Oxymorphone hydrochloride

1 INDICATIONS AND USAGE Oxymorphone Hydrochloride Extended-Release Tablets are indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids. Limitations of Usage Because of the risks of addiction, abuse, misuse, overdose and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions (5.1) ] , reserve opioid analgesics, including Oxymorphone Hydrochloride Extended-Release Tablets, for use in patients for whom alternative treatment options 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 are an opioid agonist indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids. (1) Limitations of Use (1) Because of the risks of addiction, abuse, misuse, overdose and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including Oxymorphone Hydrochloride Extended-Release Tablets for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. (1 , 5.1) Oxymorphone Hydrochloride Extended-Release Tablets are not indicated as an as-needed (prn) analgesic. (1)

2 DOSAGE AND ADMINISTRATION 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 , 5.1 ) 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. ( 2.1 , 5.1) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with Oxymorphone Hydrochloride Extended-Release Tablets, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.1 , 5.2 , 5.3 ). Oxymorphone Hydrochloride Extended-Release Tablets are administered orally twice daily (every 12 hours), on an empty stomach, at least 1 hour prior to or 2 hours after eating. (2.1 , 2.3) For patients who are not opioid tolerant, 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 ) Periodically reassess patients receiving Oxymorphone Hydrochloride Extended-Release Tablets to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.4 ) Mild Hepatic Impairment : For patients who are not opioid tolerant, initiate treatment with 5 mg and titrate slowly. For patients on prior opioid therapy, reduce starting dose by 50% and titrate slowly. Evaluate for signs of respiratory and central nervous system depression. ( 2.6) Renal Impairment : For patients who are not opioid tolerant, initiate treatment with 5 mg and titrate slowly. For patients on prior opioid therapy, reduce starting dose by 50% and titrate slowly. Evaluate for signs of respiratory and central nervous system depression. (2.7) Geriatric Patients : Initiate dosing with 5 mg, titrate slowly, and evaluate for signs of respiratory and central nervous system depression. ( 2.8 ) Do not rapidly reduce or abruptly discontinue Oxymorphone Hydrochloride Extended-Release Tablets in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5 , 5.15 ) 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. 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 the lowest effect…

5 WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. (5.6) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly Cachectic or Debilitated Patients: Regularly evaluate particularly during initiation and titration. (5.7) Anaphylaxis, Angioedema, and Other Hypersensitivity Reactions : If symptoms occur, stop administration immediately, discontinue permanently, and do not rechallenge with any other oxymorphone formulation. (5.8) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.9) Severe Hypotension : Regularly evaluate during dose initiation and titration. Avoid use of oxymorphone hydrochloride extended-release tablets in patients with circulatory shock. (5.11) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of Oxymorphone Hydrochloride Extended-Release Tablets in patients with impaired consciousness or coma. (5.12) 5.1 Addiction, Abuse, and Misuse Oxymorphone Hydrochloride Extended-Release Tablet contains, oxymorphone, a Schedule II controlled substance. As an opioid, Oxymorphone Hydrochloride Extended-Release Tablets exposes users to the risks of addiction, abuse, and misuse. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Oxymorphone Hydrochloride Extended-Release Tablets. Addiction can occur at recommended doses and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2) ] . Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Oxymorphone Hydrochloride Extended-Release Tablets and reassess all patients receiving Oxymorphone Hydrochloride Extended-Release Tablets for the development of these behaviors and conditions. Risks are 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). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Oxymorphone Hydrochloride Extended-Release Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Oxymorphone Hydrochloride Extended-Release Tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) and Warnings and Precautions (5.2) ]. Abuse, or misuse of Oxymorphone Hydrochloride Extended-Release Tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the oxymorphone and can result in overdose and death [see Overdosage (10) ] . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Oxymorphone Hydrochloride Extended-Release Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-con…

4 CONTRAINDICATIONS Oxymorphone Hydrochloride Extended-Release Tablets are contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.7)] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.7)] Hypersensitivity (e.g., anaphylaxis) to oxymorphone, any other ingredients in Oxymorphone Hydrochloride Extended-Release Tablets [see Warnings and Precautions (5.8) and Adverse Reactions (6)]. Moderate and severe hepatic impairment [see Warnings and Precautions (5.10) , Clinical Pharmacology (12.3)] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.13)] 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)

7 DRUG INTERACTIONS 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 Warnings and Precautions (5.3) and 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 [see Warnings and Precautions (5.3)] . 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 and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [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, gabapentinoids (gabapentin or pregabalin), 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 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 (5.2) ]. 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…

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)] . Available data with Oxymorphone Hydrochloride Extended-Release Tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, reduced postnatal survival of pups and an increased incidence of stillborn pups were observed following oral treatment of pregnant rats with oxymorphone during gestation and through lactation at doses 2.4 and 12 times the human daily dose of 20 mg/day (HDD), respectively. Reduced fetal weights were observed with oral administration of oxymorphone to pregnant rats and rabbits during organogenesis at exposures up to 4.9 and 48.8 times the HDD, respectively [see Data] . Based on animal data, advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinical recognized pregnancies is 2% to 4% and 14% to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4)] . Labor or delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Oxymorphone Hydrochloride Extended-Release Tablets are not recommended for use in women during and immediately prior to labor, when use of shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Oxymorphone Hydrochloride Extended-Release Tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal data Pregnant rats were treated with oxymorphone hydrochloride from Gestation Day 6 to 17 via oral gavage doses of 5 mg/kg/day, 10 mg/kg/day or 25 mg/kg/day (2.4, 4.9, or 12.2 times the HDD based on body surface area, respectively). Reduced mean fetal weights were observed at 4.9 times the HDD. Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights in all groups and mortality in the high dose group). Pregnant rabbits were treated with oxymorphone hydrochloride from Gestation Day 7 to 20 via oral gavage doses of 10 mg/kg/day, 25 mg/kg/day or 50 mg/kg/day (9.8, 24.4, or 48.8 times the HDD based on body surface area, respectively). Decreased mean fetal weights were noted at 48.8 times the HDD. Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights). Pregnant rats were treated with oxymorphone hydrochloride from Gestation Day 6 to…

6 ADVERSE REACTIONS 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 Amneal Pharmaceuticals at 1-877-835-5472 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 Patients Not Opioid Tolerant 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% < …