Oxymorphone Hydrochloride (oxymorphone hydrochloride 10 mg) Dailymed

Oxymorphone hydrochloride tablets are indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Limitations of Use:

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, [see Warnings and Precautions (5.1)], reserve oxymorphone hydrochloride for use in patients for whom alternative treatment options continue to be inadequate (e.g., non-opioid analgesics or opioid combination products):

• • Have not been tolerated or are not expected to be tolerated,
• • Have not provided adequate analgesia or are not expected to provide adequate analgesia
  Oxymorphone hydrochloride should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.
  

Oxymorphone hydrochloride is an opioid agonist indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. (1)

Limitations of Use (1)

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration (5.1), reserve oxymorphone hydrochloride for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products):

• •Have not been tolerated or are not expected to be tolerated, (1)
• •Have not provided adequate analgesia or are not expected to provide adequate analgesia (1)

Oxymorphone hydrochloride should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

• •Oxymorphone hydrochloride should be taken on an empty stomach, at least one hour prior to or two hours after eating. (2.1)
• •Oxymorphone hydrochloride 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 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. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1, 5.2)
• •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. Consider prescribing naloxone based on the patient’s risk factors for overdose. (2.2 , 5.1, 5.2, 5.3)
• •Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.3)
• •Initiate treatment with Oxymorphone hydrochloride 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. (2.3, 5)
• • Conversion to Oxymorphone Hydrochloride: Follow recommendations for conversion from other opioids or parenteral oxymorphone. (2.3)
• •Do not abruptly discontinue oxymorphone hydrochloride tablets in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.9)
• • 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, 5.3, 7)

2.1 Important Dosage and Administration Instructions

Oxymorphone hydrochloride 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 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. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5)].

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with oxymorphone hydrochloride and adjust the dosage accordingly [see Warnings and Precautions ( 5.2 )].

Oxymorphone hydrochloride 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 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 [see Warnings and Precautions (5.2), 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, 5.2 , 5.3 )].

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 as the First Opioid Analgesic:

Initiate treatment with oxymorphone hydrochloride in a dosing range of 10 to 20 mg every 4 to 6 hours as needed for pain, and 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.

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:

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. It is safer to underestimate a patient’s 24-hour oxymorphone hydrochloride dosage than to overestimate the 24-hour oxymorphone hydrochloride dosage and manage an adverse reaction due to overdose.

For conversion from other opioids to oxymorphone hydrochloride, physicians and other healthcare professionals are advised to refer to published relative potency information, keeping in mind that conversion ratios are only approximate. In general, it is safest to start oxymorphone hydrochloride therapy by administering half of the calculated total daily dose of oxymorphone hydrochloride in 4 to 6 equally divided doses, every 4-6 hours. The initial dose of oxymorphone hydrochloride can be gradually adjusted until adequate pain relief and acceptable side effects have been achieved.

Conversion from Parenteral Oxymorphone to Oxymorphone Hydrochloride:

Given oxymorphone hydrochloride’s absolute oral bioavailability of approximately 10%, patients receiving parenteral oxymorphone may be converted to oxymorphone hydrochloride by administering 10 times the patient’s total daily parenteral oxymorphone dose as oxymorphone hydrochloride, in four or six equally divided doses (e.g., [IV dose x 10] divided by 4 or 6). For example, approximately 10 mg of oxymorphone hydrochloride four times daily may be required to provide pain relief equivalent to a total daily IM dose of 4 mg oxymorphone. Due to patient variability with regard to opioid analgesic response, upon conversion patients should be closely monitored to ensure adequate analgesia and to minimize side effects.

Conversion from Oxymorphone Hydrochloride to Extended-Release Oxymorphone:

The relative bioavailability of oxymorphone hydrochloride compared to extended-release oxymorphone is unknown, so conversion to extended-release oxymorphone may lead to increased risk of excessive sedation and respiratory depression.

2.4 Dosage Modifications in Patients with Mild Hepatic Impairment

Oxymorphone hydrochloride is contraindicated in patients with moderate or severe hepatic impairment.

Use oxymorphone hydrochloride with caution in patients with mild hepatic impairment, starting with the lowest dose (e.g., 5 mg) and titrating slowly while carefully monitoring for signs of respiratory and central nervous system depression [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

2.5 Dosage Modifications in Patients with Renal Impairment

Use oxymorphone hydrochloride with caution in patients with creatinine clearance rates less than 50 mL/min, starting with the lowest dose (e.g., 5 mg) and titrating slowly while carefully monitoring for signs of respiratory and central nervous system depression [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

2.6 Dosage Modifications in Geriatric Patients

Exercise caution in the selection of the starting dose of oxymorphone hydrochloride for an elderly patient by starting with the lowest dose (e.g., 5 mg) and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression [see Use in Specific Populations (8.5)].

2.7 Dosage Modifications with Concomitant Use of Central Nervous System Depressants

Oxymorphone hydrochloride, like all opioid analgesics, should be started at one-third to one-half of the usual dose in patients who are concurrently receiving other central nervous system (CNS) depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol, because respiratory depression, hypotension and profound sedation, coma or death may result [see Warnings and Precautions (5.3) and Drug Interactions (7)]. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced.

2.8 Titration and Maintenance of Therapy

Individually titrate oxymorphone hydrochloride to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving oxymorphone hydrochloride to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as reassessing for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1, 5.14)]. 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.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the oxymorphone hydrochloride dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.9 Safe Reduction or Discontinuation of Oxymorphone Hydrochloride

Do not abruptly discontinue oxymorphone hydrochloride 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 tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including oxymorphone hydrochloride 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 reaulic. 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 comorbid pain and substance use disorders may benefit from referral to a speciaul.

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 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), Drug Abuse and Dependence (9.3)].

3 Dosage Forms And Strengths

Oxymorphone Hydrochloride Tablets, USP are available as 5 mg and 10 mg for oral administration.

5 mg tablet is supplied as a round, white to off-white, standard biconvex tablet debossed with product identification “54” over “956” on one side and plain on the other side.

10 mg tablet is supplied as a round, white to off-white, standard biconvex tablet debossed with product identification “54” over “814” on one side and plain on the other side.


Tablets: 5 mg and 10 mg (3)

4 Contraindications

Oxymorphone hydrochloride is contraindicated in patients with:

• •Significant respiratory depression [see Warnings and Precautions (5.2)]
• •Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.7)]
• •Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.12)]
• •Hypersensitivity to oxymorphone (e.g., anaphylaxis, angioedema) or [see Warnings and Precautions (5.8), Adverse Reactions (6)]
• •Moderate or severe hepatic impairment [see Warnings and Precautions (5.16)].

• •Significant respiratory depression (4)
• •Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment (4)
• •Known or suspected gastrointestinal obstruction, including paralytic ileus (4)
• •Known hypersensitivity to oxymorphone, any other ingredients in oxymorphone hydrochloride (4)
• •Moderate or severe hepatic impairment (4)

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 patients, 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 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 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 in patients with impaired consciousness or coma. (5.11)

5.1 Addiction, Abuse, and Misuse

Oxymorphone hydrochloride contains oxymorphone, a Schedule II controlled substance. As an opioid, oxymorphone hydrochloride 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. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing oxymorphone hydrochloride, and reassess all patients receiving oxymorphone hydrochloride 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, but use in such patients necessitates intensive counseling about the risks and proper use of oxymorphone hydrochloride along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing

naloxone for the emergency treatment of opioid overdose [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. 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 (CO₂) 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, 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 are essential [see Dosage and Administration (2)]. Overestimating the oxymorphone hydrochloride 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, especially by children, can result in respiratory depression and death due to an overdose of oxymorphone hydrochloride.

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 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 oxycodone hydrochloride. 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). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

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. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.2), 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 therapy. The co-ingestion of alcohol with oxymorphone hydrochloride 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 with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. 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), Warnings and Precautions (5.2)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when oxymorphone hydrochloride is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7), Patient Counseling Information (17)].

5.4 Neonatal Opioid Withdrawal Syndrome

Use of oxymorphone hydrochloride for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of timeof the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

• •Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
• •Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG
• •Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• •Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a ul of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

5.6 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. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration ( 2.9 ); Warnings and Precautions ( 5.14 )].

5.7 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of oxymorphone hydrochloride in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease:

Oxymorphone hydrochloride-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of oxymorphone hydrochloride [see Warnings and Precautions (5.2)].

Elderly, Cachectic, or Debilitated Patients:

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Use in Specific Populations (8.5)].

Regularly evaluate patients, particularly when initiating and titrating oxymorphone hydrochloride and when oxymorphone hydrochloride is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.2 , 5.7), Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients.

5.8 Anaphylaxis, Angioedema, and Other Hypersensitivity Reactions

Potentially life-threatening hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients treated with oxymorphone hydrochloride in the postmarket setting. The most commonly described clinical features in these reports were swelling of the face, eyes, mouth, lips, tongue, hands, and/or throat; dyspnea; hives, pruritus, and/or rash; and nausea/vomiting. If anaphylaxis or other hypersensitivity occurs, stop administration of oxymorphone hydrochloride immediately, discontinue oxymorphone hydrochloride permanently, and do not rechallenge with any formulation of oxymorphone. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction [see Patient Counseling Information (17)].

5.9 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.10 Severe Hypotension

Oxymorphone hydrochloride may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of oxymorphone hydrochloride. In patients with circulatory shock, oxymorphone hydrochloride may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of oxymorphone hydrochloride in patients with circulatory shock.

5.11 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), oxymorphone hydrochloride may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with oxymorphone hydrochloride.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of oxymorphone hydrochloride in patients with impaired consciousness or coma.

5.12 Risks of Use in Patients with Gastrointestinal Conditions

Oxymorphone hydrochloride is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The oxymorphone in oxymorphone hydrochloride may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

The oxymorphone in oxymorphone hydrochloride may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during oxymorphone hydrochloride therapy.

5.14 Withdrawal

Do not abruptly discontinue oxymorphone hydrochloride in a patient physically dependent on opioids. When discontinuing oxymorphone hydrochloride in a physically dependent patient, gradually taper the dosage. Rapid tapering of oxymorphone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.9), Drug Abuse and Dependence (9.3)].

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including oxymorphone hydrochloride. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)].

5.15 Risks of Driving and Operating Machinery

Oxymorphone hydrochloride 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 tolerant to the effects of oxymorphone hydrochloride and know how they will react to the medication.

5.16 Hepatic Impairment

A study of extended-release oxymorphone tablets in patients with hepatic disease indicated greater plasma concentrations than in those with normal hepatic function [see Clinical Pharmacology (12.3)]. Use oxymorphone hydrochloride with caution in patients with mild impairment, starting with the lowest dose and titrating slowly while carefully monitoring for side effects [see Dosage and Administration (2.2, 2.3)]. Oxymorphone hydrochloride is contraindicated in patients with moderate or severe hepatic impairment.

6 Adverse Reactions

The following serious adverse reactions are described, or described in greater detail, in other sections:

• •Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• •Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• •Interactions with Benzodiazepines and 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, Angioedema, and Other Hypersensitivity Reactions [see Warnings and Precautions (5.8)]
• •Adrenal Insufficiency [see Warnings and Precautions (5.9)]
• •Severe Hypotension [see Warnings and Precautions (5.10)]
• •Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.12)]
• •Seizures [see Warnings and Precautions (5.13)]
• •Withdrawal [see Warnings and Precautions (5.14)]

Adverse Reactions (≥ 2% of patients): Nausea, pyrexia, somnolence, vomiting, pruritus, headache, dizziness, constipation, and confusion. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Adult 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 practice.

A total of 591 patients were treated with oxymorphone hydrochloride in controlled clinical trials. The clinical trials consisted of patients with acute post-operative pain (n=557) and cancer pain (n=34) trials.

The following table uls adverse reactions that were reported in at least 2% of patients receiving oxymorphone hydrochloride in placebo-controlled trials (acute post-operative pain (N=557)).

Table 1: Adverse Reactions Reported in Placebo-Controlled Trials

MedDRA Preferred Term	Oxymorphone Hydrochloride (N=557)	Placebo (N=270)
Nausea	19%	12%
Pyrexia	14%	8%
Somnolence	9%	2%
Vomiting	9%	7%
Pruritus	8%	4%
Headache	7%	4%
Dizziness (Excluding Vertigo)	7%	2%
Constipation	4%	1%
Confusion	3%	<1%

The common (≥1% to <10%) adverse drug reactions reported at least once by patients treated with oxymorphone hydrochloride in the clinical trials organized by MedDRA’s (Medical Dictionary for Regulatory Activities) System Organ Class were not represented in Table 1:

•   Cardiac disorders: tachycardia
•   Gastrointestinal disorders: dry mouth, abdominal distention, and flatulence
•   General disorders and administration site conditions: sweating increased
•   Nervous system disorders: anxiety and sedation
•   Respiratory, thoracic and mediastinal disorders: hypoxia
•   Vascular disorders: hypotension

Other less common adverse reactions known with opioid treatment that were seen <1% in the oxymorphone hydrochloride trials includes the following:

Abdominal pain, ileus, diarrhea, agitation, disorientation, restlessness, feeling jittery, hypersensitivity, allergic reactions, bradycardia, central nervous system depression, depressed level of consciousness, lethargy, mental impairment, mental status changes, fatigue, depression, clamminess, flushing, hot flashes, dehydration, dermatitis, dyspepsia, dysphoria, edema, euphoric mood, hallucination, hypertension, insomnia, miosis, nervousness, palpitation, postural hypotension, syncope, dyspnea, respiratory depression, respiratory distress, respiratory rate decreased, oxygen saturation decreased, difficult micturition, urinary retention, urticaria, vision blurred, visual disturbances, weakness, appetite decreased, and weight decreased.

6.2 Postmarketing 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.
•   Immune System Disorders: Angioedema, and other hypersensitivity reactions.
•   Androgen Deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2)].
•   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).