XTAMPZA ER

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…

5 WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.7 ) Risk of life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients : Regularly evaluate. ( 5.8 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.9 ) Severe hypotension : Regularly evaluate. Avoid use of XTAMPZA ER in patients with circulatory shock. ( 5.10 ) Risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness : Monitor for sedation and respiratory depression. Avoid use of XTAMPZA ER in patients with impaired consciousness or coma. ( 5.11 ) 5.1 Addiction, Abuse, and Misuse XTAMPZA ER contains oxycodone, a Schedule II controlled substance. As an opioid, XTAMPZA ER exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed XTAMPZA ER. Addiction can occur at recommended dosages 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 XTAMPZA ER, and reassess all patients receiving XTAMPZA ER for the development of these behaviors or 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 XTAMPZA ER but use in such patients necessitates intensive counseling about the risks and proper use of XTAMPZA ER along with frequent evaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) ] . Abuse or misuse of XTAMPZA ER by snorting or by injecting the dissolved product 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 XTAMPZA ER. 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 the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents, depending on the patient's clinical status [see Overdosage (10) ] . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or…

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 )

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…

8.1 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 weight of these pups recovered. In published studies, offspring of pregnant rats administered oxycodone hydroch…

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…