FDA label 3d3e37bf-b9a1-42f8-8f3d-8a63333f1714

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS. WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. TROXYCA ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing, and monitor regularly for these behaviors and conditions. ( 5.1 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow TROXYCA ER capsules whole to avoid exposure to a potentially fatal dose of oxycodone. ( 5.2 ) Accidental ingestion of TROXYCA ER, especially by children, can result in fatal overdose of oxycodone. ( 5.2 ) Prolonged use of TROXYCA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. ( 5.3 ) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in fatal overdose of oxycodone from TROXYCA ER. ( 5.4 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.5 , 7 ) Addiction, Abuse, and Misuse TROXYCA ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing TROXYCA ER, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1) ] . Life - threatening Respiratory Depression Serious, life - threatening, or fatal respiratory depression may occur with use of TROXYCA ER. Monitor for respiratory depression, especially during initiation of TROXYCA ER or following a dose increase. Instruct patients to swallow TROXYCA ER capsules whole or to sprinkle the contents of the capsule on applesauce and swallow immediately without chewing. Crushing, chewing, or dissolving TROXYCA ER can cause rapid release and absorption of a potentially fatal dose of oxycodone [see Warnings and Precautions (5.2) ] . Accidental Ingestion Accidental ingestion of even one dose of TROXYCA ER, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.2) ] . Neonatal Opioid Withdrawal Syndrome Prolonged use of TROXYCA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life - threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3) ] . Cytochrome P450 3A4 Interaction The concomitant use of TROXYCA ER with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentrations. Monitor patients receiving TROXYCA ER and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.4) , Drug Interactions (7) , Clinical Pharmacology (12.3) ] . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.5) , Drug Interactions (7) ] . Reserve concomitant prescribing of TROXYCA ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

5 WARNINGS AND PRECAUTIONS Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration. ( 5.6 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.7 ) Severe Hypotension : Monitor during dosage initiation and titration. Avoid use of TROXYCA ER in patients with circulatory shock. ( 5.8 ) 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 TROXYCA ER in patients with impaired consciousness or coma. ( 5.9 ) 5.1 Addiction, Abuse, and Misuse TROXYCA ER contains oxycodone, a Schedule II controlled substance. As an opioid, TROXYCA ER exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ] . As extended-release products such as TROXYCA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of oxycodone present [see Drug Abuse and Dependence (9) ] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed TROXYCA ER and in those who obtain the drug illicitly. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing TROXYCA ER, and monitor all patients receiving TROXYCA 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 addiction or abuse) 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 TROXYCA ER, but use in such patients necessitates intensive counseling about the risks and proper use of TROXYCA ER along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of TROXYCA ER by cutting, breaking, chewing, crushing, or dissolving the pellets in TROXYCA ER and then swallowing, snorting or injecting will result in the uncontrolled delivery of the oxycodone and can result in overdose and death [see Overdosage (10) ] . Misuse or abuse of TROXYCA ER by these methods may also release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals [see Warnings and Precautions (5.12) ] . Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing TROXYCA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17) ] . Contact the 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 antagonists, 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 fatal respiratory depression can occur at any time during the use of TROXYCA ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24–72 hours of initiating therapy with and following dosage increases of TROXYCA ER. To reduce the risk of respiratory depression, proper dosing and titration of TROXYCA ER are essential [see Dosage and Administration (2) ] . Overestimating the TROXYCA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of TROXYCA ER, especially by children, can result in respiratory depression and death due to an overdose of oxycodone. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of TROXYCA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1) , Patient Counseling Information (17) ] . 5.4 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of TROXYCA ER with a CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.2) ] , particularly when an inhibitor is added after a stable dose of TROXYCA ER is achieved . Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in TROXYCA ER-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using TROXYCA ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in TROXYCA ER-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of TROXYCA ER until stable drug effects are achieved [see Drug Interactions (7) ]. Concomitant use of TROXYCA ER with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using TROXYCA ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7) ] . 5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of TROXYCA ER with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7) ] . If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when TROXYCA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling Information (17) ] . 5.6 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of TROXYCA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease : TROXYCA ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of TROXYCA ER [see Warnings and Precautions (5.2) ]. Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2) ]. Monitor such patients closely, particularly when initiating and titrating TROXYCA ER and when TROXYCA ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2 , 5.5) ] . Alternatively, consider the use of non-opioid analgesics in these patients. 5.7 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.8 Severe Hypotension TROXYCA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7) ] . Monitor these patients for signs of hypotension after initiating or titrating the dosage of TROXYCA ER. In patients with circulatory shock, TROXYCA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of TROXYCA ER in patients with circulatory shock. 5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), TROXYCA ER may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with TROXYCA ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of TROXYCA ER in patients with impaired consciousness or coma. 5.10 Risks of Use in Patients with Gastrointestinal Conditions TROXYCA ER is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. The oxycodone in TROXYCA ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. 5.11 Increased Risk of Seizures in Patients with Seizure Disorders The oxycodone in TROXYCA ER may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during TROXYCA ER therapy. 5.12 Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including TROXYCA ER. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. Consuming TROXYCA ER that has been altered by crushing, chewing, or dissolving the pellets can release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals. Symptoms of withdrawal usually appear within five minutes of ingestion of naltrexone, can last for up to 48 hours, and can include mental status changes, restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Significant fluid losses from vomiting and diarrhea can require intravenous fluid administration. When discontinuing TROXYCA ER, gradually taper the dosage [see Dosage and Administration (2.4) ] . Do not abruptly discontinue TROXYCA ER [see Drug Abuse and Dependence (9.3) ] . 5.13 Risks of Driving and Operating Machinery TROXYCA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of TROXYCA ER and know how they will react to the medication [see Patient Counseling Information (17) ] . 5.14 Laboratory Tests and Monitoring Naltrexone does not interfere with thin-layer, gas-liquid, or high pressure liquid chromatographic methods which may be used for the separation and detection of morphine, methadone, oxycodone, or quinine in the urine. Naltrexone may or may not interfere with enzymatic methods for the detection of opioids depending on the sensitivity and specificity of the test. Consult the test manufacturer for details. Not every urine drug test for "opioids" or "opiates" detects oxycodone reliably, especially those designed for in-office use. Further, many laboratories will report urine drug concentrations below a specified "cut-off" value as "negative". Therefore, if urine testing for oxycodone is considered in the clinical management of an individual patient, ensure that the sensitivity and specificity of the assay is appropriate, and consider the limitations of the testing used when interpreting results.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling : Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1) ] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3) ] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.5) ] Adrenal Insufficiency [see Warnings and Precautions (5.7) ] Severe Hypotension [see Warnings and Precautions (5.8) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.10) ] Seizures [see Warnings and Precautions (5.11) ] Withdrawal [see Warnings and Precautions (5.12) ] Most common adverse reactions: nausea, constipation, vomiting, headache, and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 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, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. In controlled and uncontrolled studies, the most common adverse reactions were nausea, constipation, vomiting, headache, and somnolence. The most common adverse reactions leading to discontinuation (≥1% in any of the treatment phases) were nausea, constipation, vomiting, somnolence, headache, fatigue, and dizziness. In a randomized, placebo-controlled, double-blind study in subjects with moderate-to-severe chronic low back pain, 410 subjects received TROXYCA ER. This study utilized an enriched enrollment with a randomized withdrawal design in which subjects were titrated to effect on open-label TROXYCA ER for up to 42 days. Once their pain was controlled, 280 subjects were randomized to and received active treatment with TROXYCA ER (146 subjects) or were tapered off TROXYCA ER using a double-dummy design and treated with placebo (134 subjects) for 12 weeks. Adverse reactions reported in ≥2% of subjects receiving TROXYCA ER in either the titration phase or maintenance phase of the placebo-controlled study are presented in Table 2. Table 2. Adverse Drug Reactions Reported in ≥2% of Subjects Receiving TROXYCA ER in the Placebo-Controlled Study System Organ Class Open-Label Titration Phase TROXYCA ER (N=410) Double-Blind Maintenance Phase TROXYCA ER (N=146) Double-Blind Maintenance Phase Placebo (N=134) Adverse Drug Reaction (ADR) n (%) n (%) n (%) Gastrointestinal disorders Abdominal pain Abdominal pain also includes Abdominal discomfort, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Epigastric discomfort, and Gastrointestinal pain. 12 ( 2.9) 2 ( 1.4) 8 ( 6.0) Constipation 61 (14.9) 5 ( 3.4) 3 ( 2.2) Diarrhea 9 ( 2.2) 8 ( 5.5) 6 ( 4.5) Dry mouth 13 ( 3.2) 0 0 Nausea 84 (20.5) 21 (14.4) 5 ( 3.7) Vomiting 37 ( 9.0) 9 ( 6.2) 4 ( 3.0) General disorders and administration site conditions Drug withdrawal syndrome Drug withdrawal syndrome ADR includes Drug withdrawal syndrome and Withdrawal syndrome MedDRA Preferred Terms or a score of greater than or equal to 13 on the Clinical Opiate Withdrawal Scale. 4 ( 1.0) 4 ( 2.7) 2 (1.5) Fatigue 13 ( 3.2) 5 ( 3.4) 1 ( 0.7) Edema peripheral 3 ( 0.7) 3 ( 2.1) 1 ( 0.7) Musculoskeletal and connective tissue disorders Arthralgia 3 ( 0.7) 3 ( 2.1) 1 ( 0.7) Back pain 5 ( 1.2) 3 ( 2.1) 8 ( 6.0) Muscle spasms 1 ( 0.2) 4 ( 2.7) 1 ( 0.7) Nervous system disorders Dizziness 24 ( 5.9) 6 ( 4.1) 1 ( 0.7) Headache 30 ( 7.3) 2 ( 1.4) 7 ( 5.2) Hypoesthesia 0 3 ( 2.1) 0 Somnolence Somnolence also includes Sedation. 37 ( 9.0) 1 ( 0.7) 1 ( 0.7) Psychiatric disorders Insomnia 8 ( 2.0) 1 ( 0.7) 1 ( 0.7) Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 1 ( 0.2) 4 ( 2.7) 1 ( 0.7) Skin and subcutaneous tissue disorders Hyperhidrosis Hyperhidrosis also includes Cold sweat. 10 ( 2.4) 4 ( 2.7) 1 ( 0.7) Pruritus Pruritus also includes Pruritus generalized. 27 ( 6.6) 3 ( 2.1) 0 Vascular disorders Hot flush Hot flush also includes Flushing. 10 ( 2.4) 2 ( 1.4) 3 ( 2.2) An additional 395 subjects received at least one dose of TROXYCA ER in an open-label, 12-month safety study of subjects with moderate-to-severe chronic non-cancer pain. In this study, 193 subjects received TROXYCA ER for at least 6 months and 105 subjects received TROXYCA ER for approximately 12 months. Adverse reactions reported in ≥2% of subjects of the 12-month open-label safety study are presented in Table 3. Table 3. Adverse Drug Reactions Reported in ≥2% of Subjects in the 12-Month Open-Label Safety Study System Organ Class TROXYCA ER (N=395) Adverse Drug Reaction (ADR) n (%) Gastrointestinal disorders Abdominal pain Abdominal pain also includes Abdominal discomfort, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Epigastric discomfort, and Gastrointestinal pain. 33 ( 8.4) Constipation 84 (21.3) Diarrhea 36 ( 9.1) Dry mouth 9 ( 2.3) Nausea 100 (25.3) Vomiting 55 (13.9) General disorders and administration site conditions Fatigue 36 ( 9.1) Edema peripheral 15 ( 3.8) Musculoskeletal and connective tissue disorders Arthralgia 13 ( 3.3) Back pain 25 ( 6.3) Muscle spasms 9 ( 2.3) Nervous system disorders Dizziness 34 ( 8.6) Headache 46 (11.6) Somnolence Somnolence also includes Sedation. 38 ( 9.6) Tremor 8 ( 2.0) Psychiatric disorders Depression 13 ( 3.3) Insomnia 20 ( 5.1) Restlessness 9 ( 2.3) Respiratory, thoracic and mediastinal disorders Cough 10 ( 2.5) Oropharyngeal pain 9 ( 2.3) Skin and subcutaneous tissue disorders Hyperhidrosis Hyperhidrosis also includes Cold sweat. 27 ( 6.8) Pruritus Pruritus also includes Pruritus generalized. 22 ( 5.6) Vascular disorders Hot flush Hot flush also includes Flushing. 17 ( 4.3) Less Common Adverse Reactions The following adverse reactions occurred in patients taking TROXYCA ER in controlled and uncontrolled Phase 3 clinical trials with a frequency of <2%. Adverse reactions are listed in descending order of frequency within System Organ Class. Table 4. Adverse Drug Reactions Reported in <2% of Subjects in All Phases of the TROXYCA ER Phase 3 Studies System Organ Class Adverse Drug Reaction (ADR) Preferred Term Blood and lymphatic disorders Anemia, Lymphadenopathy Cardiac disorders Tachycardia, Palpitations, Bradycardia Ear and labyrinth disorders Vertigo, Tinnitus Eye disorders Lacrimation increased Gastrointestinal disorders Dyspepsia General disorders and administration site conditions Chills, Pain, Influenza like illness, Irritability, Chest pain Chest pain also includes Chest discomfort and Non-cardiac chest pain. , Pyrexia, Edema, Malaise Immune system disorders Drug hypersensitivity Drug hypersensitivity also includes Hypersensitivity. Investigations Blood pressure increased, Blood testosterone decreased, Blood glucose increased Blood glucose increased also includes Diabetes mellitus inadequate control. , Liver function test abnormal Liver function test abnormal includes Alanine aminotransferase increased and Aspartate aminotransferase increased. Metabolism and nutrition disorders Decreased appetite, Gout Musculoskeletal and connective tissue disorders Myalgia, Muscle twitching, Musculoskeletal stiffness, Arthritis Nervous system disorders Paresthesia, Lethargy, Disturbance in attention, Migraine, Dysgeusia Psychiatric disorders Abnormal dreams, Confusional state, Disorientation, Libido decreased, Drug abuse Renal and urinary disorders Dysuria, Hematuria Respiratory, thoracic and mediastinal disorders Rhinorrhoea, Bronchitis chronic, Dyspnea, Dysphonia Skin and subcutaneous tissue disorders Rash Rash also includes Rash pruritic. , Urticaria Surgical and medical procedures Intentional drug misuse 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 uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis and pharyngeal edema : Anaphylaxis and pharyngeal edema have been reported with ingredients contained in TROXYCA ER. Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2) ] . Myocardial ischemia and ventricular fibrillation : Myocardial ischemia and ventricular fibrillation have been reported with oxycodone overdose.

<table width="90%"> <caption>Table 2. Adverse Drug Reactions Reported in &#x2265;2% of Subjects Receiving TROXYCA ER in the Placebo-Controlled Study</caption> <col width="30%" align="left" valign="top"/> <col width="20%" align="left" valign="top"/> <col width="25%" align="left" valign="top"/> <col width="25%" align="left" valign="top"/> <thead> <tr styleCode="Botrule"> <th styleCode="Lrule Rrule" valign="bottom">System Organ Class</th> <th styleCode="Rrule">Open-Label Titration Phase TROXYCA ER (N=410)</th> <th styleCode="Rrule">Double-Blind Maintenance Phase TROXYCA ER (N=146)</th> <th styleCode="Rrule">Double-Blind Maintenance Phase Placebo (N=134)</th> </tr> <tr> <th styleCode="Lrule Rrule">Adverse Drug Reaction (ADR)</th> <th styleCode="Rrule">n (%)</th> <th styleCode="Rrule">n (%)</th> <th styleCode="Rrule">n (%)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Abdominal pain<footnote>Abdominal pain also includes Abdominal discomfort, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Epigastric discomfort, and Gastrointestinal pain.</footnote> </td> <td styleCode="Rrule">12 ( 2.9)</td> <td styleCode="Rrule">2 ( 1.4)</td> <td styleCode="Rrule">8 ( 6.0)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Constipation</td> <td styleCode="Rrule">61 (14.9)</td> <td styleCode="Rrule">5 ( 3.4)</td> <td styleCode="Rrule">3 ( 2.2)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Diarrhea</td> <td styleCode="Rrule">9 ( 2.2)</td> <td styleCode="Rrule">8 ( 5.5)</td> <td styleCode="Rrule">6 ( 4.5)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Dry mouth</td> <td styleCode="Rrule">13 ( 3.2)</td> <td styleCode="Rrule">0</td> <td styleCode="Rrule">0</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Nausea</td> <td styleCode="Rrule">84 (20.5)</td> <td styleCode="Rrule">21 (14.4)</td> <td styleCode="Rrule">5 ( 3.7)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Vomiting</td> <td styleCode="Rrule">37 ( 9.0)</td> <td styleCode="Rrule">9 ( 6.2)</td> <td styleCode="Rrule">4 ( 3.0)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">General disorders and administration site conditions</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Drug withdrawal syndrome<footnote>Drug withdrawal syndrome ADR includes Drug withdrawal syndrome and Withdrawal syndrome MedDRA Preferred Terms or a score of greater than or equal to 13 on the Clinical Opiate Withdrawal Scale.</footnote> </td> <td styleCode="Rrule">4 ( 1.0)</td> <td styleCode="Rrule">4 ( 2.7)</td> <td styleCode="Rrule">2 (1.5)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Fatigue</td> <td styleCode="Rrule">13 ( 3.2)</td> <td styleCode="Rrule">5 ( 3.4)</td> <td styleCode="Rrule">1 ( 0.7)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Edema peripheral</td> <td styleCode="Rrule">3 ( 0.7)</td> <td styleCode="Rrule">3 ( 2.1)</td> <td styleCode="Rrule">1 ( 0.7)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Musculoskeletal and connective tissue disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Arthralgia</td> <td styleCode="Rrule">3 ( 0.7)</td> <td styleCode="Rrule">3 ( 2.1)</td> <td styleCode="Rrule">1 ( 0.7)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Back pain</td> <td styleCode="Rrule">5 ( 1.2)</td> <td styleCode="Rrule">3 ( 2.1)</td> <td styleCode="Rrule">8 ( 6.0)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Muscle spasms</td> <td styleCode="Rrule">1 ( 0.2)</td> <td styleCode="Rrule">4 ( 2.7)</td> <td styleCode="Rrule">1 ( 0.7)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Nervous system disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Dizziness</td> <td styleCode="Rrule">24 ( 5.9)</td> <td styleCode="Rrule">6 ( 4.1) </td> <td styleCode="Rrule">1 ( 0.7)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Headache</td> <td styleCode="Rrule">30 ( 7.3)</td> <td styleCode="Rrule">2 ( 1.4)</td> <td styleCode="Rrule">7 ( 5.2)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Hypoesthesia</td> <td styleCode="Rrule">0</td> <td styleCode="Rrule">3 ( 2.1)</td> <td styleCode="Rrule">0</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Somnolence<footnote>Somnolence also includes Sedation.</footnote> </td> <td styleCode="Rrule">37 ( 9.0)</td> <td styleCode="Rrule">1 ( 0.7)</td> <td styleCode="Rrule">1 ( 0.7)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Psychiatric disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Insomnia</td> <td styleCode="Rrule">8 ( 2.0)</td> <td styleCode="Rrule">1 ( 0.7)</td> <td styleCode="Rrule">1 ( 0.7)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Oropharyngeal pain</td> <td styleCode="Rrule">1 ( 0.2)</td> <td styleCode="Rrule">4 ( 2.7)</td> <td styleCode="Rrule">1 ( 0.7)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Skin and subcutaneous tissue disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Hyperhidrosis<footnote>Hyperhidrosis also includes Cold sweat.</footnote> </td> <td styleCode="Rrule">10 ( 2.4)</td> <td styleCode="Rrule">4 ( 2.7)</td> <td styleCode="Rrule">1 ( 0.7)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Pruritus<footnote>Pruritus also includes Pruritus generalized.</footnote> </td> <td styleCode="Rrule">27 ( 6.6)</td> <td styleCode="Rrule">3 ( 2.1)</td> <td styleCode="Rrule">0</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Vascular disorders</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Hot flush<footnote>Hot flush also includes Flushing.</footnote> </td> <td styleCode="Rrule">10 ( 2.4)</td> <td styleCode="Rrule">2 ( 1.4)</td> <td styleCode="Rrule">3 ( 2.2)</td> </tr> </tbody> </table>

<table width="75%"> <caption>Table 3. Adverse Drug Reactions Reported in &#x2265;2% of Subjects in the 12-Month Open-Label Safety Study</caption> <col width="60%" align="left" valign="top"/> <col width="40%" align="left" valign="top"/> <thead> <tr styleCode="Botrule"> <th styleCode="Lrule Rrule" valign="middle">System Organ Class</th> <th styleCode="Rrule">TROXYCA ER (N=395)</th> </tr> <tr> <th styleCode="Lrule Rrule">Adverse Drug Reaction (ADR)</th> <th styleCode="Rrule">n (%)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> </td> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Abdominal pain<footnote>Abdominal pain also includes Abdominal discomfort, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Epigastric discomfort, and Gastrointestinal pain.</footnote> </td> <td styleCode="Rrule">33 ( 8.4)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Constipation</td> <td styleCode="Rrule">84 (21.3)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Diarrhea</td> <td styleCode="Rrule">36 ( 9.1)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Dry mouth</td> <td styleCode="Rrule">9 ( 2.3)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Nausea</td> <td styleCode="Rrule">100 (25.3)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Vomiting</td> <td styleCode="Rrule">55 (13.9)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">General disorders and administration site conditions</content> </td> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Fatigue</td> <td styleCode="Rrule">36 ( 9.1)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Edema peripheral</td> <td styleCode="Rrule">15 ( 3.8)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Musculoskeletal and connective tissue disorders</content> </td> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Arthralgia</td> <td styleCode="Rrule">13 ( 3.3)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Back pain</td> <td styleCode="Rrule">25 ( 6.3)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Muscle spasms</td> <td styleCode="Rrule">9 ( 2.3)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Nervous system disorders</content> </td> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Dizziness</td> <td styleCode="Rrule">34 ( 8.6)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Headache</td> <td styleCode="Rrule">46 (11.6)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Somnolence<footnote>Somnolence also includes Sedation.</footnote> </td> <td styleCode="Rrule">38 ( 9.6)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Tremor</td> <td styleCode="Rrule">8 ( 2.0)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Psychiatric disorders</content> </td> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Depression</td> <td styleCode="Rrule">13 ( 3.3)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Insomnia</td> <td styleCode="Rrule">20 ( 5.1)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Restlessness</td> <td styleCode="Rrule">9 ( 2.3)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Respiratory, thoracic and mediastinal disorders </content> </td> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Cough</td> <td styleCode="Rrule">10 ( 2.5)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Oropharyngeal pain</td> <td styleCode="Rrule">9 ( 2.3)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Skin and subcutaneous tissue disorders</content> </td> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Hyperhidrosis<footnote>Hyperhidrosis also includes Cold sweat.</footnote> </td> <td styleCode="Rrule">27 ( 6.8)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Pruritus<footnote>Pruritus also includes Pruritus generalized.</footnote> </td> <td styleCode="Rrule">22 ( 5.6)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Vascular disorders</content> </td> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Hot flush<footnote>Hot flush also includes Flushing.</footnote> </td> <td styleCode="Rrule">17 ( 4.3)</td> </tr> </tbody> </table>

<table width="75%"> <caption>Table 4. Adverse Drug Reactions Reported in &lt;2% of Subjects in All Phases of the TROXYCA ER Phase 3 Studies</caption> <col width="40%" align="left" valign="top"/> <col width="60%" align="left" valign="top"/> <thead> <tr> <th styleCode="Lrule Rrule">System Organ Class</th> <th styleCode="Rrule">Adverse Drug Reaction (ADR) Preferred Term</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Blood and lymphatic disorders</td> <td styleCode="Rrule">Anemia, Lymphadenopathy</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Cardiac disorders</td> <td styleCode="Rrule">Tachycardia, Palpitations, Bradycardia</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Ear and labyrinth disorders</td> <td styleCode="Rrule">Vertigo, Tinnitus</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Eye disorders</td> <td styleCode="Rrule">Lacrimation increased</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Gastrointestinal disorders</td> <td styleCode="Rrule">Dyspepsia</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">General disorders and administration site conditions</td> <td styleCode="Rrule">Chills, Pain, Influenza like illness, Irritability, Chest pain<footnote>Chest pain also includes Chest discomfort and Non-cardiac chest pain.</footnote>, Pyrexia, Edema, Malaise</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Immune system disorders</td> <td styleCode="Rrule">Drug hypersensitivity<footnote>Drug hypersensitivity also includes Hypersensitivity.</footnote> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Investigations</td> <td styleCode="Rrule">Blood pressure increased, Blood testosterone decreased, Blood glucose increased<footnote>Blood glucose increased also includes Diabetes mellitus inadequate control.</footnote>, Liver function test abnormal<footnote>Liver function test abnormal includes Alanine aminotransferase increased and Aspartate aminotransferase increased.</footnote> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Metabolism and nutrition disorders</td> <td styleCode="Rrule">Decreased appetite, Gout</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Musculoskeletal and connective tissue disorders</td> <td styleCode="Rrule">Myalgia, Muscle twitching, Musculoskeletal stiffness, Arthritis</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Nervous system disorders</td> <td styleCode="Rrule">Paresthesia, Lethargy, Disturbance in attention, Migraine, Dysgeusia</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Psychiatric disorders</td> <td styleCode="Rrule">Abnormal dreams, Confusional state, Disorientation, Libido decreased, Drug abuse</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Renal and urinary disorders</td> <td styleCode="Rrule">Dysuria, Hematuria</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Respiratory, thoracic and mediastinal disorders</td> <td styleCode="Rrule">Rhinorrhoea, Bronchitis chronic, Dyspnea, Dysphonia</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Skin and subcutaneous tissue disorders</td> <td styleCode="Rrule">Rash<footnote>Rash also includes Rash pruritic.</footnote>, Urticaria</td> </tr> <tr> <td styleCode="Lrule Rrule">Surgical and medical procedures</td> <td styleCode="Rrule">Intentional drug misuse</td> </tr> </tbody> </table>