FDA label 572d02a9-d3b9-4c1b-bd85-af3c64201012

WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, ACCIDENTAL EXPOSURE, and INTERACTION WITH ALCOHOL Abuse Potential AVINZA ® contains pellets of morphine sulfate, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit [see Warnings and Precautions (5.1) ] . Assess each patient's risk for opioid abuse or addiction prior to prescribing AVINZA. The risk for opioid abuse is 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 depressive disorder). Routinely monitor all patients receiving AVINZA for signs of misuse, abuse, and addiction during treatment [see Drug Abuse and Dependence (9) ]. Life-threatening Respiratory Depression Respiratory depression, including fatal cases, may occur with use of AVINZA, even when the drug has been used as recommended and not misused or abused [see Warnings and Precautions (5.2) ] . Proper dosing and titration are essential and AVINZA should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Monitor for respiratory depression, especially during initiation of AVINZA or following a dose increase . Instruct patients to swallow AVINZA capsules whole or to sprinkle the contents of the capsule on applesauce and swallow immediately without chewing. Crushing, dissolving, or chewing the pellets within the capsule can cause rapid release and absorption of a potentially fatal dose of morphine. Accidental Exposure Accidental ingestion of AVINZA, especially in children, can result in a fatal overdose of morphine [see Warnings and Precautions (5.3) ] . Interaction with Alcohol The co-ingestion of alcohol with AVINZA may result in an increase of plasma levels and potentially fatal overdose of morphine [see Warnings and Precautions (5.4) . Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while on AVINZA therapy. WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, ACCIDENTAL EXPOSURE, and INTERACTION WITH ALCOHOL See full prescribing information for complete boxed warning . AVINZA contains pellets of morphine sulfate, a Schedule II controlled substance. Monitor for signs of misuse, abuse, and addiction during AVINZA therapy. ( 5.1 , 9 ) Fatal respiratory depression may occur, with highest risk at initiation and with dose increases. Instruct patients on proper administration of AVINZA capsules to reduce the risk. ( 5.2 ) Accidental ingestion of AVINZA can result in fatal overdose of morphine, especially in children. ( 5.3 ) Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while taking AVINZA because of the risk of increased, and potentially fatal, plasma morphine levels. ( 5.4 )

5 WARNINGS AND PRECAUTIONS Elderly, cachectic, and debilitated patients, and patients with chronic pulmonary disease: Monitor closely because of increased risk of respiratory depression. ( 5.5 , 5.6 ) Interaction with CNS depressants: Consider dose reduction of one or both drugs because of additive effects. ( 5.7 , 7.2 ) Hypotensive effect: Monitor during dose initiation and titration ( 5.8 ) Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of AVINZA in patients with impaired consciousness or coma susceptible to intracranial effects of CO 2 retention. ( 5.9 ) 5.1 Abuse Potential AVINZA contains morphine, an opioid agonist and a Schedule II controlled substance. Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing AVINZA in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain. Assess each patient's risk for opioid abuse or addiction prior to prescribing AVINZA. The risk for opioid abuse is 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). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use. Misuse or abuse of AVINZA by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the opioid and pose a significant risk that could result in overdose and death [see Overdosage (10) ] . 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 Respiratory depression is the primary risk of AVINZA. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a "sighing" pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. 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) ] . While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of AVINZA, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with AVINZA and following dose increases. Instruct patients against use by individuals other than the patient for whom AVINZA was prescribed and to keep AVINZA out of the reach of children, as such inappropriate use may result in fatal respiratory depression. To reduce the risk of respiratory depression, proper dosing and titration of AVINZA are essential [see Dosage and Administration (2.2 , 2.3) ] . Overestimating the AVINZA dose when converting patients from another opioid product can result in fatal overdose with the first dose. Respiratory depression has also been reported with use of modified-release opioids when used as recommended and not misused or abused. To further reduce the risk of respiratory depression, consider the following: Proper dosing and titration are essential and AVINZA should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. AVINZA 90 mg and 120 mg capsules are for use in opioid-tolerant patients only. Ingestion of this strength of AVINZA capsules or of the pellets within the capsule may cause fatal respiratory depression when administered to patients not already tolerant to high doses of opioids. Instruct patients to swallow AVINZA capsules intact or to sprinkle the capsule contents on applesauceand swallow immediately without chewing. The pellets in the capsules are not to be crushed, dissolved, or chewed as the resulting morphine dose may be fatal, particularly in opioid-naïve individuals. AVINZA is contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression [see Contraindications (4) ] . 5.3 Accidental Exposure Accidental consumption of AVINZA, especially in children, can result in a fatal overdose of morphine. 5.4 Interaction with Alcohol The co-ingestion of alcohol with AVINZA can result in an increase of morphine plasma levels and potentially fatal overdose of morphine. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on AVINZA therapy [see Clinical Pharmacology (12.3) ] . 5.5 Elderly, Cachectic, and Debilitated Patients Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance compared to younger, healthier patients. Therefore, monitor such patients closely, particularly when initiating and titrating AVINZA and when AVINZA is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2) ] . 5.6 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with AVINZA, as in these patients, even usual therapeutic doses of AVINZA may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2) ] . Consider the use of alternative non-opioid analgesics in these patients if possible. 5.7 Interactions with CNS Depressants and Illicit Drugs Hypotension, profound sedation, coma, or respiratory depression may result if AVINZA is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of AVINZA in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient's use, if any, of alcohol or illicit drugs that cause CNS depression. If AVINZA therapy is to be initiated in a patient taking a CNS depressant, start with a lower AVINZA dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.2) ] . 5.8 Hypotensive Effect AVINZA 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 (7.2) ] . Monitor these patients for signs of hypotension after initiating or titrating the dose of AVINZA. In patients with circulatory shock, AVINZA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of AVINZA in patients with circulatory shock. 5.9 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking AVINZA who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with AVINZA. AVINZA may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure . Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of AVINZA in patients with impaired consciousness or coma. 5.10 Use in Patients with Gastrointestinal Conditions AVINZA is contraindicated in patients with paralytic ileus. Avoid the use of AVINZA in patients with other GI obstruction. The morphine in AVINZA may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase. 5.11 Use in Patients with Convulsive or Seizure Disorders The morphine in AVINZA may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during AVINZA therapy. 5.12 Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients who have received or are receiving a course of therapy with a opioid agonist analgesic, including AVINZA. In these patients, mixed agonist/antagonistanalgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing AVINZA, gradually taper the dose [see Dosage and Administration (2.3) ] . Do not abruptly discontinue AVINZA. 5.13 Driving and Operating Machinery AVINZA 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 AVINZA and know how they will react to the medication.

6 ADVERSE REACTIONS The following serious adverse reactions and/or conditions are discussed elsewhere in the labeling: Respiratory Depression [see Warnings and Precautions (5.2) ] Chronic Pulmonary Disease [see Warnings and Precautions (5.6) ] Head Injuries and Increased Intracranial Pressure [see Warnings and Precautions (5.9) ] Interactions with Other CNS Depressants [see Warnings and Precautions (5.7) ] Hypotensive Effect [see Warnings and Precautions (5.8) Gastrointestinal Effects [see Warnings and Precautions (5.10) Seizures [see Warnings and Precautions (5.11) The most common adverse reactions with AVINZA include constipation, nausea and somnolence. Most common adverse reactions (≥10%) are constipation, nausea, somnolence, vomiting and headache. ( 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 Studies 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 open-label clinical studies, 560 patients with chronic malignant or non-malignant pain were treated with AVINZA. The most common serious adverse events reported with administration of AVINZA were vomiting, nausea, death, dehydration, dyspnea, and sepsis. (Deaths occurred in patients treated for pain due to underlying malignancy.) Serious adverse events caused by morphine include respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest. The most common adverse events (seen in greater than 10%) reported by patients treated with AVINZA during the clinical trials at least once during therapy were constipation, nausea, somnolence, vomiting, and headache. Adverse events occurring in 5–10% of study patients were peripheral edema, diarrhea, abdominal pain, infection, urinary tract infection, accidental injury, flu syndrome, back pain, rash, sweating, fever, insomnia, depression, paresthesia, anorexia, dry mouth, asthenia and dyspnea. Other less common side effects expected from opioid analgesics, including morphine, or seen in fewer than 5% of patients taking AVINZA in the clinical trials were: Body as a Whole: malaise, withdrawal syndrome. Cardiovascular System: bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia. Digestive System: biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst. Hemic and Lymphatic System: anemia, thrombocytopenia. Metabolic and Nutritional Disorders: edema, weight loss. Musculoskeletal: skeletal muscle rigidity. Nervous System: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo . Respiratory System: hiccup, hypoventilation, voice alteration. Skin and Appendages: dry skin, urticaria. Special Senses: amblyopia, eye pain, taste perversion. Urogenital System: abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention. Anaphylaxis has been reported with ingredients contained in AVINZA. Advise patients how to recognize such a reaction and when to seek medical attention.