloride Extended-Release Tablets if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3) ]. Intervention: The use of Oxymorphone Hydrochloride Extended-Release Tablets are not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Oxymorphone Hydrochloride Extended-Release Tablets and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Muscle Relaxants Clinical Impact: Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of Oxymorphone Hydrochloride Extended-Release Tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) and Warnings and Precautions (5.2 , 5.3) ] . Examples: cyclobenzaprine, metaxalone Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when Oxymorphone Hydrochloride Extended-Release Tablets are used concomitantly with anticholinergic drugs. Cimetidine Clinical Impact: Cimetidine can potentiate opioid-induced respiratory depression. Intervention: Evaluate patients for respiratory depression when Oxymorphone Hydrochloride Extended-Release Tablets and cimetidine are used concurrently. Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue Oxymorphone Hydrochloride Extended-Release Tablets if serotonin syndrome is suspected. ( 7 ) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Oxymorphone Hydrochloride Extended-Release Tablets because they may reduce analgesic effect of Oxymorphone Hydrochloride Extended-Release Tablets or precipitate withdrawal symptoms. ( 7 ) Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of oxymorphone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. ( 7 )