FDA label dca637ff-97ef-4583-baeb-bb4096591ba1

WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. Do not confuse hydromorphone hydrochloride injection [high potency formulation (HPF)] with standard parenteral formulations of hydromorphone hydrochloride injection or other opioids, as overdose and death could result. ( 5.1 ) Hydromorphone hydrochloride injection [high potency formulation (HPF)] exposes users to risks of addictions, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and monitor regularly for these behaviors and conditions. ( 5.2 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. ( 5.3 ) Prolonged use of hydromorphone hydrochloride injection [high potency formulation (HPF)] 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. ( 5.4 ) 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 ) Risk of Medication Errors Hydromorphone hydrochloride injection [high potency formulation (HPF)] is a more concentrated solution of hydromorphone than hydromorphone hydrochloride injection, and is for use in opioid-tolerant patients only. Do not confuse hydromorphone hydrochloride injection [high potency formulation (HPF)] with standard parenteral formulations of hydromorphone hydrochloride injection or other opioids, as overdose and death could result [see Warnings and Precautions ( 5.1 ) ]. Addiction, Abuse, and Misuse Hydromorphone hydrochloride injection [high potency formulation (HPF)] 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 hydromorphone hydrochloride injection [high potency formulation (HPF)] and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.2 ) ]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of hydromorphone hydrochloride injection [high potency formulation (HPF)]. Monitor for respiratory depression, especially during initiation of hydromorphone hydrochloride injection [high potency formulation (HPF)] or following a dose increase [see Warnings and Precautions ( 5.3 ) ]. Neonatal Opioid Withdrawal Syndrome Prolonged use of hydromorphone hydrochloride injection [high potency formulation (HPF)] 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 ( 5.4 ) ]. 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 hydromorphone hydrochloride [high potency formulation (HPF)] 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 hydromorphone hydrochloride injection [high potency formulation (HPF)] 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 hydromorphone hydrochloride injection (HPF) in patients with impaired consciousness or coma. ( 5.9 ) Hydromorphone hydrochloride injection (HPF) contains sodium metabisulfite. There is a risk of anaphylactic symptoms and life-threatening asthmatic episodes in susceptible people. ( 5.14 ) 5.1 Risk of Medication Errors Hydromorphone hydrochloride injection [high potency formulation (HPF)] 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 hydromorphone hydrochloride injection (HPF) with standard parenteral formulations of hydromorphone hydrochloride injection (1 mg/mL, 2 mg/mL, 4 mg/mL) or other opioids, as overdose and death could result. 5.2 Addiction, Abuse, and Misuse Hydromorphone hydrochloride injection [high potency formulation (HPF)] contains hydromorphone, a Schedule II controlled substance. As an opioid, hydromorphone hydrochloride injection (HPF) 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 hydromorphone hydrochloride injection (HPF). 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 hydromorphone hydrochloride injection (HPF), and monitor all patients receiving hydromorphone hydrochloride injection (HPF) for the development of these behaviors and 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 hydromorphone hydrochloride injection (HPF), but use in such patients necessitates intensive counseling about the risks and proper use of hydromorphone hydrochloride injection (HPF) along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing hydromorphone hydrochloride injection (HPF). Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. 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. 5.3 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 hydromorphone hydrochloride injection [high potency formulation (HPF)], 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 to 72 hours of initiating therapy with and following dosage increases of hydromorphone hydrochloride injection (HPF). To reduce the risk of respiratory depression, proper dosing and titration of hydromorphone hydrochloride injection (HPF) are essential [see Dosage and Administration ( 2 ) ]. Overestimating the hydromorphone hydrochloride injection (HPF) dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Hydromorphone hydrochloride injection (HPF) is for use in opioid-tolerant patients only . Administration of this formulation may cause fatal respiratory depression when administered to patients who are not tolerant to the respiratory depressant effects of opioids. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.6 ) ]. 5.4 Neonatal Opioid Withdrawal Syndrome Prolonged use of hydromorphone hydrochloride injection [high potency formulation (HPF)] 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 ) ]. 5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of hydromorphone hydrochloride injection [high potency formulation (HPF)] with benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine 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 hydromorphone hydrochloride injection (HPF) 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 hydromorphone hydrochloride injection [high potency formulation (HPF)] 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 Hydromorphone hydrochloride injection [high potency formulation (HPF)] 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 hydromorphone hydrochloride injection (HPF) [see Warnings and Precautions ( 5.3 ) ]. 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 ( 5.3 ) ]. Monitor such patients closely, particularly when initiating and titrating hydromorphone hydrochloride injection [high potency formulation (HPF)] and when hydromorphone hydrochloride injection (HPF) is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.3 ) ]. Alternatively, consider the use of nonopioid 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 Hydromorphone hydrochloride injection [high potency formulation (HPF)] may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is 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 hydromorphone hydrochloride injection (HPF). In patients with circulatory shock, hydromorphone hydrochloride injection (HPF) may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of hydromorphone hydrochloride injection (HPF) 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), hydromorphone hydrochloride injection [high potency formulation (HPF)] 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 hydromorphone hydrochloride injection (HPF). Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of hydromorphone hydrochloride injection (HPF) in patients with impaired consciousness or coma. 5.10 Risks of Use in Patients with Gastrointestinal Conditions Hydromorphone hydrochloride injection [high potency formulation (HPF)] is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The hydromorphone in hydromorphone hydrochloride injection (HPF) 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 hydromorphone in hydromorphone hydrochloride injection [high potency formulation (HPF)] may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during hydromorphone hydrochloride injection (HPF) 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 are receiving a full opioid agonist analgesic, including hydromorphone hydrochloride injection [high potency formulation (HPF)]. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions ( 7 ) ]. When discontinuing hydromorphone hydrochloride injection [high potency formulation (HPF)], in a physicallydependent patient, gradually taper the dosage [see Dosage and Administration ( 2.6 ) ]. Do not abruptly discontinue hydromorphone hydrochloride injection (HPF) in these patients [see Drug Abuse and Dependence ( 9.3 ) ]. 5.13 Risks of Driving and Operating Machinery Hydromorphone hydrochloride injection (HPF) 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 hydromorphone hydrochloride injection (HPF) and know how they will react to the medication [see Patient Counseling Information ( 17 ) ]. 5.14 Sulfites Hydromorphone hydrochloride injection (HPF) contain sodium metabisulfite, a sulfite that may cause allergictype 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. 5.15 Increased Risk of Hypotension and Respiratory Depression with Rapid Intravenous Administration Hydromorphone hydrochloride injection [high potency formulation (HPF)] 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 Administration ( 2 ) ].

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.2 ) ] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.3 ) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 ) ] Interactions with Benzodiazepines and 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 ) ] Seizures [see Warnings and Precautions ( 5.11 ) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.10 ) ] Withdrawal [see Warnings and Precautions ( 5.12 ) ] The following adverse reactions associated with the use of hydromorphone were identified in clinical studies or postmarketing reports. Because some of these reactions were 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. Serious adverse reactions associated with hydromorphone hydrochloride injection [high potency formulation (HPF)] include respiratory depression and apnea and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. 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. 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 Akorn, Inc. at 1-800-932-5676 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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, fatigue, injection site reactions, peripheral edema Hepatobiliary disorders: biliary colic Immune system disorders: anaphylactic reactions, hypersensitivity reactions Investigations: hepatic enzymes increased Metabolism and nutrition disorders: decreased appetite Musculoskeletal and connective tissue disorders: muscle rigidity Nervous system disorders: headache, tremor, paresthesia, nystagmus, increased intracranial pressure, syncope, taste alteration, involuntary muscle contractions, presyncope, convulsion, drowsiness, dyskinesia, hyperalgesia, lethargy, myoclonus, somnolence Psychiatric disorders: agitation, mood altered, nervousness, anxiety, depression, hallucination, disorientation, insomnia, abnormal dreams Renal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effects Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic, and mediastinal disorders: bronchospasm, laryngospasm, dyspnea, oropharyngeal swelling Skin and subcutaneous tissue disorders: injection site pain, urticaria, rash, hyperhidrosis Vascular disorders: flushing, hypotension, hypertension 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: Anaphylaxis has been reported with ingredients contained in hydromorphone hydrochloride injection [high potency formulation (HPF)]. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2 ) ].