Oxymorphone Hydrochloride Tablet, Film Coated, Extended Release
FDA Label NDC 64896-700

Addiction, Abuse, and Misuse

Because the use of Oxymorphone Hydrochloride Extended-Release Tablets exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of Oxymorphone Hydrochloride Extended-Release Tablets, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Oxymorphone Hydrochloride Extended-Release Tablets are essential. Instruct patients to swallow Oxymorphone Hydrochloride Extended-Release Tablets whole; crushing, chewing, or dissolving Oxymorphone Hydrochloride Extended-Release Tablets can cause rapid release and absorption of a potentially fatal dose of oxymorphone [see Dosage and Administration (2.1) and Warnings and Precautions (5.2)].

Accidental Ingestion

Accidental ingestion of even one dose of Oxymorphone Hydrochloride Extended-Release Tablets, especially by children, can result in a fatal overdose of oxymorphone [see Warnings and Precautions (5.2)].

Interaction with Alcohol

Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking Oxymorphone Hydrochloride Extended-Release Tablets. The co-ingestion of alcohol with Oxymorphone Hydrochloride Extended-Release Tablets may result in increased plasma levels and a potentially fatal overdose of oxymorphone [see Warnings and Precautions (5.2, 5.3)].

Risks From Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of Oxymorphone Hydrochloride Extended-Release Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3), Drug Interactions (7)].

Neonatal Opioid Withdrawal Syndrome (NOWS)

Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.4)].

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

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 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 effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Oxymorphone Hydrochloride Extended-Release Tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
• Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Oxymorphone Hydrochloride Extended-Release Tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5.2)].
• Oxymorphone Hydrochloride Extended-Release Tablets are administered orally twice daily (every 12 hours).
• Instruct patients to swallow Oxymorphone Hydrochloride Extended-Release Tablets whole. Crushing, chewing, or dissolving Oxymorphone Hydrochloride Extended-Release Tablets will result in uncontrolled delivery of oxymorphone and can lead to overdose or death [see Warnings and Precautions (5.2)].
• Administer on an empty stomach, at least 1 hour prior to or 2 hours after eating.

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.

It is safer to underestimate a patient’s 24-hour oral morphine dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral morphine dosage and manage an adverse reaction due to an overdose. While useful tables of opioid equivalents are readily available, there is inter-patient variability in the potency of opioid drugs and opioid formulations. Frequently reevaluate patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to Oxymorphone Hydrochloride Extended-Release Tablets.

Use of Oxymorphone Hydrochloride Extended-Release Tablets in Patients who are not Opioid Tolerant

The starting dose for patients who are not opioid tolerant is Oxymorphone Hydrochloride Extended-Release Tablets 5 mg orally every 12 hours.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression [see Warnings and Precautions (5.2)].

Conversion from Other Oral Opioids to Oxymorphone Hydrochloride Tablets to Oxymorphone Hydrochloride Extended-Release Tablets

Patients receiving oral oxymorphone hydrochloride tablets may be converted to Oxymorphone Hydrochloride Extended-Release Tablets by administering half the patient’s total daily oral oxymorphone hydrochloride tablets dose as Oxymorphone Hydrochloride Extended-Release Tablets, every 12 hours.

Conversion from Parenteral Oxymorphone to Oxymorphone Hydrochloride Extended-Release Tablets

The absolute oral bioavailability of Oxymorphone Hydrochloride Extended-Release Tablets are approximately 10%. Convert patients receiving parenteral oxymorphone to Oxymorphone Hydrochloride Extended-Release Tablets by administering 10 times the patient’s total daily parenteral oxymorphone dose as Oxymorphone Hydrochloride Extended-Release Tablets in two equally divided doses (e.g., [IV dose x 10] divided by 2). Due to patient variability with regards to opioid analgesic response, upon conversion monitor patients closely to evaluate for adequate analgesia and side effects.

Conversion from Other Oral Opioid Analgesics to Oxymorphone Hydrochloride Extended-Release Tablets

When Oxymorphone Hydrochloride Extended-Release Tablets therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

In an Oxymorphone Hydrochloride Extended-Release Tablets clinical trial with an open-label titration period, patients were converted from their prior opioid to Oxymorphone Hydrochloride Extended-Release Tablets using Table 1 as a guide for the initial Oxymorphone Hydrochloride Extended-Release Tablets dose.

Consider the following when using the information in the below Table 1:

• This is not a table of equianalgesic doses.
• The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to Oxymorphone Hydrochloride Extended-Release Tablets.
• This table cannot be used to convert from Oxymorphone Hydrochloride Extended-Release Tablets to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose.

Table 1: CONVERSION FACTORS TO OXYMORPHONE HYDROCHLORIDE EXTENDED-RELEASE TABLETS

Prior Oral Opioid	Approximate Oral Conversion Factor
Oxymorphone	1
Hydrocodone	0.5
Oxycodone	0.5
Methadone	0.5
Morphine	0.333

 

To calculate the estimated Oxymorphone Hydrochloride Extended-Release Tablet dose using the above table:

• For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the conversion factor to calculate the approximate oral (active opioid) daily dose.
• For patients on a regimen of more than one opioid, calculate the approximate oral (active opioid) dose for each opioid and sum the totals to obtain the approximate total (active opioid) daily dose.
• For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.

Always round the dose down, if necessary, to the appropriate Oxymorphone Hydrochloride Extended-Release Tablet strength(s) available.

Example conversion from a single opioid to Oxymorphone Hydrochloride Extended-Release Tablets:

Step 1:             Sum the total daily dose of the opioid oxycodone 20 mg twice daily 20 mg former opioid 2 times daily = 40 mg total daily dose of former opioid

Step 2:             Calculate the approximate equivalent dose of oral (active opioid) based on the total daily dose of the current opioid using Table 1 40 mg total daily dose of former opioid x 0.5 mg Conversion Factor = 20 mg of oral (active opioid) daily

Step 3:             Calculate the approximate starting dose of Oxymorphone Hydrochloride Extended-Release Tablets to be given every 12 hours. Round down, if necessary, to the appropriate Oxymorphone Hydrochloride Extended-Release Tablets strengths available.

10 mg Oxymorphone Hydrochloride Extended-Release Tablets every 12 hours

Conversion from Methadone to Oxymorphone Hydrochloride Extended-Release Tablets

Regular evaluation is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

Individually titrate Oxymorphone Hydrochloride Extended-Release Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Oxymorphone Hydrochloride Extended-Release Tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, and misuse [see Warnings and Precautions (5.1, 5.15)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dose increase of Oxymorphone Hydrochloride Extended-Release Tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic.

If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing Oxymorphone Hydrochloride Extended-Release Tablets dose.

If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Because steady-state plasma concentrations are approximated within 3 days, Oxymorphone Hydrochloride Extended-Release Tablets dosage adjustments, preferably at increments of 5 mg to 10 mg every 12 hours, may be done every 3 to 7 days.

Do not rapidly reduce or abruptly discontinue Oxymorphone Hydrochloride Extended-Release Tablets in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Oxymorphone Hydrochloride Extended-Release Tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including Oxymorphone Hydrochloride Extended-Release Tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Oxymorphone Hydrochloride Extended-Release Tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.15) and Drug Abuse and Dependence (9.3)].

Oxymorphone Hydrochloride Extended-Release Tablets are contraindicated in patients with moderate or severe hepatic impairment.

In patients with mild hepatic impairment who are not opioid tolerant, initiate treatment with the 5 mg dose. For patients on prior opioid therapy, start Oxymorphone Hydrochloride Extended-Release Tablets at 50% lower than the starting dose for a patient with normal hepatic function on prior opioids and titrate slowly. Regularly evaluate patients for signs of respiratory or central nervous system depression [see Warnings and Precautions (5.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

In patients with creatinine clearance rates less than 50 mL/min, start Oxymorphone Hydrochloride Extended-Release Tablets in patients who are not opioid tolerant with the 5 mg dose. For patients on prior opioid therapy, start Oxymorphone Hydrochloride Extended-Release Tablets at 50% lower than the starting dose for a patient with normal renal function on prior opioids and titrate slowly. Regularly evaluate patients for signs of respiratory or central nervous system depression [see Warnings and Precautions (5.2), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

The steady-state plasma concentrations of oxymorphone are higher in elderly subjects than in young subjects. Initiate dosing with Oxymorphone Hydrochloride Extended-Release Tablets in patients 65 years of age and over using the 5 mg dose and regularly evaluate for signs of respiratory and central nervous system depression when initiating and titrating Oxymorphone Hydrochloride Extended-Release Tablets to adequate analgesia [see Warnings and Precautions (5.2), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. For patients on prior opioid therapy, start Oxymorphone Hydrochloride Extended-Release Tablets at 50% lower than the starting dose for a younger patient on prior opioids and titrate slowly.

Oxymorphone Hydrochloride Extended-Release Tablets USP, 5 mg dosage form is a purple, round, film-coated extended-release tablet debossed with “G71” on one side and blank on the other side.

Oxymorphone Hydrochloride Extended-Release Tablets USP, 7.5 mg dosage form is a gray, round, film-coated extended-release tablet debossed with “G75” on one side and blank on the other side.

Oxymorphone Hydrochloride Extended-Release Tablets USP, 10 mg dosage form is an orange, round, film-coated extended-release tablet debossed with “G72” on one side and blank on the other side.

Oxymorphone Hydrochloride Extended-Release Tablets USP, 15 mg dosage form is a white, round, film-coated extended-release tablet debossed with “G76” on one side and blank on the other side.

Oxymorphone Hydrochloride Extended-Release Tablets USP, 20 mg dosage form is a green, round, film-coated extended-release tablet debossed with “G73” on one side and blank on the other side.

Oxymorphone Hydrochloride Extended-Release Tablets USP, 30 mg dosage form is a brown, round, film-coated extended-release tablet debossed with “G77” on one side and blank on the other side.

Oxymorphone Hydrochloride Extended-Release Tablets USP, 40 mg dosage form is an orange, round, film-coated extended-release tablet debossed with “G74” on one side and blank on the other side.

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)]

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-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression from opioid use, 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 overdose reversal agents, 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 Extended-Release Tablets, the risk is greatest during the initiation of therapy or following a dose increase.

To reduce the risk of respiratory depression, proper dosing and titration of Oxymorphone Hydrochloride Extended-Release Tablets are essential [see Dosage and Administration (2)]. Overestimating the Oxymorphone Hydrochloride Extended-Release Tablets dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of Oxymorphone Hydrochloride Extended-Release 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.

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 (2.5)].

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, 5.7), Overdosage (10)].

Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on Oxymorphone Hydrochloride Extended-Release Tablets therapy. The co-ingestion of alcohol with Oxymorphone Hydrochloride Extended-Release Tablets may result in increased plasma oxymorphone 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 Extended-Release Tablets with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and 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 recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2) and Overdosage (10)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when Oxymorphone Hydrochloride Extended-Release Tablets are 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 depressants 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)].

Use of Oxymorphone Hydrochloride Extended-Release Tablets 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 time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)].

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 list 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.

 

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 (2.5) and Warnings and Precautions (5.15)].

The use of Oxymorphone Hydrochloride Extended-Release Tablets 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 Extended-Release Tablets 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 Extended-Release Tablets [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 Warnings and Precautions (5.2)].

Regularly evaluate patients, particularly when initiating and titrating Oxymorphone Hydrochloride Extended-Release Tablets and when Oxymorphone Hydrochloride Extended-Release Tablets are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2, 5.3) and Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Potentially life-threatening hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients treated with Oxymorphone Hydrochloride Extended-Release Tablets 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 Extended-Release Tablets immediately, discontinue Oxymorphone Hydrochloride Extended-Release Tablets 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.

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.

A study of Oxymorphone Hydrochloride Extended-Release Tablets in patients with hepatic disease indicated greater plasma concentrations than those with normal hepatic function [see Clinical Pharmacology (12.3)]. Oxymorphone Hydrochloride Extended-Release Tablets are contraindicated in patients with moderate or severe hepatic impairment. In patients with mild hepatic impairment reduce the starting dose to the lowest dose and regularly evaluate for signs of respiratory and central nervous system depression [see Dosage and Administration (2.6)].

Oxymorphone Hydrochloride Extended-Release Tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an 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 Drug Interactions (7)]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of Oxymorphone Hydrochloride Extended-Release Tablets. In patients with circulatory shock, Oxymorphone Hydrochloride Extended-Release Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Oxymorphone Hydrochloride Extended-Release Tablets in patients with circulatory shock.

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 Extended-Release Tablets 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 Extended-Release Tablets.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Oxymorphone Hydrochloride Extended-Release Tablets in patients with impaired consciousness or coma.

Oxymorphone Hydrochloride Extended-Release Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The oxymorphone in Oxymorphone Hydrochloride Extended-Release Tablets 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.

Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2)].

The oxymorphone in Oxymorphone Hydrochloride Extended-Release Tablets 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 Extended-Release Tablets therapy.

Do not rapidly reduce or abruptly discontinue Oxymorphone Hydrochloride Extended-Release Tablets in a patient physically dependent on opioids. When discontinuing Oxymorphone Hydrochloride Extended-Release Tablets 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 (2.5) and Drug Abuse and Dependence (9.3)].

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

Oxymorphone Hydrochloride Extended-Release Tablets 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 Extended-Release Tablets and know how they will react to the medication.

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)]

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)

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)

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

The common (≥1% to <10%) adverse drug reactions reported at least once by patients treated with Oxymorphone Hydrochloride Extended-Release Tablets in the clinical trials organized by MedDRA’s (Medical Dictionary for Regulatory Activities) System Organ Class and not represented in Table 2 were:

Eye disorders: vision blurred

Gastrointestinal disorders: diarrhea, abdominal pain, dyspepsia

General disorders and administration site conditions: dry mouth, appetite decreased, fatigue, lethargy, weakness, pyrexia, dehydration, weight decreased, edema

Nervous system disorders: insomnia

Psychiatric disorders: anxiety, confusion, disorientation, restlessness, nervousness, depression

Respiratory, thoracic and mediastinal disorders: dyspnea

Vascular disorders: flushing and hypertension

Other less common adverse reactions known with opioid treatment that were seen <1% in the Oxymorphone Hydrochloride Extended-Release Tablet trials include the following: Bradycardia, palpitation, syncope, tachycardia, postural hypotension, miosis, abdominal distention, ileus, hot flashes, allergic reactions, hypersensitivity, urticaria, oxygen saturation decreased, central nervous system depression, depressed level of consciousness, agitation, dysphoria, euphoric mood, hallucination, mental status changes, difficult micturition, urinary retention, hypoxia, respiratory depression, respiratory distress, clamminess, dermatitis, hypotension.

The following adverse reactions have been identified during post approval use of opioids. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous system disorder: amnesia, convulsion, memory impairment.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Oxymorphone Hydrochloride Extended-Release Tablets.

Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12)].

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.6)]

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids, and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions (5.13)].

Adverse Reactions from Observational Studies

A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months.

Over 12 months:

• approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and
• approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence (9.2)], respectively, as measured with a validated self-reported instrument.

A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5 to 11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.

The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

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

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.

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 Lactation Day 20 via oral gavage doses of 1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, or 25 mg/kg/day (0.5, 2.4, 4.9, or 12.2 times the HDD based on body surface area, respectively). Increased neonatal death (postnatal day 0 to 1) was noted at 2.4 times the HDD. Decreased pup survival over the first week of life, reduced pup birth weight, and reduced postnatal weight gain were noted 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 10 mg/kg/day and 25 mg/kg/day groups).

In a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of 153 mg/kg oxymorphone hydrochloride (62.2 times the HDD) on Gestation Day 8 to pregnant hamsters. This dose also produced significant maternal toxicity (20% maternal deaths).

Risk Summary

There is no information regarding the presence of oxymorphone in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Oxymorphone Hydrochloride Extended-Release Tablets.

Clinical Considerations

Monitor infants exposed to oxymorphone through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Infertility

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [Clinical Pharmacology (12.2) and Nonclinical Toxicology (13.1)].

The safety and effectiveness of Oxymorphone Hydrochloride Extended-Release Tablets in patients below the age of 18 years have not been established. Two open-label studies were conducted in a total of 42 pediatric patients between the ages of 7 to 17 years requiring continuous, around the clock opioid treatment. The available safety and efficacy data were inconclusive for chronic use of Oxymorphone Hydrochloride Extended-Release Tablets. Limited data from one of the studies suggested that Oxymorphone Hydrochloride Extended-Release Tablets is not recommended for post-surgical pain.

Of the total number of subjects in clinical studies of Oxymorphone Hydrochloride Extended-Release Tablets, 27% were 65 and over, while 9% were 75 and over. No overall differences in effectiveness were observed between these subjects and younger subjects. There were several adverse events that were more frequently observed in subjects 65 and over compared to younger subjects. These adverse events included dizziness, somnolence, confusion, and nausea. On average, age greater than 65 years was associated with an increase in oxymorphone AUC and C_max. Initiate dosing with Oxymorphone Hydrochloride Extended-Release Tablets in patients 65 years of age and over using the 5 mg dose and frequently reevaluate the patient for signs of respiratory and central nervous system depression when initiating and titrating Oxymorphone Hydrochloride Extended-Release Tablets [see Warnings and Precautions (5.2)]. For patients on prior opioid therapy, start at 50% of the starting dose for a younger patient on prior opioids and titrate slowly.

Oxymorphone is known to be substantially excreted by the kidney and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because the elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Patients with mild hepatic impairment have an increase in oxymorphone bioavailability compared to the subjects with normal hepatic function. In patients who are not opioid tolerant with mild hepatic impairment, initiate Oxymorphone Hydrochloride Extended-Release Tablets using the 5 mg dose and regularly evaluate patients for respiratory and central nervous system depression. Oxymorphone Hydrochloride Extended-Release Tablets are contraindicated for patients with moderate and severe hepatic impairment [see Dosage and Administration (2.6), Contraindications (4), Warnings and Precautions (5.10) and Clinical Pharmacology (12.3)]. For patients on prior opioid therapy, start at the 50% of the dose for that a patient with normal hepatic function on prior opioids and titrate slowly.

Patients with moderate to severe renal impairment were shown to have an increase in oxymorphone bioavailability compared to the subjects with normal renal function [see Clinical Pharmacology (12.3)]. Start patients who are not opioid tolerant with the 5 mg dose of Oxymorphone Hydrochloride Extended-Release Tablets and titrate slowly while regularly evaluating for respiratory and central nervous system depression [see Dosage and Administration (2.6)]. For patients on prior opioid therapy, start at 50% of the dose for a patient with normal renal function on prior opioids and titrate slowly.

Oxymorphone Hydrochloride Extended-Release Tablets contain oxymorphone, a Schedule II controlled substance.

Oxymorphone Hydrochloride Extended-Release Tablets contain oxymorphone, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than to other activities and obligations), and possible tolerance or  physical dependence.

Misuse and abuse of Oxymorphone Hydrochloride Extended-Release Tablets increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of Oxymorphone Hydrochloride Extended-Release Tablets with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Oxymorphone Hydrochloride Extended-Release Tablets abuse include those with a history of prolonged use of any opioid, including products containing oxymorphone, those with a history of drug or alcohol abuse, or those who use Oxymorphone Hydrochloride Extended-Release Tablets in combination with other abused drugs.

“Drug seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Pre-occupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Oxymorphone Hydrochloride Extended-Release Tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Oxymorphone Hydrochloride Extended-Release Tablets

Abuse of Oxymorphone Hydrochloride Extended-Release Tablets poses a risk of overdose and death. This risk is increased with concurrent use of Oxymorphone Hydrochloride Extended-Release Tablets with alcohol and/or other CNS depressants. Taking cut, broken, chewed, crushed, or dissolved Oxymorphone Hydrochloride Extended-Release Tablets enhance drug release and increases the risk of overdose and death [see Warnings and Precautions (5.1, 5.3) and Drug Interactions (7)].

Oxymorphone Hydrochloride Extended-Release Tablets are approved for oral use only. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Do not rapidly reduce or abruptly discontinue Oxymorphone Hydrochloride Extended-Release Tablets in a patient physically dependent on opioids. Rapid reduction or abrupt discontinuation of Oxymorphone Hydrochloride Extended-Release Tablets in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing Oxymorphone Hydrochloride Extended-Release Tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Oxymorphone Hydrochloride Extended-Release Tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5) and Warnings and Precautions (5.15)].

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

Clinical Presentation

Acute overdosage with oxymorphone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or completed airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with severe hypoxia in overdose situations [see Clinical Pharmacology (12.2)]. Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication.

Treatment of Overdose

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support measures.

For clinically significant respiratory or circulatory depression secondary to oxymorphone overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene.

Because the duration of opioid reversal is expected to be less than the duration of action of oxymorphone in Oxymorphone Hydrochloride Extended-Release Tablets, carefully monitor the patient until spontaneous respiration is reliably re-established. Oxymorphone Hydrochloride Extended-Release Tablets will continue to release oxymorphone and add to the oxymorphone load for 24 to 48 hours or longer following ingestion, necessitating prolonged monitoring. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the opioid overdose reversal agent will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the reversal agent administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent.

Oxymorphone Hydrochloride Extended-Release Tablets, USP are for oral use and contain oxymorphone, an opioid agonist. Oxymorphone Hydrochloride Extended-Release Tablets, USP are supplied in 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg and 40 mg tablet strengths for oral administration. The tablet strength describes the amount of oxymorphone hydrochloride per tablet.

The tablets contain the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, hypromellose, xanthan gum, magnesium stearate, polyvinyl alcohol - partially hydrolyzed, polyethylene glycol, talc, and titanium dioxide. The 5 mg, 7.5 mg, 10 mg, 20 mg and 40 mg tablets contain FD&C Yellow No. 6 Aluminum Lake. In addition, the 5 mg tablets contain FD&C Blue No. 2 and D&C Red No. 27. The 7.5 mg tablets contain FD&C Blue No. 2 and FD&C Red No. 40. The 10 mg tablets contain FD&C Red No. 40. The 20 mg tablets contain D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1, and FD&C Blue No. 2. The 30 mg tablets contain Iron Oxide Yellow and Iron Oxide Black. The 40 mg tablets contain D&C Yellow No. 10 Aluminum Lake.

The chemical name of oxymorphone hydrochloride is 4,5α-epoxy-3, 14-dihydroxy-17-methylmorphinan-6-one hydrochloride. Oxymorphone hydrochloride, USP is a white or slightly off-white, odorless powder, which is sparingly soluble in alcohol and ether, but freely soluble in water. The molecular weight of oxymorphone hydrochloride is 337.80. The pKa1 and pKa2 of oxymorphone at 37°C are 8.17 and 9.54, respectively. The octanol/aqueous partition coefficient at 37°C and pH 7.4 is 0.98.

The structural formula for oxymorphone hydrochloride is as follows:

10 (Oxymorphone Extended Release Tablets Speciality 1)

FDA approved dissolution test specifications differ from USP.

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.

CNS Depressant/Alcohol Interaction

Additive pharmacodynamic effects may be expected when Oxymorphone Hydrochloride Extended-Release Tablets are used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

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 origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and on 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 is 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. Release of histamine can occur and may contribute to opioid-induced hypotension. Manifestations of histamine release and/ or peripheral vasodilation may include pruritis, flushing, red eyes, 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.

Use 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 opioid agonists. The minimum effective analgesic concentration of oxymorphone for any individual patient may increase over time due to an increase in pain, development of a new pain syndrome and/or development of analgesic tolerance [see Dosage and Administration (2.1, 2.4)].

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, 2.4)].

Absorption

The absolute oral bioavailability of oxymorphone is approximately 10%.

Steady-state levels are achieved after three days of multiple dose administration. Under both single-dose and steady-state conditions, dose proportionality has been established for the 5 mg, 10 mg, 20 mg, and 40 mg doses of Oxymorphone Hydrochloride Extended-Release Tablets, for both peak plasma levels (C_max) and extent of absorption (AUC) (see Table 6).

Table 6: Mean (±SD) Oxymorphone Hydrochloride Extended-Release Tablets Pharmacokinetic Parameters

Food Effect

Two studies examined the effect of food on the bioavailability of single doses of 20 mg and 40 mg of Oxymorphone Hydrochloride Extended-Release Tablets in healthy volunteers. In both studies, after the administration of Oxymorphone Hydrochloride Extended-Release Tablets, the C_max was increased by approximately 50% in fed subjects compared to fasted subjects. A similar increase in C_max was also observed with oxymorphone solution.

The AUC was unchanged in one study and increased by approximately 18% in the other study in fed subjects following the administration of Oxymorphone Hydrochloride Extended-Release Tablets. Examination of the AUC suggests that most of the difference between fed and fasting conditions occurs in the first four hours after dose administration. After oral dosing with a single dose of 40 mg, a peak oxymorphone plasma level of 2.8 ng/ml is achieved at 1 hour in fasted subjects and a peak of 4.25 ng/ml is achieved at 2 hours in fed subjects and that beyond the 12-hour time point, there is very little difference in the curves. As a result, Oxymorphone Hydrochloride Extended-Release Tablets should be dosed at least one hour prior to or two hours after eating [see Dosage and Administration (2.1, 2.3)].

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

Metabolism

Oxymorphone is highly metabolized, principally in the liver, and undergoes reduction or conjugation with glucuronic acid to form both active and inactive metabolites. 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 less than 1% 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

Geriatric Patients

The steady-state plasma concentrations of oxymorphone, 6-OH-oxymorphone, and oxymorphone-3-glucuronide are approximately 40% higher in elderly subjects (≥65 years of age) than in young subjects (18 to 40 years of age). On average, age greater than 65 years was associated with a 1.4-fold increase in oxymorphone AUC and a 1.5-fold increase in C_max. This observation does not appear related to a difference in body weight, metabolism, or excretion of oxymorphone [see Use in Specific Populations (8.5)].

Sex

The effect of sex was evaluated following single- and multiple-doses of Oxymorphone Hydrochloride Extended-Release Tablets in male and female adult volunteers. 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 bioavailability of orally administered oxymorphone is markedly increased in patients with moderate to severe liver disease. The disposition of oxymorphone was compared in six patients with mild, five patients with moderate, and one patient with severe hepatic impairment and 12 subjects with normal hepatic function. The bioavailability of oxymorphone was increased by 1.6-fold in patients with mild hepatic impairment and by 3.7-fold in patients with moderate hepatic impairment. In one patient with severe hepatic impairment, the bioavailability was increased by 12.2-fold. The half-life of oxymorphone was not significantly affected by hepatic impairment.

Renal Impairment

Data from a pharmacokinetic study involving 24 patients with renal dysfunction show an increase of 26%, 57%, and 65% in oxymorphone bioavailability in mild (creatinine clearance 51 mL/min to 80 mL/min; n=8), moderate (creatinine clearance 30 mL/min to 50 mL/min; n=8), and severe (creatinine clearance < 30 mL/min; n=8) patients, respectively, compared to healthy controls.

Drug Interaction Studies

Alcohol Interaction

An in vivo study of the effect of alcohol (40%, 20%, 4% and 0%) on the bioavailability of a single dose of 40 mg of Oxymorphone Hydrochloride Extended-Release Tablets in healthy, fasted volunteers demonstrated a highly variable effect on C_max with concomitant administration of alcohol and Oxymorphone Hydrochloride Extended-Release Tablets. The change in C_max ranged from a decrease of 50% to an increase of 270% across all conditions studied. Following administration of 240 mL of 40% ethanol, the C_max increased on average by 70% and up to 270% in individual subjects. Following the concomitant administration of 240 mL of 20% ethanol, the C_max increased on average by 31% and up to 260% in individual subjects. Following the concomitant administration of 240 mL of 4% ethanol, the C_max increased 7% on average and by as much as 110% for individual subjects. After oral dosing with a single dose of 40 mg in fasted subjects, the mean peak oxymorphone plasma level is 2.4 ng/mL and the median T_max is 2 hours. Following co-administration of Oxymorphone Hydrochloride Extended-Release Tablets and alcohol (240 mL of 40% ethanol) in fasted subjects, the mean peak oxymorphone level is 3.9 ng/mL and the median T_max is 1.5 hours (range 0.75 to 6 hours). The oxymorphone mean AUC was 13% higher after co-administration of 240 mL of 40% alcohol. The AUC was essentially unaffected in subjects following the co-administration of Oxymorphone Hydrochloride Extended-Release Tablets and ethanol (240 mL of 20% or 4% ethanol).

In vitro studies have demonstrated that Oxymorphone Hydrochloride Extended-Release Tablets do not release oxymorphone more rapidly in 500 mL of 0.1N Hydrochloride solutions containing ethanol (4%, 20% and 40%).

Instruct patients to avoid use of alcohol when taking Oxymorphone Hydrochloride Extended-Release Tablets.

In vitro studies revealed little to no biotransformation of oxymorphone to 6-OH-oxymorphone by any of the major cytochrome P450 (CYP P450) isoforms at therapeutically relevant oxymorphone plasma concentrations.

No inhibition of any of the major CYP P450 isoforms was observed when oxymorphone was incubated with human liver microsomes at concentrations of ≤15.1 mcg/mL. An inhibition of CYP3A4 activity occurred at oxymorphone concentrations ≥45.3 mcg/mL. Therefore, it is not expected that oxymorphone, or its metabolites will act as inhibitors of any of the major CYP P450 enzymes in vivo.

Increases in the activity of the CYP 2C9 and CYP 3A4 isoforms occurred when oxymorphone was incubated with human hepatocytes. However, clinical drug interaction studies with Oxymorphone Hydrochloride Extended-Release Tablets showed no induction of CYP450 3A4 or 2C9 enzyme activity, indicating that no dose adjustment for CYP 3A4- or 2C9-mediated drug-drug interactions is required.

Carcinogenesis

No evidence of carcinogenic potential was observed in long-term animal studies in mice and rats. Oxymorphone hydrochloride was administered to Sprague Dawley rats (2.5 mg/kg/day, 5 mg/kg/day and 10 mg/kg/day in males and 5 mg/kg/day, 10 mg/kg/day and 25 mg/kg/day in females) for 2 years by oral gavage. Systemic drug exposure (AUC) at the highest doses tested in male and female rats was 4.8 times and 21.2 times the human exposure at a dose of 20 mg/day, respectively. Oxymorphone hydrochloride was administered to male and female CD-1 mice (10 mg/kg/day, 25 mg/kg/day, 75 mg/kg/day and 150 mg/kg/day) for 2 years by oral gavage. Systemic drug exposure (AUC) at 150 mg/kg/day in male and female mice was 205 times and 243 times the human exposure at a dose of 20 mg/day, respectively.

Mutagenesis

Oxymorphone hydrochloride was not mutagenic when tested in the in vitro bacterial reverse mutation assay (Ames test), or in an in vitro mammalian cell chromosome aberration assay performed with human peripheral blood lymphocytes. Oxymorphone hydrochloride tested positive in both the rat and mouse in vivo micronucleus assays. An increase in micronucleated polychromatic erythrocytes occurred in mice given doses ≥ 250 mg/kg and in rats given doses of 20 mg/kg and 40 mg/kg. A subsequent study demonstrated that oxymorphone hydrochloride was not aneugenic in mice following administration of up to 500 mg/kg. Additional studies indicate that the increased incidence of micronucleated polychromatic erythrocytes in rats may be secondary to increased body temperature following oxymorphone administration. Doses associated with increased micronucleated polychromatic erythrocytes also produce a marked, rapid increase in body temperature. Pretreatment of animals with sodium salicylate minimized the increase in body temperature and prevented the increase in micronucleated polychromatic erythrocytes after administration of 40 mg/kg oxymorphone.

Impairment of Fertility

Female rats were treated with oxymorphone hydrochloride beginning 14 days prior to mating through Gestation Day 7 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 human daily dose of 20 mg/day based on body surface area, respectively). Male rats were treated via oral gavage with the same oxymorphone hydrochloride doses beginning 28 days prior to and throughout mating. In female rats, an increase in the length of the estrus cycle and decrease in the mean number of viable embryos, implantation sites and corpora lutea were observed at 4.9 times the human dose of 20 mg/day. No adverse effects of oxymorphone on male reproductive function or sperm parameters were observed.

The efficacy and safety of Oxymorphone Hydrochloride Extended-Release Tablets have been evaluated in double-blind, controlled clinical trials in patients who were not opioid tolerant and opioid-experienced patients with moderate to severe pain including low back pain.

12-Week Study in Patients who were not Opioid Tolerant with Low Back Pain

Patients with chronic low back pain who were suboptimally responsive to their non-opioid therapy entered a 4-week, open-label dose titration phase. Patients initiated therapy with two days of treatment with Oxymorphone Hydrochloride Extended-Release Tablets 5 mg, every 12 hours. Thereafter, patients were titrated to a stabilized dose, at increments of 5 mg to 10 mg every 12 hours every 3 to 7 days. Of the patients who were able to stabilize within the Open-Label Titration Period, the mean±SD VAS score at Screening was 69.4±11.8 mm and at Baseline (beginning of Double-Blind Period) were 18.5±11.2 mm and 19.3±11.3 mm for the oxymorphone ER and placebo groups, respectively. Sixty-three percent of the patients enrolled were able to titrate to a tolerable dose and were randomized into a 12-week double-blind treatment phase with placebo or their stabilized dose of Oxymorphone Hydrochloride Extended-Release Tablets. The mean±SD stabilized doses were 39.2±26.4 mg and 40.9±25.3 mg for the Oxymorphone Hydrochloride Extended-Release Tablets and placebo groups, respectively; total daily doses ranged from 10 mg to 140 mg. During the first 4 days of double-blind treatment patients were allowed an unlimited number of oxymorphone hydrochloride tablets, an immediate-release (IR) formulation of oxymorphone, 5 mg tablets, every 4 to 6 hours as supplemental analgesia; thereafter the number of oxymorphone hydrochloride tablets was limited to two tablets per day. This served as a tapering method to minimize opioid withdrawal symptoms in placebo patients. Sixty-eight percent of patients treated with Oxymorphone Hydrochloride Extended-Release Tablets completed the 12-week treatment compared to 47% of patients treated with placebo. Oxymorphone Hydrochloride Extended-Release Tablets provided superior analgesia compared to placebo. The analgesic effect of Oxymorphone Hydrochloride Extended-Release Tablets was maintained throughout the double-blind treatment period in 89% of patients who completed the study. These patients reported a decrease, no change, or a ≤ 10 mm increase in VAS score from Day 7 until the end of the study.

The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 1. The figure is cumulative, so that patients whose change from baseline is, for example, 30%, are also included at every level of improvement below 30%. Patients who did not complete the study were assigned 0% improvement.

Figure 1: Percent Reduction in Average Pain Intensity from Screening to Final Visit

1 (Oxymorphone Extended Release Tablets Speciality 2)

12-Week Study in Opioid-Experienced Patients with Low Back Pain

Patients on chronic opioid therapy entered a 4-week, open-label titration phase with Oxymorphone Hydrochloride Extended-Release Tablets dosed every 12 hours at an approximated equianalgesic dose of their pre-study opioid medication. Of the patients who were able to stabilize within the Open‑Label Titration Period, the mean±SD VAS score at Screening was 69.5±17.0 mm and at Baseline (beginning of Double-Blind Period) were 23.9±12.1 mm and 22.2±10.8 mm for the oxymorphone ER and placebo groups, respectively. Stabilized patients entered a 12‑week double-blind treatment phase with placebo or their stabilized dose of Oxymorphone Hydrochloride Extended-Release Tablets. The mean±SD stabilized doses were 80.9±59.3 mg and 93.3±61.3 mg for the Oxymorphone Hydrochloride Extended-Release Tablets and placebo groups, respectively; total daily doses ranged from 20 mg to 260 mg. During the first 4 days of double-blind treatment, patients were allowed an unlimited number of oxymorphone hydrochloride 5 mg tablets, every 4 to 6 hours as supplemental analgesia; thereafter the number of oxymorphone hydrochloride tablets was limited to two tablets per day. This served as a tapering method to minimize opioid withdrawal symptoms in placebo patients. Fifty-seven percent of patients were titrated to a stabilized dose within approximately 4 weeks of Oxymorphone Hydrochloride Extended-Release Tablets dose titration. Seventy percent of patients treated with Oxymorphone Hydrochloride Extended-Release Tablets and 26% of patients treated with placebo completed the 12-week treatment. Oxymorphone Hydrochloride Extended-Release Tablets provided superior analgesia compared to placebo. The analgesic effect of Oxymorphone Hydrochloride Extended-Release Tablets was maintained throughout the double-blind treatment period in 80% of patients who completed the study. These patients reported a decrease, no change, or a ≤ 10 mm increase in VAS score from Day 7 until the end of the study.

The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 2. The figure is cumulative, so that patients whose change from baseline is, for example, 30%, are also included at every level of improvement below 30%. Patients who did not complete the study were assigned 0% improvement.

Figure 2: Percent Reduction in Average Pain Intensity from Screening to Final Visit

10 (Oxymorphone Extended Release Tablets Speciality 3)

Oxymorphone Hydrochloride Extended-Release Tablets, USP are supplied as the following strengths:

Oxymorphone Hydrochloride Extended-Release Tablets USP, 5 mg are purple, round, film-coated extended-release tablets debossed with “G71” on one side and blank on the other side.

They are available as follows:

Bottles of 30:                                                  NDC 64896-695-08

Bottles of 60:                                                  NDC 64896-695-13

Bottles of 100:                                                NDC 64896-695-01

Bottles of 1000:                                              NDC 64896-695-03

Oxymorphone Hydrochloride Extended-Release Tablets USP, 7.5 mg are gray, round, film-coated extended-release tablets debossed with “G75” on one side and blank on the other side.

They are available as follows:

Bottles of 30:                                                  NDC 64896-696-08

Bottles of 60:                                                  NDC 64896-696-13

Bottles of 100:                                                NDC 64896-696-01

Bottles of 1000:                                              NDC 64896-696-03

Oxymorphone Hydrochloride Extended-Release Tablets USP, 10 mg are orange, round, film-coated extended-release tablets debossed with “G72” on one side and blank on the other side.

They are available as follows:

Bottles of 30:                                                  NDC 64896-697-08

Bottles of 60:                                                  NDC 64896-697-13

Bottles of 100:                                                NDC 64896-697-01

Bottles of 1000:                                              NDC 64896-697-03

Oxymorphone Hydrochloride Extended-Release Tablets USP, 15 mg are white, round, film-coated extended-release tablets debossed with “G76” on one side and blank on the other side.

They are available as follows:

Bottles of 30:                                                  NDC 64896-698-08

Bottles of 60:                                                  NDC 64896-698-13

Bottles of 100:                                                NDC 64896-698-01

Bottles of 1000:                                              NDC 64896-698-03

Oxymorphone Hydrochloride Extended-Release Tablets USP, 20 mg are green, round, film-coated extended-release tablets debossed with “G73” on one side and blank on the other side.

They are available as follows:

Bottles of 30:                                                  NDC 64896-699-08

Bottles of 60:                                                  NDC 64896-699-13

Bottles of 100:                                                NDC 64896-699-01

Bottles of 1000:                                              NDC 64896-699-03

Oxymorphone Hydrochloride Extended-Release Tablets USP, 30 mg are brown, round, film-coated extended-release tablets debossed with “G77” on one side and blank on the other side.

They are available as follows:

Bottles of 30:                                                  NDC 64896-700-08

Bottles of 60:                                                  NDC 64896-700-13

Bottles of 100:                                                NDC 64896-700-01

Bottles of 1000:                                              NDC 64896-700-03

Oxymorphone Hydrochloride Extended-Release Tablets USP, 40 mg are orange, round, film-coated extended-release tablets debossed with “G74” on one side and blank on the other side.

They are available as follows:

Bottles of 30:                                                  NDC 64896-701-08

Bottles of 60:                                                  NDC 64896-701-13

Bottles of 100:                                                NDC 64896-701-01

Bottles of 1000:                                              NDC 64896-701-03

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in tight container as defined in the USP, with a child-resistant closure (as required).

Store Oxymorphone Hydrochloride Extended-Release Tablets securely and dispose of properly.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Storage and Disposal

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Oxymorphone Hydrochloride Extended-Release Tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving Oxymorphone Hydrochloride Extended-Release Tablets unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.2) and Drug Abuse and Dependence (9.2)].

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused Oxymorphone Hydrochloride Extended-Release Tablets should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

Addiction, Abuse, and Misuse

Inform patients that the use of Oxymorphone Hydrochloride Extended-Release Tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see Warnings and Precautions (5.1)]. Instruct patients not to share Oxymorphone Hydrochloride Extended-Release Tablets with others and to take steps to protect Oxymorphone Hydrochloride Extended-Release Tablets from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Oxymorphone Hydrochloride Extended-Release Tablets or when the dosage is increased, and that it can occur even at recommended doses.

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 Warnings and Precautions (5.2)].

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)].

Interactions with Benzodiazepines and other CNS Depressants

Instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter products that contain alcohol, during treatment with Oxymorphone Hydrochloride Extended-Release Tablets. The co-ingestion of alcohol with Oxymorphone Hydrochloride Extended-Release Tablets may result in increased plasma levels and a potentially fatal overdose of oxymorphone [see Warnings and Precautions (5.3) and Drug Interactions (7)].

Inform patients and caregivers that potentially fatal additive effects may occur if Oxymorphone Hydrochloride Extended-Release Tablets are used with benzodiazepines or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids)l, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.3) and Drug Interactions (7)].

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.

Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

Explain to patients and caregivers that effects of opioid overdose reversal agents like naloxone and nalmefene are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if an opioid overdose reversal agent is administered [see Overdosage (10)].

Advise patients and caregivers:

• how to treat with the overdose reversal agent in the event of an opioid overdose.
• to tell family and friends about their opioid overdose reversal agent, and to keep it in a place where family and friends can access it in an emergency.
• to read the Patient Information (or other educational material) that will come with their opioid overdose reversal agent. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

 

Hyperalgesia and Allodynia

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.6) and Adverse Reactions (6.2)].

 

Anaphylaxis, Angioedema, and Other Hypersensitivity Reactions

Inform patients that anaphylaxis and other hypersensitivity reactions have been reported with ingredients contained in Oxymorphone Hydrochloride Extended-Release Tablets. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Warnings and Precautions (5.8) and Adverse Reactions (6)].

 

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see Drug Interactions (7)].

 

MAOI Interaction

Inform patients to avoid taking Oxymorphone Hydrochloride Extended-Release Tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Oxymorphone [see Drug Interactions (7)].

 

Important Administration Instructions

Instruct patients how to properly take Oxymorphone Hydrochloride Extended-Release Tablets, including the following:

• Oxymorphone Hydrochloride Extended-Release Tablets are designed to work properly only if swallowed intact. Taking cut, broken, chewed, crushed, or dissolved Oxymorphone Hydrochloride Extended-Release Tablets can result in a fatal overdose [see Dosage and Administration (2.1)].
• Use Oxymorphone Hydrochloride Extended-Release Tablets exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) [see Dosage and Administration (2) and Warnings and Precautions (5.2)].

Important Discontinuation Instructions

 

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Oxymorphone Hydrochloride Extended-Release Tablets without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.5)].

 

Driving or Operating Heavy Machinery

Inform patients that Oxymorphone Hydrochloride Extended-Release Tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.16)].

 

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6) and Clinical Pharmacology (12.2)].

Adrenal Insufficiency

Inform patients that Oxymorphone Hydrochloride Extended-Release Tablets could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.9)].

 

Hypotension

Inform patients that Oxymorphone Hydrochloride Extended-Release Tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).

 

Pregnancy

 

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that use of Oxymorphone Hydrochloride Extended-Release Tablets for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].

 

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that Oxymorphone Hydrochloride Extended-Release Tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

 

Lactation

Advise patients that breastfeeding is not recommended during treatment with Oxymorphone Hydrochloride Extended-Release Tablets [see Use in Specific Populations (8.2)].

 

Infertility

Inform patients that use of opioids for an extended period of  time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2) and Use in Specific Populations (8.3)].

 

Manufactured by:
Amneal Pharmaceuticals of NY, LLC
Brookhaven, NY 11719

Distributed by:
Amneal Specialty, a division of Amneal Pharmaceuticals LLC
Bridgewater, NJ 08807

Rev. 01-2026-08