OXYMORPHONE HYDROCHLORIDE

Boxed Warning 10/2025 Indications and Usage ( 1 ) 10/2025 Dosage and Administration ( 2.2 , 2.9 ) 10/2025 Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.12 , 5.14 ) 10/2025

1 INDICATIONS AND USAGE Oxymorphone hydrochloride tablets are an opioid agonist indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Limitations of Use 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 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 tablets are an opioid agonist indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics including oxymorphone hydrochloride tablets for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain ( 1 , 5.1 ).

2 DOSAGE AND ADMINISTRATION Oxymorphone hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. (2.1) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of oxymorphone hydrochloride tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (2.1, 5) Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. (2.1) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (2.1, 5.1) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with oxymorphone hydrochloride tablets. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1, 5.2) Initiate treatment with oxymorphone hydrochloride tablets in a dosing range of 10 mg to 20 mg every four to six hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of oxymorphone hydrochloride tablets. (2.3, 5) Oxymorphone hydrochloride tablets should be taken on an empty stomach, at least one hour prior to or two hours after eating. (2.1) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with oxymorphone hydrochloride tablets, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. (2.2, 5.1, 5.2, 5.3) Conversion to oxymorphone hydrochloride tablets: Follow recommendations for conversion from other opioids or parenteral oxymorphone. (2.3) Periodically reassess patients receiving oxymorphone hydrochloride tablets to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. (2.8) Do not rapidly reduce or abruptly discontinue oxymorphone hydrochloride tablets in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.9, 5.14) Mild Hepatic Impairment : Initiate treatment with 5 mg and titrate slowly. Monitor for signs of respiratory and central nervous system depression. (2.4) Renal Impairment : Initiate treatment with 5 mg and titrate slowly. Monitor for signs of respiratory and central nervous system depression. (2.5) Geriatric Patients : Initiate dosing with 5 mg, titrate slowly, and monitor for signs of respiratory and central nervous system depression. (2.6) CNS Depressants : Initiate treatment with 1/3 to 1/2 the recommended starting dose, consider using a lower dosage of the concomitant CNS depressant, and monitor closely. (2.7, 5.7, 7) 2.1 Important Dosage and Administration Instructions Oxymorphone hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of oxymorphone hydrochloride tablets for patients in whom lower doses are …

3 DOSAGE FORMS AND STRENGTHS Oxymorphone Hydrochloride Tablets, USP are available as 5 mg and 10 mg for oral administration. 5 mg tablet is supplied as a round, white to off-white, standard biconvex tablet debossed with product identification “54” over “956” on one side and plain on the other side. 10 mg tablet is supplied as a round, white to off-white, standard biconvex tablet debossed with product identification “54” over “814” on one side and plain on the other side. Tablets: 5 mg and 10 mg ( 3 )

4 CONTRAINDICATIONS Oxymorphone hydrochloride tablets are contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.2) ] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.7) ] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.12) ] • Hypersensitivity to oxymorphone (e.g., anaphylaxis, angioedema) or [see Warnings and Precautions (5.8) , Adverse Reactions (6) ] • Moderate or severe hepatic impairment [see Warnings and Precautions (5.16) ]. • Significant respiratory depression ( 4 ) • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment ( 4 ) • Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 ) • Known hypersensitivity to oxymorphone, any other ingredients in oxymorphone hydrochloride tablets ( 4 ) • Moderate or severe hepatic impairment ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] • Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] • Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions ( 5.3 )] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] • Opioid-induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.6 )] • Anaphylaxis, Angioedema, and Other Hypersensitivity Reactions [see Warnings and Precautions ( 5.8 )] • Adrenal Insufficiency [see Warnings and Precautions ( 5.9 )] • Severe Hypotension [see Warnings and Precautions ( 5.10 )] • Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.12 )] • Seizures [see Warnings and Precautions ( 5.13 )] • Withdrawal [see Warnings and Precautions ( 5.14 )] Adverse Reactions (≥ 2% of patients): Nausea, pyrexia, somnolence, vomiting, pruritus, headache, dizziness, constipation, and confusion. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Adult Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 591 patients were treated with oxymorphone hydrochloride in controlled clinical trials. The clinical trials consisted of patients with acute post-operative pain (n=557) and cancer pain (n=34) trials. The following table lists adverse reactions that were reported in at least 2% of patients receiving oxymorphone hydrochloride in placebo-controlled trials (acute post-operative pain (N=557)). Table 1: Adverse Reactions Reported in Placebo-Controlled Trials MedDRA Preferred Term Oxymorphone Hydrochloride (N=557) Placebo (N=270) Nausea 19% 12% Pyrexia 14% 8% Somnolence 9% 2% Vomiting 9% 7% Pruritus 8% 4% Headache 7% 4% Dizziness (Excluding Vertigo) 7% 2% Constipation 4% 1% Confusion 3% <1% The common (≥1% to <10%) adverse drug reactions reported at least once by patients treated with oxymorphone hydrochloride in the clinical trials organized by MedDRA’s (Medical Dictionary for Regulatory Activities) System Organ Class were not represented in Table 1: Cardiac disorders : tachycardia Gastrointestinal disorders : dry mouth, abdominal distention, and flatulence General disorders and administration site conditions : sweating increased Nervous system disorders : anxiety and sedation Respiratory, thoracic and mediastinal disorders : hypoxia Vascular disorders : hypotension Other less common adverse reactions known with opioid treatment that were seen <1% in the oxymorphone hydrochloride trials includes the following: Abdominal pain, ileus, diarrhea, agitation, disorientation, restlessness, feeling jittery, hypersensitivity, allergic reactions, bradycardia, central nervous system depression, depressed level of consciousness, lethargy, mental impairment, mental status changes, fatigue, depression, clamminess, flushing, hot flashes, dehydration, dermatitis, dyspepsia, dysphoria, edema, euphoric mood, hallucination, hypertension, insomnia, miosis, nervousness, palpitation, postural hypotension, syncope, dyspnea, respiratory depression, respiratory distress, respiratory rate decreased, oxygen saturation decreased, difficult micturition, urinary retention, urticaria, vision blurred, visual disturbances, weakness, appetite decreased, and weight decreased. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of opioids. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estima …

7 DRUG INTERACTIONS Table 2 includes clinically significant drug interactions with oxymorphone hydrochloride tablets. Table 2: Clinically Significant Drug Interactions with Oxymorphone Hydrochloride Tablets Alcohol Clinical Impact: The concomitant use of alcohol with oxymorphone hydrochloride tablets can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone. Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on oxymorphone hydrochloride tablets therapy [see Clinical Pharmacology 12.3) ]. Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2 , 2.7 ), Warnings and Precautions (5.1 , 5.3 , 5.5 )]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue oxymorphone hydrochloride tablets if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2) ]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Intervention: The use of oxymorphone hydrochloride tablets are not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Oxymorphone Hydrochloride Tablets and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine, Muscle Relaxants Clinical Impact: Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of oxymorphone hydrochloride tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precauti …

8 USE IN SPECIFIC POPULATIONS • Pregnancy: May cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary: Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions( 5.4 ) and Clinical Considerations]. Data from randomized controlled trials with oxymorphone use in pregnant women during labor and delivery have been conducted. However, these studies were not designed to identify a drug-associated risk for major birth defects and miscarriage because oxymorphone exposure occurred after the first trimester. There are reports of respiratory depression in infants in some of these trials [see Clinical Considerations]. 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 estimated 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 clinically recognized pregnancies is 2 to 4% and 15 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 is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including oxymorphone hydrochloride, 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 dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data: Animal Data: Pregnant rats were treated with oxymorphone hydrochloride from Gestation Day 6 to 17 via oral gavage doses of 5, 10, 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, 25, or 50 mg/kg/day (9.8, 24.4, or 48.8 times the HDD based on body surface area, respectively). Decre …

12.1 Mechanism of Action Oxymorphone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxymorphone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxymorphone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

11 DESCRIPTION Oxymorphone Hydrochloride Tablets are an opioid agonist available in 5 mg and 10 mg tablet strengths for oral administration. The chemical name for oxymorphone hydrochloride is 4, 5α-epoxy-3, 14-dihydroxy-17-methylmorphinan-6-one hydrochloride. The molecular weight is 337.80. The molecular formula is C 17 H 19 NO 4 • HCl and it has the following chemical structure. Oxymorphone hydrochloride is white to off white odorless powder, which is sparingly soluble in alcohol and ether, but freely soluble in water. The inactive ingredients in oxymorphone hydrochloride tablets include: lactose monohydrate, magnesium stearate, pregelatinized starch‐and sodium lauryl sulfate. In addition, the 5 mg tablets contain iron oxide red #30. The 10 mg tablets contain D&C yellow #10 aluminum lake. FDA approved dissolution test specifications differ from USP. structure-formula.jpg

10 OVERDOSAGE Clinical Presentation Acute overdose with oxymorphone hydrochloride tablets 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, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)] . 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 and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to oxymorphone overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to Oxymorphone overdose. Because the duration of opioid reversal is expected to be less than the duration of action of oxymorphone in oxymorphone hydrochloride tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist 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 antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

16 HOW SUPPLIED/STORAGE AND HANDLING Oxymorphone Hydrochloride Tablets, USP are supplied as follows: 5 mg Tablet: Blue, round, biconvex tablets debossed with “K” above “70” on one side and plain on the other. Bottles of 60 tablets with child-resistant closure NDC 10702-070-06 Bottles of 100 tablets with child-resistant closure NDC 10702-070-01 10 mg Tablet: Red, round, biconvex tablets debossed with “K” above “71” on one side and plain on the other. Bottles of 60 tablets with child-resistant closure NDC 10702-071-06 Bottles of 100 tablets with child-resistant closure NDC 10702-071-01 Store at 20° to 25°C (68° to 77°F), with excursions permitted between 15° to 30°C (59° to 86°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 Tablets, USP securely and dispose of properly [see Patient Counseling Information ( 17 )] .