XTAMPZA

Boxed Warning 12/2025 Indications and Usage ( 1 ) 12/2025 Dosage and Administration ( 2.1 , 2.3 , 2.5 ) 12/2025 Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.14 ) 12/2025

1 INDICATIONS AND USAGE XTAMPZA ER is 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. XTAMPZA ER is an opioid agonist 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. ( 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 XTAMPZA ER, for use in patients for whom alternative treatment optionsare ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 , 5.1 ) XTAMPZA ER is not indicated as an as-needed (prn) analgesic. ( 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 XTAMPZA ER, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. XTAMPZA ER is not indicated as an as-needed (prn) analgesic.

2 DOSAGE AND ADMINISTRATION XTAMPZA ER 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. ( 2.1 ) XTAMPZA ER at a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone hydrochloride [HCl]) or a single dose greater than 36 mg (equivalent to 40 mg oxycodone HCl) is only for use in patients in whom tolerance to an opioid of comparable potency has been established. ( 2.1 ) Patients considered opioid-tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone HCl 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. ( 2.1 ) Use the lowest effective dose for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of XTAMPZA ER 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 , 5 ) 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 XTAMPZA ER. 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 XTAMPZA ER, 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 ) XTAMPZA ER is administered, twice daily, every 12 hours, and must be taken with food . Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose to ensure consistent plasma levels are achieved. ( 2.1 , 2.3 ) For patients who are not opioid tolerant, initiate with 9 mg (equivalent to 10 mg oxycodone HCl per day). ( 2.3 ) The daily dose of XTAMPZA ER must be limited to a maximum of 288 mg per day (equivalent to 320 mg oxycodone HCl per day). ( 2.1 ) Hepatic impairment : Initiate therapy at 1/3 to 1/2 the usual dosage and titrate carefully. Regularly evaluate. Use alternate analgesia for patients requiring less than 9 mg. ( 2.4 , 8.6 ) Periodically reassess patients receiving XTAMPZA ER 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. ( 2.5 ) Do not rapidly reduce or abruptly discontinue XTAMPZA ER in a physically-dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.6 , 5.14 ) Instruct patients to take XTAMPZA ER capsules with food in order to ensure consistent plasma levels are achieved. For patients who have difficulty swallowing, XTAMPZA ER can also be taken by sprinkling the capsule contents on soft foods or into a cup and then administering directly into the mouth, or through a gastrostomy or nasogastric feeding tube. ( 2.7 ) 2.1 Important Dosage and Administration Instructions XTAMPZA ER 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. XTAMPZA ER single doses greater than 36 mg (equivalent to 40 mg oxycodone hydrochloride [HCl]) or a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone HCl) are to be administered only to patients in whom tolerance to an opio …

3 DOSAGE FORMS AND STRENGTHS XTAMPZA ER capsules contain yellow to light brown microspheres, and each available strength has an outer opaque capsule with colors as identified below. Strength Capsule Description 9 mg (equivalent to 10 mg oxycodone HCl) Size 3, ivory cap printed with "XTAMPZA ER" and white body printed with "9 mg" 13.5 mg (equivalent to 15 mg oxycodone HCl) Size 2, Swedish orange cap printed with "XTAMPZA ER" and white body printed with "13.5 mg" 18 mg (equivalent to 20 mg oxycodone HCl) Size 1, rich yellow cap printed with "XTAMPZA ER" and white body printed with "18 mg" 27 mg (equivalent to 30 mg oxycodone HCl) Size 0, light gray cap printed with "XTAMPZA ER" and white body printed with "27 mg" 36 mg (equivalent to 40 mg oxycodone HCl) Size 00, flesh color cap printed with "XTAMPZA ER" and white body printed with "36 mg" Extended-release capsules: 9 mg (equivalent to 10 mg oxycodone HCl) 13.5 mg (equivalent to 15 mg oxycodone HCl) 18 mg (equivalent to 20 mg oxycodone HCl) 27 mg (equivalent to 30 mg oxycodone HCl) 36 mg (equivalent to 40 mg oxycodone HCl). ( 3 )

4 CONTRAINDICATIONS XTAMPZA ER 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 (e.g., anaphylaxis) to oxycodone. 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 ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described 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 (5.7) ] 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 (>5%) were nausea, headache, constipation, somnolence, pruritus, vomiting, and dizziness. ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Collegium Pharmaceutical, Inc. at 1-855-331-5615 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. The safety of XTAMPZA ER was evaluated in a Phase 3, randomized-withdrawal, double-blind clinical trial involving 740 patients with moderate-to-severe chronic lower back pain. In the double-blind maintenance phase, 389 patients were randomized and 193 patients were assigned to the XTAMPZA ER treatment group. The most common AEs (>5%) reported by patients in the Phase 3 clinical trial during the titration phase were: nausea (16.6%), headache (13.9%), constipation (13.0%), somnolence (8.8%), pruritus (7.4%), vomiting (6.4%), and dizziness (5.7%). The most common adverse reactions (>5%) reported by patients in the Phase 3 clinical trial comparing XTAMPZA ER with placebo are shown in Table below: Table 2: Common Adverse Reactions (>5%) Titration Maintenance Adverse Reaction XTAMPZA ER (n = 740) (%) XTAMPZA ER (n = 193) (%) Placebo (n = 196) (%) Nausea 16.6 10.9 4.6 Headache 13.9 6.2 11.7 Constipation 13.0 5.2 0.5 Somnolence 8.8 <1 <1 Pruritus 7.4 2.6 1.5 Vomiting 6.4 4.1 1.5 Dizziness 5.7 1.6 0 In the Phase 3 clinical trial, the following adverse reactions were reported in patients treated with XTAMPZA ER with incidences of 1% to 5%: Eye disorders : vision blurred Gastrointestinal disorders : abdominal pain, upper abdominal pain, diarrhea, gastroesophageal reflux disease General disorders and administration site conditions : chills, drug withdrawal syndrome, fatigue, irritability, edema, pyrexia Injury, poisoning and procedural complications : excoriation Metabolism and nutrition disorders : decreased appetite, hyperglycemia Musculoskeletal and connective tissue disorders : arthralgia, back pain, musculoskeletal pain, myalgia Nervous system disorders : migraine, tremor Psychiatric disorders : anxiety, insomnia, withdrawal syndrome Respiratory, thoracic and mediastinal disorders : cough, oropharyngeal pain Skin and subcutaneous tissue disorders : hyperhidrosis, rash Vascular disorders : hot flush, hypertension In the Phase 3 clinical trial, the following treatment-related adverse reactions were reported in patients treated with XTAMPZA ER with incidences of less than 1% of patients. Investigations : increased gamma-glutamyl transferase, increased heart rate Nervous system disorders : lethargy, memory impairment, poor-quality sleep Psychiatric disorders : abnormal dreams, euphoric mood, restlessness Respiratory, thoracic and mediastinal disorders : dyspnea Skin and subcutaneous tissue disorders : night sweats 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of oxycodone. Because these reactions are reported voluntarily from a population of uncert …

7 DRUG INTERACTIONS Table includes clinically significant drug interactions with XTAMPZA ER. Table 3: Clinically Significant Drug Interactions with XTAMPZA ER Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of XTAMPZA ER 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 XTAMPZA ER and CYP2D6 and CYP3A4 inhibitors , particularly when an inhibitor is added after a stable dose of XTAMPZA ER 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 XTAMPZA ER until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the XTAMPZA ER dosage until stable drug effects are achieved. Assess 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 XTAMPZA ER 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 XTAMPZA ER dosage until stable drug effects are achieved [see Dosage and Administration (2.5) ] . Evaluate patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider XTAMPZA ER 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 pharmacological 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 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 XTAMPZA ER if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake …

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Not recommended. ( 8.2 ) 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 XTAMPZA ER in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, there was no embryo-fetal toxicity when oxycodone hydrochloride was orally administered to rats and rabbits, during the period of organogenesis, at doses 1.3 to 40 times the adult human dose of 60 mg/day, respectively. In a pre- and postnatal toxicity study, when oxycodone was orally administered to rats, there was transiently decreased pup body weight during lactation and the early post-weaning period at the dose equivalent to an adult dose of 160 mg/day. In several published studies, treatment of pregnant rats with oxycodone hydrochloride 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 of use, and severity of neonatal opioid withdrawal syndrome may 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. XTAMPZA ER is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including XTAMPZA ER, 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. Data Animal Data Studies with oral doses of oxycodone hydrochloride in rats up to 8 mg/kg/day and rabbits up to 125 mg/kg/day, equivalent to 1.3 and 40 times an adult human dose of 160 mg/day, respectively on a mg/m 2 basis, did not reveal evidence of harm to the fetus due to oxycodone. In a pre- and postnatal toxicity study, female rats received oxycodone during gestation and lactation. There were no drug-related effects on reproductive performance in these females or any long-term developmental or reproductive effects in pups born to these rats. Decreased body weight was found during lactation and the early post-weaning phase in pups nursed by dams given the highest dose used (6 mg/kg/day, equivalent to an adult human dose of 160 mg/day, on a mg/m 2 basis). However, body weig …

12.1 Mechanism of Action Oxycodone is a full opioid agonist and is relatively selective for the mu 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 to analgesia for 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. In addition, when oxycodone binds to mu-opioid receptors, it results in positive subjective effects, such as drug liking, euphoria, and high.

11 DESCRIPTION XTAMPZA ER (oxycodone) extended-release capsules are an opioid agonist for oral use. The capsules contain microspheres formulated with oxycodone base and are supplied in strengths of 9 mg (equivalent to 10 mg oxycodone HCl), 13.5 mg (equivalent to 15 mg oxycodone HCl), 18 mg (equivalent to 20 mg oxycodone HCl), 27 mg (equivalent to 30 mg oxycodone HCl), and 36 mg (equivalent to 40 mg oxycodone HCl) capsules. The capsule strengths describe the amount of oxycodone base per capsule. The structural formula for oxycodone is as follows: C 18 H 21 NO 4 MW 315.37 g/mol The chemical name is 4,5 α-Epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one. Oxycodone base is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone is present as myristate salt in the XTAMPZA ER formulation. Each XTAMPZA ER capsule contains either 9, 13.5, 18, 27, or 36 mg of oxycodone (equivalent to 10, 15, 20, 30, or 40 mg of oxycodone HCl, respectively) and the following inactive ingredients: myristic acid, yellow beeswax, carnauba wax, stearoyl polyoxyl-32 glycerides, magnesium stearate, and colloidal silicon dioxide. The capsule shells collectively contain titanium dioxide, hypromellose, and water. Additionally, the 9 mg and 18 mg strength capsule shells contain yellow iron oxide, the 13.5 and 36 mg strength capsule shells contain red iron oxide, and the 27 mg strength capsule shells contain black iron oxide. Chemical Structure

10 OVERDOSAGE Clinical Presentation Acute overdosage 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 due to 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 oxycodone overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. Because the duration of reversal would be expected to be less than the duration of action of oxycodone in XTAMPZA ER, carefully monitor the patient until spontaneous respiration is reliably reestablished. XTAMPZA ER will continue to release oxycodone and add to the oxycodone load for 24 to 48 hours or longer following ingestion necessitating prolonged monitoring. If the response to opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed in the product's prescribing information. In an individual physically dependent on opioids, administration of the 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 begun with care and by titration with smaller than usual doses of the reversal agent.

16 HOW SUPPLIED/STORAGE AND HANDLING XTAMPZA ER capsules are supplied in 100-count bottles with a child-resistant closure and as a hospital unit dose package with 10 individually blistered capsules per card; two cards per carton as follows: Table 9: Summary of XTAMPZA ER Capsule Strengths and Packaging Configurations Strength Capsule Description NDC Number (100-count Bottles with a child-resistant closure) NDC Number (20-count Hospital Unit Dose Blister Cartons) 9 mg (equivalent to 10 mg oxycodone HCl) Size 3, ivory cap printed with "XTAMPZA ER" and white body printed with "9 mg" NDC 24510-110-10 NDC 24510-110-20 13.5 mg (equivalent to 15 mg oxycodone HCl) Size 2, Swedish orange cap printed with "XTAMPZA ER" and white body printed with "13.5 mg" NDC 24510-115-10 NDC 24510-115-20 18 mg (equivalent to 20 mg oxycodone HCl) Size 1, rich yellow cap printed with "XTAMPZA ER" and white body printed with "18 mg" NDC 24510-120-10 NDC 24510-120-20 27 mg (equivalent to 30 mg oxycodone HCl) Size 0, light gray cap printed with "XTAMPZA ER" and white body printed with "27 mg" NDC 24510-130-10 NDC 24510-130-20 36 mg (equivalent to 40 mg oxycodone HCl) Size 00, flesh color cap printed with "XTAMPZA ER" and white body printed with "36 mg" NDC 24510-140-10 NDC 24510-140-20 Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant container, with child-resistant closure. Store XTAMPZA ER securely and dispose of properly [see Patient Counseling Information (17) ] .