FDA label be9316a1-bcee-477f-a610-70cf3aef1cbe

BOX WARNING WARNING: RISK OF RESPIRATORY DEPRESSION, ABUSE, AND MEDICATION ERRORS DILAUDID-HP INJECTION IS FOR USE IN OPIOID-TOLERANT PATIENTS ONLY Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer. DILAUDID-HP INJECTION is a more concentrated solution of hydromorphone than DILAUDID INJECTION, and is for use in opioid-tolerant patients only. Do not confuse DILAUDID-HP INJECTION with standard parenteral formulations of DILAUDID INJECTION or other opioids, as overdose and death could result. DILAUDID INJECTION and DILAUDID-HP INJECTION contain hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. DILAUDID INJECTION and DILAUDID-HP INJECTION can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing DILAUDID INJECTION and DILAUDID-HP INJECTION in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid agonists, including morphine, oxymorphone, hydromorphone, oxycodone, fentanyl and methadone, have the highest potential for abuse and risk of producing fatal overdose due to respiratory depression. Ethanol, other opioids, and other central nervous system depressants (e.g., sedative-hypnotics, skeletal muscle relaxants) can potentiate the respiratory-depressant effects of hydromorphone and increase the risk of adverse outcomes, including death. WARNING: RISK OF RESPIRATORY DEPRESSION, ABUSE, AND MEDICATION ERRORS DILAUDID-HP ® INJECTION IS FOR USE IN OPIOID-TOLERANT PATIENTS ONLY See full prescribing information for complete boxed warning. Do not confuse DILAUDID-HP INJECTION with standard parenteral formulations of DILAUDID or other opioids, as overdose and death could result. (5) Hydromorphone is a potent Schedule II opioid agonist. Schedule II opioid agonists have the highest potential for abuse and risk of producing respiratory depression. Ethanol, other opioids, and other central nervous system depressants can potentiate the respiratory-depressant effects of hydromorphone and increase the risk of adverse outcomes, including death. (5.1 , 7.1)

5 WARNINGS AND PRECAUTIONS DILAUDID-HP INJECTION is a concentrated formulation of hydromorphone. Do NOT confuse DILAUDID-HP INJECTION with DILAUDID INJECTION. Overdose and death could result. (5.1) May cause respiratory depression, use with extreme caution in patients at risk of respiratory depression, elderly, and debilitated patients. (5.2) Abuse of DILAUDID INJECTION and DILAUDID-HP INJECTION poses a hazard of overdose and death. (5.3) Risk of medication errors: Morphine does not convert to hydromorphone on a milligram per milligram basis. Use Table 1 to convert. (5.1) Alcohol, other opioids and central nervous system depressants potentiate the respiratory depressant effects of hydromorphone. (5.4) Infants born to mothers physically dependent on DILAUDID INJECTION or DILAUDID-HP INJECTION will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms. (5.5) Respiratory depression may be markedly increased in patients with head injury, other intracranial lesions, or preexisting increase in intracranial pressure. (5.6) May cause hypotension, use with caution in patients at increased risk of hypotension and in patients in circulatory shock. (5.7) DILAUDID INJECTION and DILAUDID-HP INJECTION contain sodium metabisulfite. There is a risk of anaphylactic symptoms and life-threatening asthmatic episodes in susceptible people. (5.8) Use with caution in patients with biliary tract disease including pancreatitis. (5.9) Use with caution and in reduced initial doses in the elderly, debilitated, or other patient populations with increased risk of adverse reactions from opioids. (5.10) Use with caution in patients with alcoholism or other drug dependencies. (5.11) May impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. (5.12) 5.1 Risk of Medication Errors DILAUDID-HP INJECTION is a 10 mg/mL concentrated solution of hydromorphone, and is intended for use in opioid-tolerant patients only. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer. Do not confuse DILAUDID-HP INJECTION with standard parenteral formulations of DILAUDID INJECTION (1 mg/mL, 2 mg/mL, 4 mg/mL) or other opioids, as overdose and death could result. Morphine does not convert to hydromorphone on a mg per mg basis. Use Table 1 when converting a patient from morphine to hydromorphone to avoid errors that can lead to overdose or death. 5.2 Respiratory Depression Respiratory depression is the chief hazard of DILAUDID INJECTION and DILAUDID-HP INJECTION. Respiratory depression occurs most frequently in the elderly, in the debilitated, and in those suffering from conditions accompanied by hypoxia or hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may dangerously decrease pulmonary ventilation. Respiratory depression is also a particular problem following large initial doses in non opioid-tolerant patients or when opioids are given in conjunction with other agents that depress respiration. Use DILAUDID INJECTION and DILAUDID-HP INJECTION with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression. In such patients, even usual therapeutic doses of opioid analgesics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Consider using non-opioid analgesics, and administer DILAUDID only under careful medical supervision at the lowest effective dose in such patients. 5.3 Misuse, Abuse and Diversion of Opioids DILAUDID INJECTION and DILAUDID-HP INJECTION contain hydromorphone, an opioid agonist with an abuse liability similar to morphine, and a Schedule II, controlled substance. Hydromorphone has the potential for being abused, is sought by drug abusers and people with addiction disorders, and is subject to criminal diversion. Diversion of Schedule II products is an act subject to criminal penalty. Abuse of DILAUDID INJECTION and DILAUDID-HP INJECTION, poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol or other substances. Schedule II opioid agonists have the highest potential for abuse and risk of fatal respiratory depression. DILAUDID INJECTION and DILAUDID-HP INJECTION can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing DILAUDID INJECTION and DILAUDID-HP INJECTION in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. 5.4 Interactions with Alcohol and other CNS Depressants The concurrent use of DILAUDID INJECTION or DILAUDID-HP INJECTION with other central nervous system (CNS) depressants, including, but not limited to, other opioids, illicit drugs, sedatives, hypnotics, general anesthetics, phenothiazines, muscle relaxants, other tranquilizers, and alcohol, increases the risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. Use with caution and in reduced dosages in patients taking CNS depressants. 5.5 Neonatal Withdrawal Syndrome Infants born to mothers physically dependent on DILAUDID INJECTION or DILAUDID-HP INJECTION will also be physically dependent and may exhibit signs of withdrawal. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. Neonatal opioid withdrawal syndrome may be life-threatening and should be treated according to protocols developed by neonatology experts [see DRUG ABUSE AND DEPENDENCE (9.3) ] . 5.6 Use in Increased Intracranial Pressure or Head Injury The respiratory depressant effects of DILAUDID INJECTION and DILAUDID-HP INJECTION promote carbon dioxide retention which results in elevation of cerebrospinal fluid pressure. This increase in intracranial pressure may be markedly exaggerated in the presence of head injury, intracranial lesions, or other conditions that predispose patients to increased intracranial pressure. DILAUDID INJECTION and DILAUDID-HP INJECTION may produce effects on pupillary response and consciousness which can obscure the clinical course and neurologic signs of further increase in pressure in patients with head injuries. 5.7 Hypotensive Effect DILAUDID INJECTION and DILAUDID-HP INJECTION may cause severe hypotension in patients whose ability to maintain blood pressure is compromised by a depleted blood volume, or a concurrent administration of drugs such as phenothiazines, general anesthetics, or other agents which compromise vasomotor tone [see DRUG INTERACTIONS (7.1) ] . DILAUDID INJECTION and DILAUDID-HP INJECTION may produce orthostatic hypotension in ambulatory patients. Administer DILAUDID INJECTION and DILAUDID-HP INJECTION with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. 5.8 Sulfites DILAUDID INJECTION and DILAUDID-HP INJECTION contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. 5.9 Use in Pancreatic/Biliary Tract Disease and Other Gastrointestinal Conditions The administration of DILAUDID INJECTION or DILAUDID-HP INJECTION may obscure the diagnosis or clinical course in patients with acute abdominal conditions [see CONTRAINDICATIONS (4.0) ] . Use DILAUDID INJECTION and DILAUDID-HP with caution in patients who are at risk of developing ileus. Use DILAUDID INJECTION and DILAUDID-HP INJECTION with caution in patients with biliary tract disease, including acute pancreatitis, as hydromorphone may cause spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions. 5.10 Special Risk Patients Give DILAUDID INJECTION and DILAUDID-HP INJECTION with caution and the initial dose should be reduced in the elderly or debilitated and those with severe impairment of hepatic, pulmonary, or renal function; myxedema or hypothyroidism; adrenocortical insufficiency (e.g., Addison's Disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis associated with respiratory depression. The administration of opioid analgesics including DILAUDID INJECTION and DILAUDID-HP INJECTION may aggravate preexisting convulsions in patients with convulsive disorders. DILAUDID INJECTION and DILAUDID-HP INJECTION, as with other opioids, may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Reports of mild to severe seizures and myoclonus have been reported in severely compromised patients administered high doses of parenteral hydromorphone. 5.11 Use in Drug and Alcohol Dependent Patients Use DILAUDID INJECTION and DILAUDID-HP INJECTION with caution in patients with alcoholism and other drug dependencies due to the increased frequency of opioid tolerance, dependence, and the risk of addiction observed in these patient populations. Abuse of DILAUDID INJECTION or DILAUDID-HP INJECTION in combination with other CNS depressant drugs can result in serious risk to the patient. DILAUDID INJECTION and DILAUDID-HP INJECTION contain hydromorphone, an opioid with no approved use in the management of addiction disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission, is for the management of pain requiring opioid analgesia. 5.12 Use in Ambulatory Patients DILAUDID INJECTION and DILAUDID-HP INJECTION may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Patients should be cautioned accordingly. DILAUDID INJECTION and DILAUDID-HP INJECTION may produce orthostatic hypotension in ambulatory patients. 5.13 Parenteral Administration DILAUDID INJECTION may be given intravenously, but the injection should be given very slowly. Rapid intravenous injection of opioid analgesics increases the possibility of side effects such as hypotension and respiratory depression [see DOSAGE AND ADMINSTRATION (2.3) ] .

6 ADVERSE REACTIONS 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 clinical practice. Serious adverse reactions associated with DILAUDID INJECTION and DILAUDID-HP INJECTION include respiratory depression and apnea and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. The following serious adverse reactions described elsewhere in the labeling include: - Respiratory depression and secondary effects on intracranial pressure [see WARNINGS AND PRECAUTIONS (5.2 , 5.6) ] - Hypotension [see WARNINGS AND PRECAUTIONS (5.7) ] - Gastrointestinal effects and effects in sphincter of Oddi [see WARNINGS AND PRECAUTIONS (5.9) ] - Drug abuse, addiction, and dependence [see DRUG ABUSE AND DEPENDENCE (9.2 , 9.3) ] - Effects on the ability to drive and operate machinery [see WARNINGS AND PRECAUTIONS (5.12) ] The most common adverse effects are lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. These effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain. Less Frequently Observed Adverse Reactions Cardiac disorders: tachycardia, bradycardia, palpitations Eye disorders: vision blurred, diplopia, miosis, visual impairment Gastrointestinal disorders: constipation, ileus, diarrhea, abdominal pain General disorders and administration site conditions: weakness, feeling abnormal, chills, injection site urticaria Hepatobiliary disorders: biliary colic Metabolism and nutrition disorders: decreased appetite Musculoskeletal and connective tissue disorders: muscle rigidity Nervous system disorders: headache, tremor, paraesthesia, nystagmus, increased intracranial pressure, syncope, taste alteration, involuntary muscle contractions, presyncope Psychiatric disorders: agitation, mood altered, nervousness, anxiety, depression, hallucination, disorientation, insomnia, abnormal dreams Renal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effects Respiratory, thoracic, and mediastinal disorders: bronchospasm, laryngospasm Skin and subcutaneous tissue disorders: injection site pain, urticaria, rash, hyperhidrosis Vascular disorders: flushing, hypotension, hypertension Most common adverse reactions are lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. (6) To report Suspected Adverse Reactions, contact Purdue Pharma L.P. at 1-888-726-7535 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Postmarketing Experience The following adverse reactions have been identified during post-approval use of hydromorphone. Because these events 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: anaphylactic reactions, confusional state, convulsions, drowsiness, dyskinesia, dyspnea, erectile dysfunction, fatigue, hepatic enzymes increased, hyperalgesia, hypersensitivity reaction, injection site reactions, lethargy, myoclonus, oropharyngeal swelling, peripheral edema, and somnolence.