oxymorphone hydrochloride 10 MG Oral Tablet

INDICATIONS AND USAGE 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.

DOSAGE AND ADMINISTRATION Oxymorphone hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of 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 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) Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. (2.1) 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 tablets. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1, 5.2) Initiate treatment with oxymorphone hydrochloride tablets in a dosing range of 10 mg to 20 mg every four to six hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of oxymorphone hydrochloride tablets. (2.3, 5) Oxymorphone hydrochloride tablets should be taken on an empty stomach, at least one hour prior to or two hours after eating. (2.1) 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 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) Conversion to oxymorphone hydrochloride tablets: Follow recommendations for conversion from other opioids or parenteral oxymorphone. (2.3) Periodically reassess patients receiving oxymorphone hydrochloride 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. (2.8) Do not rapidly reduce or abruptly discontinue oxymorphone hydrochloride 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. (2.9, 5.14) Mild Hepatic Impairment : Initiate treatment with 5 mg and titrate slowly. Monitor for signs of respiratory and central nervous system depression. (2.4) Renal Impairment : Initiate treatment with 5 mg and titrate slowly. Monitor for signs of respiratory and central nervous system depression. (2.5) Geriatric Patients : Initiate dosing with 5 mg, titrate slowly, and monitor for signs of respiratory and central nervous system depression. (2.6) CNS Depressants : Initiate treatment with 1/3 to 1/2 the recommended starting dose, consider using a lower dosage of the concomitant CNS depressant, and monitor closely. (2.7, 5.7, 7) 2.1 Important Dosage and Administration Instructions Oxymorphone hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of 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 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. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. 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 tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5)]. Oxymorphone hydrochloride tablets should be administered on an empty stomach, at least one hour prior to or two hours after eating [see Clinical Pharmacology (12.3)]. To avoid medication errors, prescribers and pharmacists must be aware that oxymorphone is available as both immediate-release 5 mg and 10 mg tablets and extended-release 5 mg and 10 mg tablets [see Dosage Forms and Strengths (3)]. 2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.1, 5.2, 5.3)] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions (5.2)] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. 2.3 Initial Dosage Use of Oxymorphone Hydrochloride Tablets as the First Opioid Analgesic Initiate treatment with oxymorphone hydrochloride tablets in a dosing range of 10 mg to 20 mg every 4 to 6 hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of oxymorphone hydrochloride tablets. Do not initiate treatment with doses higher than 20 mg because of the potential serious adverse reactions [see Clinical Studies (14.1)]. Conversion from Other Opioids to Oxymorphone Hydrochloride Tablets There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of oxymorphone hydrochloride tablets. It is safer to underestimate a patient’s 24-hour oxymorphone hydrochloride tablets dosage than to overestimate the 24-hour oxymorphone hydrochloride tablets dosage and manage an adverse reaction due to overdose. For conversion from other opioids to oxymorphone hydrochloride tablets, physicians and other healthcare professionals are advised to refer to published relative potency information, keeping in mind that conversion ratios are only appro

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, closely, particularly during initiation and titration. (5.2) Anaphylaxis, Angioedema, and Other Hypersensitivity Reactions : If symptoms occur, stop administration immediately, discontinue permanently, and do not rechallenge with any 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 dosage initiation and titration. Avoid use of oxymorphone hydrochloride tablets in patients with circulatory shock. (5.10) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Regularly evaluate for sedation and respiratory depression. Avoid use of oxymorphone hydrochloride tablets in patients with impaired consciousness or coma. (5.11) 5.1 Addiction, Abuse, and Misuse Oxymorphone hydrochloride tablet contains oxymorphone, a Schedule II controlled substance. As an opioid, oxymorphone hydrochloride tablets exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed oxymorphone hydrochloride tablets. Addiction can occur at recommended dosages 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 Postmarketing Experience (6.2)]. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing oxymorphone hydrochloride tablets, and reassess all patients receiving oxymorphone hydrochloride 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 tablets, but use in such patients necessitates intensive counseling about the risks and proper use of oxymorphone hydrochloride tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2)] . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing oxymorphone hydrochloride 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-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of oxymorphone hydrochloride tablets, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of oxymorphone hydrochloride tablets are essential [see Dosage and Administration (2)]. Overestimating the oxymorphone hydrochloride tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of oxymorphone hydrochloride tablets, especially by children, can result in respiratory depression and death due to an overdose of oxymorphone. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)]. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.9)]. Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.1, 5.3)]. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)]. 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on oxymorphone hydrochloride tablets therapy. The co-ingestion of alcohol with oxymorphone hydrochloride tablets may result in increased plasma levels and a potentially fatal overdose of oxymorphone [see Clinical Pharmacology (12.3)]. Profound sedation, respiratory depression, coma, and death may result from the concomitant use of oxymorphone hydrochloride tablets with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids, other opio

CONTRAINDICATIONS 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 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Oxymorphone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxymorphone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxymorphone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug. 12.2 Pharmacodynamics Effects on the Central Nervous System Oxymorphone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Oxymorphone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Oxymorphone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on the Cardiovascular System Oxymorphone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. U se of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration-Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with extended-release agonist opioids. The minimum effective analgesic concentration of oxymorphone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.3)]. Concentration-Adverse Reaction Relationships There is a relationship between increasing oxymorphone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.3, 2.7)]. 12.3 Pharmacokinetics Absorption The absolute oral bioavailability of oxymorphone is approximately 10%. Studies in healthy volunteers reveal predictable relationships between oxymorphone hydrochloride tablets dosage and plasma oxymorphone concentrations. Steady-state levels were achieved after three days of multiple dose administration. Under both single-dose and steady-state conditions, dose proportionality has been established for 5 mg, 10 mg and 20 mg doses of oxymorphone hydrochloride tablets, for both peak plasma levels (C max ) and extent of absorption (AUC) (see Table 3). After oral dosing with 40 mg of oxymorphone hydrochloride tablets in healthy volunteers under fasting conditions or with a high-fat meal, the C max and AUC were increased by approximately 38% in fed subjects relative to fasted subjects. As a result, oxymorphone hydrochloride tablets should be dosed at least one hour prior to or two hours after eating [see Dosage and Administration (2.1)]. Distribution Formal studies on the distribution of oxymorphone in various tissues have not been conducted. Oxymorphone is not extensively bound to human plasma proteins; binding is in the range of 10% to 12%. Elimination Half-life ranges from approximately 9-11 hours after a single oral dose (5-40 mg). Metabolism Oxymorphone is highly metabolized, principally in the liver, and undergoes reduction or conjugation with glucuronic acid to form both active and inactive products. The two major metabolites of Oxymorphone are oxymorphone-3-glucuronide and 6-OH-oxymorphone. The mean plasma AUC for oxymorphone-3-glucuronide is approximately 90-fold higher than the parent compound. The pharmacologic activity of the glucuronide metabolite has not been evaluated. 6-OH-oxymorphone has been shown in animal studies to have analgesic bioactivity. The mean plasma 6-OH-oxymorphone AUC is approximately 70% of the oxymorphone AUC following single oral doses but is essentially equivalent to the parent compound at steady-state. Excretion Because oxymorphone is extensively metabolized, <1% of the administered dose is excreted unchanged in the urine. On average, 33% to 38% of the administered dose is excreted in the urine as oxymorphone-3-glucuronide and 0.25% to 0.62% is excreted as 6-OH-oxymorphone in subjects with normal hepatic and renal function. In animals given radiolabeled oxymorphone, approximately 90% of the administered radioactivity was recovered within 5 days of dosing. The majority of oxymorphone-derived radioactivity was found in the urine and feces. Specific Populations Age: Geriatric Population The plasma levels of oxymorphone administered as an extended-release tablet were about 40% higher in elderly (≥65 years of age) than in younger subjects [see Use in Specific Populations (8.5)]. Sex: The effect of sex on the pharmacokinetics of oxymorphone hydrochloride tablets has not been studied. In a study with an extended-release formulation of oxymorphone, there was a consistent tendency for female subjects to have slightly higher AUC ss and C max values than male subjects. However, sex differences were not observed when AUC ss and C max were adjusted by body weight. Hepatic Impairment The liver plays an important role in the pre-systemic clearance of orally administered oxymorphone. Accordingly, the bioavailability of orally administered oxymorphone may be markedly increased in patients with moderate to severe liver disease. The effect of hepatic impairment on the pharmacokinetics of oxymorphone hydrochloride tablets has not been studied. However, in a study with an extended-release formulation of oxymorphone, the disposition of oxymorphone