OXAYDO

Boxed Warning 12/2025 Indications and Usage ( 1 ) 12/2025 Dosage and Administration ( 2.2 , 2.5 ) 12/2025 Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.12 , 5.14 ) 12/2025

1 INDICATIONS AND USAGE OXAYDO is indicated for the management of acute and chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, 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 OXAYDO, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. OXAYDO is an opioid agonist indicated for the management of acute and chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Limitations of Use ( 1 ) Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including OXAYDO, 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 OXAYDO 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 OXAYDO 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 OXAYDO. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with OXAYDO, 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 ) For opioid naïve patients, initiate treatment with 5 mg to 15 mg every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of OXAYDO. ( 2.2 , 2.4 ) Must be swallowed whole and is not amenable to crushing and dissolution. Do not use OXAYDO for administration via nasogastric, gastric, or other feeding tubes as it may cause obstruction of feeding tubes ( 2.1 , 17 ) Must take tablets one at a time, with enough water to ensure complete swallowing immediately after placing in mouth. ( 2.1 ) Periodically reassess patients receiving OXAYDO to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.4 ) Do not rapidly reduce or abruptly discontinue OXAYDO in a physically-dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.4 , 5.14 ) 2.1 Important Dosage and Administration Instructions OXAYDO 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 OXAYDO for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings an …

3 DOSAGE FORMS AND STRENGTHS Tablets: 5 mg and 7.5 mg of oxycodone HCl, USP: Strength Description 5 mg Round, convex, white tablet, debossed “5” on one side, letter “O” on other side. 7.5 mg Round, convex, white tablet, debossed “7.5” on one side, letter “O” on other side. Tablets: 5 mg and 7.5 mg oxycodone HCl ( 3 )

4 CONTRAINDICATIONS OXAYDO is contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.2 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.8 )] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.12 )] Hypersensitivity to oxycodone, oxycodone salts, or any components of the product (e.g., anaphylaxis) [see Adverse Reactions ( 6.2 )] Significant respiratory depression. ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) Hypersensitivity to oxycodone, oxycodone salts, or any components of the product. ( 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 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 ( 5.7 )] 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 )] Most common adverse reactions (incidence ≥3%) were nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zyla Life Sciences US Inc. at 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the 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. Serious adverse reactions that may be associated with OXAYDO include: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock [see Warnings and Precautions ( 5 ) and Overdosage ( 10 )] . The common adverse reactions seen on initiation of therapy with OXAYDO are dose-dependent, and their frequency depends on the clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual. They should be expected and managed as a part of opioid therapy. The most frequent of the adverse reactions include nausea, constipation, vomiting, headache, and pruritus. The frequency of adverse reactions during initiation of opioid therapy may be minimized by careful individualization of starting dosage, slow titration and the avoidance of large rapid swings in plasma concentration of the opioid. Many of these adverse reactions will abate as therapy is continued and some degree of tolerance is developed, but others may be expected to remain throughout therapy. In all patients for whom dosing information was available (n=191) from open-label and double-blind studies involving oxycodone, the following adverse reactions were recorded in oxycodone-treated patients with an incidence of ≥3%. In descending order of frequency they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. The following adverse reactions occurred in less than 3% of patients involved in clinical trials with oxycodone: Body as a Whole: abdominal pain, accidental injury, allergic reaction, back pain, chills and fever, fever, flu syndrome, infection, neck pain, pain, photosensitivity reaction, and sepsis. Cardiovascular: deep vein thrombophlebitis, heart failure, hemorrhage, hypotension, migraine, palpitation, and tachycardia. Digestive: anorexia, diarrhea, dyspepsia, dysphagia, gingivitis, glossitis, and nausea and vomiting. Hematopoietic and Lymphatic: anemia and leukopenia. Metabolism and Nutrition: edema, gout, hyperglycemia, iron deficiency anemia, and peripheral edema. Musculoskeletal: arthralgia, arthritis, bone pain, myalgia, and pathological fracture. Nervous System: agitation, anxiety, confusion, dry mouth, hypertonia, hypesthesia, nervousness, neuralgia, personality disorder, tremor, and vasodilation. Respiratory: bronchitis, cough increased, dyspnea, epistaxis, laryngismus, lung disorder, pharyngitis, rhinitis, and sinusitis. Skin and Appendages: herpes simplex, rash, sweating, and urticaria. Special Senses: amblyopia. Urogenital: …

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with OXAYDO. Table 1: Clinically Significant Drug Interactions with OXAYDO Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of OXAYDO and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of OXAYDO and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of OXAYDO is achieved [ see Warnings and Precautions ( 5.6 ) ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [ see Clinical Pharmacology ( 12.3 ) ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone. Intervention: If concomitant use is necessary, consider dosage reduction of OXAYDO until stable drug effects are achieved. Evaluate patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the OXAYDO dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of OXAYDO and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions ( 5.6 )] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the OXAYDO dosage until stable drug effects are achieved [see Dosage and Administration ( 2.3 )] . Evaluate patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OXAYDO dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples Rifampin, carbamazepine, phenytoin Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death [see Warnings and Precautions ( 5.3 )]. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the for 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 ( 5.1 , 5.2 , 5.3 ) ]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue OXAYDO if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyc …

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 )] . There are no available data with OXAYDO in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies with oral administrations of oxycodone HCl in rats and rabbits during the period of organogenesis at doses 2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal toxicity. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below resulted in neurobehavioral effects in offspring [ 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 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. OXAYDO is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including OXAYDO, 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 In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone HCl administered during the period of organogenesis up to 16 mg/kg/day and up 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m 2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m 2 basis). 8.2 Lactation Risk Summary Available data from lactation studies indicate that oxycodone is pr …

12.1 Mechanism of Action Oxycodone 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 oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxycodone. 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 OXAYDO (oxycodone HCl) 5 mg and 7.5 mg tablets are an immediate-release opioid agonist intended for oral administration only. Chemically, oxycodone HCl is 4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one HCl, a white, odorless crystalline powder. Oxycodone HCl is soluble in water (1 g in 6 to 7 mL). The molecular weight of oxycodone HCl is 351.82. The molecular formula for oxycodone HCl is C 18 H 21 NO 4 •HCl, and the structure is: The inactive ingredients in OXAYDO include: colloidal silicon dioxide NF; crospovidone NF; magnesium stearate NF; microcrystalline cellulose NF; polyethylene oxide NF; and sodium lauryl sulfate NF. The tablets are round, convex, white and debossed with the strength (5 or 7.5) on one side and the letter “O” on the other side. Oxado Chemical structure

10 OVERDOSAGE Clinical Presentation Acute overdose with oxycodone 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 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 )] . 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 and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias may require advanced life-support measures. For clinically significant respiratory or circulatory depression secondary to opioid 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 oxycodone in OXAYDO, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the 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.

16 HOW SUPPLIED/STORAGE AND HANDLING OXAYDO (oxycodone HCl) 5 mg tablets are round, convex, white tablets debossed with the strength “5” on one side and the letter “O” on the other side and supplied as: NDC 69344-113-11 Bottles of 100 tablets OXAYDO 7.5 mg tablets are round, convex, white tablets debossed with the strength “7.5” on one side and the letter “O” on the other side and supplied as: NDC 69344-213-11 Bottles of 100 tablets Dispense in tight container as defined in the USP, with a child-resistant closure. Store at 25°C (77°F); with excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature]. Protect from moisture. Store OXAYDO securely and dispose of properly.