Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Hydromorphone Hydrochloride Injection is a clear, colorless, sterile, aqueous solution available in multi-dose clear glass vial containing 40 mg/20 mL (2 mg/mL). It is supplied in the following packaging configuration: Carton containing 1 multi-dose vial: NDC 0641-6254-01 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from light.; PRINCIPAL DISPLAY PANEL NDC 0641- 6254 -01 Rx Only HYDROmorphone HCI Injection CII 40 mg per 20 mL (2 mg/mL) For Subcutaneous, Intramuscular, or slow Intravenous use 20 mL Multiple-Dose Vial NDC 0641- 6254 -01 Rx Only HYDROmorphone HCI Injection CII 40 mg per 20 mL (2 mg/mL) For Subcutaneous, Intramuscular, or slow Intravenous use 1 x 20 mL Multiple-Dose Vial Hydromorphone 20 mL MDV Label Hydromorphone 20 mL MDV Carton
- 16 HOW SUPPLIED/STORAGE AND HANDLING Hydromorphone Hydrochloride Injection is a clear, colorless, sterile, aqueous solution available in multi-dose clear glass vial containing 40 mg/20 mL (2 mg/mL). It is supplied in the following packaging configuration: Carton containing 1 multi-dose vial: NDC 0641-6254-01 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from light.
- PRINCIPAL DISPLAY PANEL NDC 0641- 6254 -01 Rx Only HYDROmorphone HCI Injection CII 40 mg per 20 mL (2 mg/mL) For Subcutaneous, Intramuscular, or slow Intravenous use 20 mL Multiple-Dose Vial NDC 0641- 6254 -01 Rx Only HYDROmorphone HCI Injection CII 40 mg per 20 mL (2 mg/mL) For Subcutaneous, Intramuscular, or slow Intravenous use 1 x 20 mL Multiple-Dose Vial Hydromorphone 20 mL MDV Label Hydromorphone 20 mL MDV Carton
Overview
Hydromorphone Hydrochloride is an opioid agonist. The chemical name of hydromorphone hydrochloride is 4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride. The molecular weight is 321.80. Its molecular formula is C 17 H 19 NO 3 ·HCl, and it has the following chemical structure: Hydromorphone hydrochloride is a white to off-white powder that is freely soluble in water, very slightly soluble in ethanol (96%), and practically insoluble in methylene chloride. Hydromorphone Hydrochloride Injection 40 mg/20 mL is available as a sterile, clear, colorless aqueous solution in a multiple-dose clear glass vial, for slow intravenous, subcutaneous, or intramuscular administration. Each 1 mL contains 2 mg of hydromorphone hydrochloride (equivalent to 1.8 mg hydromorphone). The inactive ingredients include edetate disodium dihydrate (0.5 mg/mL), methylparaben (1.8 mg/mL), and propylparaben (0.2 mg/mL) . Hydrochloric acid and sodium hydroxide are added to adjust the pH between 3.5 and 5.5. Structural Formula
Indications & Usage
Hydromorphone Hydrochloride Injection is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions (5.1) ] , reserve Hydromorphone Hydrochloride Injection for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): Have not been tolerated or are not expected to be tolerated Have not provided adequate analgesia or are not expected to provide adequate analgesia Hydromorphone Hydrochloride Injection should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. Hydromorphone Hydrochloride Injection is an opioid agonist indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. ( 1 ) Limitations of Use: ( 1 ) Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration ( 5.1 ) , reserve Hydromorphone Hydrochloride Injection for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): Have not been tolerated, or are not expected to be tolerated Have not provided adequate analgesia or are not expected to provide adequate analgesia Hydromorphone Hydrochloride Injection should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.
Dosage & Administration
Hydromorphone Hydrochloride Injection should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. Reserve titration to higher doses of Hydromorphone Hydrochloride Injection for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.1 ) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Hydromorphone Hydrochloride Injection. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Initial Dosage: - Intramuscular or Subcutaneous Use: The usual starting dose is 1 mg to 2 mg every 2 to 3 hours as necessary. ( 2.2 ) - Intravenous Use : The usual starting dose is 0.2 mg to 1 mg every 2 to 3 hours. The injection should be given slowly, over at least 2 to 3 minutes. ( 2.2 ) Hepatic Impairment: Initiate treatment with one-fourth to one-half the usual starting dose, depending on degree of hepatic impairment. ( 2.3 ) Renal Impairment : Initiate treatment with one-fourth to one-half the usual starting dose, depending on degree of renal impairment. ( 2.4 ) Do not abruptly discontinue Hydromorphone Hydrochloride Injection in a physically-dependent patient. ( 2.6 , 5.12 ) 2.1 Important Dosage and Administration Instructions Hydromorphone Hydrochloride Injection should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions ( 5 ) ] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Hydromorphone Hydrochloride Injection for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1) ] . Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Hydromorphone Hydrochloride Injection. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5.2) ] . Inspect Hydromorphone Hydrochloride Injection for particulate matter and discoloration prior to administration. A 0.2 mg/mL admixture of Hydromorphone Hydrochloride Injection in 0.9% sodium chloride or 5% dextrose is physically compatible and chemically stable for 24 hours at 25°C, protected from light. Use or discard multi-dose vials within 28 days of the first use. 2.2 Initial Dosage Use of Hydromorphone Hydrochloride Injection as the First Opioid Analgesic Subcutaneous or Intramuscular Administration: Initiate treatment with Hydromorphone Hydrochloride Injection in a dosing range of 1 mg to 2 mg every 2 to 3 hours as needed for pain, and the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Hydromorphone Hydrochloride Injection. Intravenous Administration: The initial starting dose is 0.2 mg to 1 mg every 2 to 3 hours. Intravenous administration should be given slowly , over at least 2 to 3 minutes, depending on the dose. The initial dose should be reduced in the elderly or debilitated and may be lowered to 0.2 mg. Conversion from Other Opioids to Hydromorphone Hydrochloride Injection There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Hydromorphone Hydrochloride Injection. It is safer to underestimate a patient’s 24-hour Hydromorphone Hydrochloride Injection dosage than to overestimate the 24-hour Hydromorphone Hydrochloride Injection dosage and manage an adverse reaction due to overdose. If the decision is made to convert to Hydromorphone Hydrochloride Injection from another opioid analgesic using publicly available data, convert the current total daily amount(s) of opioid(s) received to an equivalent total daily dose of Hydromorphone Hydrochloride Injection and reduce by one-half due to the possibility of incomplete cross tolerance. Divide the new total amount by the number of doses permitted based on dosing interval (e.g., 8 doses for every-three-hour dosing). Titrate the dose according to the patient's response. 2.3 Dosage Modifications in Patients with Hepatic Impairment Start patients with hepatic impairment on one-fourth to one-half the usual Hydromorphone Hydrochloride Injection starting dose depending on the extent of impairment [see Clinical Pharmacology (12.3) ]. 2.4 Dosage Modifications in Patients with Renal Impairment Start patients with renal impairment on one-fourth to one-half the usual Hydromorphone Hydrochloride Injection starting dose depending on the degree of impairment [see Clinical Pharmacology ( 12.3 ) ] . 2.5 Titration and Maintenance of Therapy Titrate the dose based upon the individual patient’s response to their initial dose of Hydromorphone Hydrochloride Injection. Individually titrate Hydromorphone Hydrochloride Injection to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Hydromorphone Hydrochloride Injection to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1 , 5.12 )] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Hydromorphone Hydrochloride Injection dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions (5) ] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.6 Safe Reduction or Discontinuation of Hydromorphone Hydrochloride Injection When a patient who has been taking Hydromorphone Hydrochloride Injection regularly and may be physically dependent no longer requires therapy with Hydromorphone Hydrochloride Injection, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Hydromorphone Hydrochloride Injection in a physically-dependent patient [see Warnings and Precautions (5.12) , Drug Abuse and Dependence (9.3) ].
Warnings & Precautions
Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.5 ) 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 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 in patients with impaired consciousness or coma. ( 5.9 ) 5.1 Addiction, Abuse, and Misuse Hydromorphone Hydrochloride Injection contains hydromorphone, a Schedule II controlled substance. As an opioid, Hydromorphone Hydrochloride Injection 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. 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 and monitor all patients receiving Hydromorphone Hydrochloride Injection 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 but use in such patients necessitates intensive counseling about the risks and proper use of Hydromorphone Hydrochloride Injection along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Hydromorphone Hydrochloride Injection. 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. 5.2 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 Hydromorphone Hydrochloride Injection, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Hydromorphone Hydrochloride Injection are essential [see Dosage and Administration (2) ]. Overestimating the Hydromorphone Hydrochloride Injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. 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) ]. 5.3 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 with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). 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. Monitor patients closely for signs and symptoms of respiratory depression and sedation. 5.4 Neonatal Opioid Withdrawal Syndrome Use of Hydromorphone Hydrochloride Injection for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that management by neonatology experts will be available at delivery [see Use in Specific Populations (8.1) ]. 5.5 Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Drug Abuse and Dependence (9.3) ] . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.6) , Warnings and Precautions (5.12) ] . 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 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 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 [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 Hydromorphone Hydrochloride Injection and when Hydromorphone Hydrochloride Injection is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2 , 5.3 ), Drug Interactions (7) ] . 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 Hydromorphone Hydrochloride Injection 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. In patients with circulatory shock, Hydromorphone Hydrochloride Injection may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Hydromorphone Hydrochloride Injection 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 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 Hydromorphone Hydrochloride Injection. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Hydromorphone Hydrochloride Injection in patients with impaired consciousness or coma. 5.10 Risks of Use in Patients with Gastrointestinal Conditions Hydromorphone Hydrochloride Injection is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The hydromorphone in Hydromorphone Hydrochloride Injection 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 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 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. 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 in a physically-dependent patient, gradually taper the dosage [see Dosage and Administration (2.6) ]. Do not abruptly discontinue Hydromorphone Hydrochloride Injection in these patients [see Drug Abuse and Dependence (9.3) ]. 5.13 Risks of Driving and Operating Machinery Hydromorphone Hydrochloride Injection 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 and know how they will react to the medication. 5.14 Increased Risk of Hypotension and Respiratory Depression with Rapid Intravenous Administration Hydromorphone Hydrochloride 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 Administration (2)] .
Boxed Warning
SERIOUS AND LIFE-THREATENING RISKS FROM USE OF HYDROMORPHONE HYDROCHLORIDE WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF HYDROMORPHONE HYDROCHLORIDE INJECTION Addiction, Abuse, and Misuse Because the use of Hydromorphone Hydrochloride Injection 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 and reassess 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 Hydromorphone Hydrochloride Injection, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Hydromorphone Hydrochloride Injection are essential [see Warnings and Precautions ( 5.2 ) ] . 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 . Reserve concomitant prescribing of Hydromorphone Hydrochloride Injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3 ), Drug Interactions (7) ] . Neonatal Opioid Withdrawal Syndrome (NOWS) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions ( 5. 4 ) ] . WARNING: S ERIOUS AND LIFE-THREATENING RISKS FROM USE OF HYDROMORPHONE HYDROCHLORIDE INJECTION See full prescribing information for complete boxed warning. Hydromorphone Hydrochloride Injection 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 dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Hydromorphone Hydrochloride Injection are essential. ( 5.2 ) 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. ( 5.3 , 7 ) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. ( 5.4 )
Contraindications
Hydromorphone Hydrochloride Injection is contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.2) ] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.2) ] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.10) ] • Hypersensitivity to hydromorphone, hydromorphone salts, any other components of the product. Significant respiratory depression. ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) Known hypersensitivity to hydromorphone, hydromorphone salts, or any other components of the product. ( 4 )
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 (5.1) ] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2) ] Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.3) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4) ] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.5) ] 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) ] 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 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. 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, hypophagia 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, paraesthesia, nystagmus, increased intracranial pressure, syncope, taste alteration, involuntary muscle contractions, presyncope, convulsion, drowsiness, dyskinesia, hyperalgesia, lethargy, myoclonus, somnolence, intoxication by breastfeeding 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, pre-eclampsia Respiratory, thoracic, and mediastinal disorders: bronchospasm, laryngospasm, dyspnea, oropharyngeal swelling Skin and subcutaneous tissue disorders: injection site pain, urticaria, rash, hyperhidrosis, Impetigo herpetiformis 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. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2) ]. Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.5) ]. Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). 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 Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
Drug Interactions
Table 1 includes clinically significant drug interactions with Hydromorphone Hydrochloride Injection. TABLE 1. Clinically Significant Drug Interactions with Hydromorphone Hydrochloride Injection Benzodiazepines and other Central Nervous System Depressants (CNS) Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions (5.3) ] . Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.3) ] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Hydromorphone Hydrochloride Injection if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2) ] . Intervention: The use of Hydromorphone Hydrochloride Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Hydromorphone Hydrochloride Injection and/or precipitate withdrawal syndrome. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Hydromorphone Hydrochloride Injection and/or the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Hydromorphone Hydrochloride Injection is used concomitantly with anticholinergic drugs. Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue Hydromorphone Hydrochloride Injection if serotonin syndrome is suspected. ( 7 ) Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of hydromorphone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. ( 7 ) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Hydromorphone Hydrochloride Injection because they may reduce analgesic effect of Hydromorphone Hydrochloride Injection or precipitate withdrawal symptoms. ( 7 )
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