Hydromorphone Hydrochloride
Hydromorphone Hydrochloride Prescribing Information
Boxed Warning | 12/2023 |
Indications and 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. Hydromorphone Hydrochloride Injection is an opioid agonist 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 , reserve Hydromorphone Hydrochloride Injection for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products):
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. Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, which can occur atany 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):
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. | 12/2023 |
Dosage and Administration (
Use of Hydromorphone Hydrochloride Injection as the First Opioid Analgesic Subcutaneous or Intramuscular Administration Initiate treatment in a dosing range of 1 mg to 2 mg every 2 to 3 hours as necessary for pain, and at the lowest dose necessary to achieve adequate analgesia . Depending on the clinical situation, the initial starting dose may be lowered in patients who are opioid naïve.Titrate the dose based upon the individual patient’s response to their initial dose of Hydromorphone Hydrochloride Injection. Intravenous Administration Initiate treatment in a dosing range of 0.2 mg to 1 mg every 2 to 3 hours as necessary for pain control, and at the lowest dose necessary to achieve adequate analgesia . Intravenous administration should be given slowly, over at least 2 to 3 minutes, depending on the dose. Titrate the dose to achieve acceptable pain management and tolerable adverse events. 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. 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 andsymptoms of opioid withdrawal, and other adverse reactions, as well asto 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)] | 12/2023 |
Warnings and Precautions ( 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 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)] . | 12/2023 |
Hydromorphone Hydrochloride Injection is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
• 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 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 durationof timeconsistent 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 thepatient’s underlying cause andseverity of pain, prior analgesic treatmentand response, and risk factors for addiction, abuse, and misuse[see Warnings and Precautions (5.1)].• Respiratory depressioncan 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)].• InspectHydromorphone Hydrochloridefor particulate matter and discoloration prior to administration.Do not use if there is any discoloration or precipitate.A slight yellowish discoloration may develop in Hydromorphone Hydrochloride Injection ampuls. No loss of potency has been demonstrated. Hydromorphone Hydrochloride Injection is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions.• Discard any unused portion in an appropriate manner.
• 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 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 durationof timeconsistent 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 thepatient’s underlying cause andseverity of pain, prior analgesic treatmentand response, and risk factors for addiction, abuse, and misuse[see Warnings and Precautions (5.1)].• Respiratory depressioncan 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)].• InspectHydromorphone Hydrochloridefor particulate matter and discoloration prior to administration.Do not use if there is any discoloration or precipitate.A slight yellowish discoloration may develop in Hydromorphone Hydrochloride Injection ampuls. No loss of potency has been demonstrated. Hydromorphone Hydrochloride Injection is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions.• Discard any unused portion in an appropriate manner.
)5 WARNINGS AND 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. • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration.• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.• Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Hydromorphone Hydrochloride Injection in patients with circulatory shock.• 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.
5.1 Addiction, Abuse, and MisuseHydromorphone 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 DepressionSerious, 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 (CO2) 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 (2.1)]. 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 (2.1)].5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS DepressantsProfound 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.
Advise both patients and caregivers about the risks of respiratory depression and sedation when Hydromorphone Hydrochloride Injection 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)].5.4 Neonatal Opioid Withdrawal SyndromeUse 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 AllodyniaOpioid-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[seeDependence (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)[seeDosage 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 PatientsThe 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[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 InsufficiencyCases 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 HypotensionHydromorphone 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 ConsciousnessIn patients who may be susceptible to the intracranial effects of CO2retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Hydromorphone Hydrochloride Injection may reduce respiratory drive, and the resultant CO2retention can further increase intracranial pressure. Monitor such patients for worsening of signs of increasing intracranial pressure. Monitor 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 ConditionsHydromorphone 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 DisordersThe 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 WithdrawalAvoid 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 MachineryHydromorphone 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 AdministrationHydromorphone 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 (2.1)].• 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 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 durationof timeconsistent 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 thepatient’s underlying cause andseverity of pain, prior analgesic treatmentand response, and risk factors for addiction, abuse, and misuse[see Warnings and Precautions (5.1)].• Respiratory depressioncan 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)].• InspectHydromorphone Hydrochloridefor particulate matter and discoloration prior to administration.Do not use if there is any discoloration or precipitate.A slight yellowish discoloration may develop in Hydromorphone Hydrochloride Injection ampuls. No loss of potency has been demonstrated. Hydromorphone Hydrochloride Injection is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions.• Discard any unused portion in an appropriate manner.
• 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 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 durationof timeconsistent 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 thepatient’s underlying cause andseverity of pain, prior analgesic treatmentand response, and risk factors for addiction, abuse, and misuse[see Warnings and Precautions (5.1)].• Respiratory depressioncan 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)].• InspectHydromorphone Hydrochloridefor particulate matter and discoloration prior to administration.Do not use if there is any discoloration or precipitate.A slight yellowish discoloration may develop in Hydromorphone Hydrochloride Injection ampuls. No loss of potency has been demonstrated. Hydromorphone Hydrochloride Injection is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions.• Discard any unused portion in an appropriate manner.
)5.1 Addiction, Abuse, and MisuseHydromorphone 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.
• 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 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 durationof timeconsistent 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 thepatient’s underlying cause andseverity of pain, prior analgesic treatmentand response, and risk factors for addiction, abuse, and misuse[see Warnings and Precautions (5.1)].• Respiratory depressioncan 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)].• InspectHydromorphone Hydrochloridefor particulate matter and discoloration prior to administration.Do not use if there is any discoloration or precipitate.A slight yellowish discoloration may develop in Hydromorphone Hydrochloride Injection ampuls. No loss of potency has been demonstrated. Hydromorphone Hydrochloride Injection is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions.• Discard any unused portion in an appropriate manner.
)5.2 Life-Threatening Respiratory DepressionSerious, 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 (CO2) 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 (2.1)]. 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 (2.1)].• Intramuscular and Subcutaneous Use: The usual starting dose is 1 mg to 2 mg every 2 to 3 hours as necessary. ()2.2 Initial DosageUse of Hydromorphone Hydrochloride Injection as the First Opioid AnalgesicSubcutaneous or Intramuscular AdministrationInitiate treatment in a dosing range of1 mg to 2 mg every 2 to 3 hours as necessary for pain, and at the lowest dose necessary to achieve adequate analgesia. Depending on the clinical situation, the initial starting dose may be lowered in patients who are opioid naïve.Titrate the dose based upon the individual patient’s response to their initial dose of Hydromorphone Hydrochloride Injection.Intravenous AdministrationInitiate treatment in a dosing range of0.2 mg to 1 mg every 2 to 3 hours as necessary for pain control, and at the lowest dose necessary to achieve adequate analgesia. Intravenous administration should be given slowly, over at least 2 to 3 minutes, depending on the dose. Titrate the dose to achieve acceptable pain management and tolerable adverse events. 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 InjectionThere 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.
• 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 Initial DosageUse of Hydromorphone Hydrochloride Injection as the First Opioid AnalgesicSubcutaneous or Intramuscular AdministrationInitiate treatment in a dosing range of1 mg to 2 mg every 2 to 3 hours as necessary for pain, and at the lowest dose necessary to achieve adequate analgesia. Depending on the clinical situation, the initial starting dose may be lowered in patients who are opioid naïve.Titrate the dose based upon the individual patient’s response to their initial dose of Hydromorphone Hydrochloride Injection.Intravenous AdministrationInitiate treatment in a dosing range of0.2 mg to 1 mg every 2 to 3 hours as necessary for pain control, and at the lowest dose necessary to achieve adequate analgesia. Intravenous administration should be given slowly, over at least 2 to 3 minutes, depending on the dose. Titrate the dose to achieve acceptable pain management and tolerable adverse events. 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 InjectionThere 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.
• Hepatic Impairment: Initiate treatment with one-fourth to one-half the usual starting dose, depending on degree of hepatic impairment. ()2.3 Dosage Modifications in Patients with Hepatic ImpairmentStart patients with hepatic impairment on one-fourth to one-half the usual dose of Hydromorphone Hydrochloride Injection depending on the extent of impairment
[see Clinical Pharmacology (12.3)].• Renal Impairment: Initiate treatment with one-fourth to one-half the usual starting dose, depending on degree of renal impairment. ()2.4 Dosage Modifications in Patients with Renal ImpairmentStart patients with renal impairment on one-fourth to one-half the usual starting dose of Hydromorphone Hydrochloride Injection depending on the degree of impairment
[seeClinical Pharmacology (12.3)].• Do not abruptly discontinue Hydromorphone Hydrochloride Injection in a physically-dependent patient. ()2.6 Discontinuation of Hydromorphone Hydrochloride InjectionWhen 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
[seeWarnings and Precautions (5.12), Drug Abuse and Dependence (9.3)].
Hydromorphone Hydrochloride Injection, USP is available as:
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The drug product is a clear, colorless to nearly colorless aqueous sterile solution. Each 1 mL of sterile solution contains 1 mg, 2 mg or 4 mg of hydromorphone hydrochloride.
• Pregnancy: May cause fetal harm. ()8.1 PregnancyRisk SummaryUse of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome
[seeWarnings and Precautions (5.4)]. There are no available data with Hydromorphone Hydrochloride Injection in pregnant women to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics(see Clinical Considerations).In published animal reproduction studies, neural tube defects were noted following subcutaneous injection of hydromorphone to pregnant hamsters at doses 6.4 times the HDD and soft tissue and skeletal abnormalities were noted following subcutaneous continuous infusion of 3 times the HDD to pregnant mice. No malformations were noted at 4 or 40.5 times the HDD in pregnant rats or rabbits, respectively
[see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical ConsiderationsFetal/Neonatal Adverse ReactionsUse of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly
[seeWarnings and Precautions (5.4)].Labor or DeliveryOpioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Hydromorphone Hydrochloride Injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Hydromorphone Hydrochloride Injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
DataAnimal DataNo effects on teratogenicity or embryotoxicity were observed in pregnant rats given oral doses up to 7 mg/kg/day which is 3-fold higher than the human dose of 24 mg Hydromorphone Hydrochloride Injection (4 mg every 4 hours), on a body surface area basis.
In a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of hydromorphone hydrochloride (19 to 258 mg/kg) on Gestation Day 8 to pregnant hamsters (6.4 to 87.2 times the HDD of 24 mg/day based on body surface area). The findings cannot be clearly attributed to maternal toxicity. No neural tube defects were noted at 14 mg/kg (4.7 times the human daily dose of 24 mg/day).
In a published study, CF-1 mice were treated subcutaneously with continuous infusion of 7.5, 15, or 30 mg/kg/day hydromorphone hydrochloride (1.5, 3, or 6.1 times the human daily dose of 24 mg based on body surface area) via implanted osmotic pumps during organogenesis (Gestation Days 7 to 10). Soft tissue malformations (cryptorchidism, cleft palate, malformed ventricles and retina), and skeletal variations (split supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites) were observed at doses 3 times the human dose of 24 mg/day based on body surface area. The findings cannot be clearly attributed to maternal toxicity.
• Geriatric Patients: Use caution during dose selection, starting at the low end of the dosing range while carefully monitoring for side effects. ()8.5 Geriatric UseElderly patients (aged 65 years or older) may have increased sensitivity to hydromorphone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Hydromorphone Hydrochloride Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression
[seeWarnings and Precautions (5.6)].Hydromorphone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Hydromorphone Hydrochloride Injection is contraindicated in patients with:
• Significant respiratory depression[see]5.2 Life-Threatening Respiratory DepressionSerious, 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 (CO2) 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 (2.1)]. 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 (2.1)].• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment[see5.6 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated PatientsThe 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[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.]• Known or suspected gastrointestinal obstruction, including paralytic ileus[see5.10 Risks of Use in Patients with Gastrointestinal ConditionsHydromorphone 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.
]• Hypersensitivity to hydromorphone (e.g., anaphylaxis)[see]6 ADVERSE REACTIONSThe 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 or Other CNS Depressants[seeWarnings 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[seeWarnings and Precautions (5.7)]• Severe Hypotension[seeWarnings and Precautions (5.8)]• Gastrointestinal Adverse Reactions[seeWarnings and Precautions (5.10)]• Seizures[seeWarnings and Precautions (5.11)]• Withdrawal[seeWarnings 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.
The most common adverse effects are light-headedness, 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 light-headedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus.
Serious adverse reactions include respiratory depression and apnea, circulatory depression, respiratory arrest, shock and cardiac arrest.
To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov.medwatch.Less Frequently Observed Adverse ReactionsCardiac disorders: tachycardia, bradycardia, palpitationsEye disorders: vision blurred, diplopia, miosis, visual impairmentGastrointestinal disorders: constipation, ileus, diarrhea, abdominal painGeneral disorders and administration site conditions: weakness, feeling abnormal, chills, injection site urticariaHepatobiliary disorders: biliary colicMetabolism and nutrition disorders: decreased appetiteMusculoskeletal and connective tissue disorders: muscle rigidityNervous system disorders: headache, tremor, paraesthesia, nystagmus, increased intracranial pressure, syncope, taste alteration, involuntary muscle contractions, presyncopePsychiatric disorders: agitation, mood altered, nervousness, anxiety, depression, hallucination, disorientation, insomnia, abnormal dreamsRenal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effectsRespiratory, thoracic and mediastinal disorders: bronchospasm, laryngospasmSkin and subcutaneous tissue disorders: injection site pain, urticaria, rash, hyperhidrosisVascular disorders: flushing, hypotension, hypertensionSerotonin 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 use of opioids for an extended period of time.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).