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Hydromorphone: Drug information

Hydromorphone: Drug information
(For additional information see "Hydromorphone: Patient drug information" and see "Hydromorphone: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Addiction, abuse, and misuse:

Hydromorphone exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing hydromorphone and monitor all patients regularly for the development of these behaviors or conditions.

Opioid analgesic risk evaluation and mitigation strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are strongly encouraged to complete a REMS-compliant education program and counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and consider other tools to improve patient, household, and community safety.

Life-threatening respiratory depression:

Serious, life-threatening, or fatal respiratory depression may occur with use of hydromorphone. Monitor for respiratory depression, especially during initiation of hydromorphone or following a dose increase. Instruct patients to swallow hydromorphone ER tablets whole; crushing, chewing, or dissolving hydromorphone ER can cause rapid release and absorption of a potentially fatal dose of hydromorphone.

Accidental ingestion:

Accidental ingestion of even one dose of hydromorphone, especially by children, can result in a fatal overdose of hydromorphone.

Neonatal withdrawal syndrome:

Prolonged use of hydromorphone during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risk of medication errors:

Injection: High-potency hydromorphone (10 mg/mL) is a more concentrated solution of hydromorphone than hydromorphone 1, 2, or 4 mg/mL, and is for use in opioid-tolerant patients only. Do not confuse high-potency hydromorphone with standard parenteral formulations of hydromorphone or other opioids, as overdose and death could result.

Oral solution: Ensure accuracy when prescribing, dispensing, and administering hydromorphone oral solution. Dosing errors due to confusion between mg and mL can result in accidental overdose and death.

Risks from concomitant use with benzodiazepines or other CNS depressants:

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of hydromorphone and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Brand Names: US
  • Dilaudid;
  • Exalgo [DSC]
Brand Names: Canada
  • APO-HYDROmorphone;
  • APO-HYDROmorphone CR;
  • Dilaudid;
  • Hydromorph Contin;
  • HYDROmorphone HCl HP;
  • HYDROmorphone HCl HP Forte;
  • HYDROmorphone HP;
  • HYDROmorphone HP Forte;
  • PMS-HYDROmorphone;
  • TEVA-HYDROmorphone [DSC]
Pharmacologic Category
  • Analgesic, Opioid
Dosing: Adult

Note:

Place in therapy: When used for managing moderate to severe pain, opioids may be part of a comprehensive, multimodal, patient-specific treatment plan for pain. Maximize nonopioid analgesia, if appropriate, prior to initiation of opioid analgesia (Ref).

Dose selection: Dosing provided is based on typical doses and some patients may require higher or lower doses. Individualize dosing and dosing intervals based on patient-specific factors (eg, comorbidities, severity of pain, concomitant medications, cachexia, general condition, degree of opioid experience/tolerance) and titrate to patient-specific treatment goals (eg, improvement in function and quality of life, decrease in pain using a validated pain rating scale). Use the lowest effective dose for the shortest period of time.

Safety: Consider prescribing naloxone for patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally [equivalent to ≥12.5 mg oral hydromorphone/day]), and/or concomitant benzodiazepine use (Ref).

Acute pain in opioid-naive patients

Acute pain in opioid-naive patients:

General dosing: Note: For acute non–cancer-related pain severe enough to require an opioid, utilize multimodal pain control, maximize nonopioid analgesics, and limit the quantity prescribed to the expected duration of acute pain; a quantity sufficient for ≤3 days is often adequate, whereas >7 days is rarely needed. Do not use long-acting preparations for treatment of acute pain (Ref).

Oral: Opioid-naive patients:

Immediate release: Oral: Initial: 1 to 2 mg every 4 to 6 hours as needed; adjust dose according to patient response. Usual dosage range: 1 to 4 mg every 4 to 6 hours as needed. If usual dose and frequency is insufficient, reassess patient and reconsider pain management strategies. For outpatient use, usually up to 8 mg/day for moderate pain or up to 12 mg/day for severe pain will suffice (Ref).

IV: Opioid-naive patients:

Note: Highly concentrated 10 mg/mL (hydromorphone HP) formulation is not for use in patients who are opioid naive.

Intermittent dosing: IV: Initial: 0.2 to 0.5 mg every 2 to 4 hours as needed; adjust dose according to patient response under close monitoring. Usual dosage range: 0.2 to 1 mg every 2 to 4 hours as needed. If usual dose and frequency is insufficient, reassess patient and reconsider pain management strategies (Ref).

Patient-controlled analgesia:

Note: Reserve for use in patients who are alert and have the capacity to repeatedly press a button to titrate analgesia (eg, postoperatively). Initiate patient-controlled analgesia only after initial pain control is achieved (Ref).

Example Hydromorphone IV Patient-Controlled Analgesia Initial Dose Ranges for Patients Who Are Opioid Naive

a May adjust dosing and provide rescue bolus doses (eg, 0.1 to 0.4 mg) if analgesia is inadequate (Mariano 2021).

b The use of a continuous basal infusion for patient-controlled analgesia is generally not recommended for most patients because of the risk of respiratory depression, and use should be limited to carefully selected patients who are opioid tolerant and/or receiving care in an ICU (Carr 2021; Mariano 2021).

Usual concentration

0.2 mg/mL

Demand dose

Usual range: 0.1 to 0.4 mga

Basal dose

In general, a continuous (basal) infusion is not recommended in an opioid-naive patient (ISMP 2009)b

Lockout interval

10 to 15 minutes

Maximum cumulative dose

~1.5 mg within 1 hour (or 6 mg within a 4-hour period)

IM, SUBQ: Opioid-naive patients:

Note: Not recommended for routine use. Reserve for patients without IV or oral access. IM administration is generally not recommended due to pain associated with injection, variable absorption, and delayed time to peak effect (Ref). Although SUBQ absorption is ~80% of the IV route, some experts use a 1:1 (SUBQ:IV) ratio for dosing (Ref).

IM, SUBQ: Initial: 0.2 to 0.5 mg every 2 to 3 hours as needed; adjust dose according to patient response under close monitoring. If usual dose and frequency is insufficient, reassess patient and reconsider pain management strategies.

Rectal: Opioid-naive patients:

Note: May be used as an alternative to IV or oral administration.

Rectal: Initial: 3 mg (1 suppository) every 6 to 8 hours as needed.

Acute pain, opioid-tolerant patients

Acute pain, opioid-tolerant patients (eg, breakthrough cancer pain):

Oral, IV, SUBQ: Usual dose: In conjunction with the scheduled long-acting opioid, administer 5% to 15% (rarely up to 20%) of the 24-hour hydromorphone requirement (or MME) as needed using an IR or parenteral formulation every 3 to 6 hours with subsequent dosage adjustments based on response (Ref). Note: If chronic opioid is not hydromorphone, use MME calculations cautiously due to lack of complete cross-tolerance; generally, reduce calculated dose by 25% to 50%. Conversions from methadone are highly variable and require extreme caution (Ref).

Critically ill patients in the ICU, pain and sedation

Critically ill patients in the ICU, pain and sedation (off-label use):

Note: Employ multimodal approaches (eg, a combination of analgesics, including adjunctive nonopioid agents, and techniques) for pain control in this setting. Monitor pain using validated scales (eg, behavioral pain scale, critical-care observation tool) in ICU patients who are unable to self-report. Intermittent as-needed therapy is preferred where appropriate (Ref).

Intermittent dosing:

IV: Initial: 0.2 to 1 mg every 1 to 3 hours as needed; titrate to clinical effect (ie, pain control or sedation) (Ref).

Continuous IV infusion (alternative therapy): Note: May be used for breakthrough pain/sedation in patients receiving opioids or to transition from another opioid (eg, tolerance) (Ref).

IV: After initial intermittent dose (see "Intermittent Dosing"), begin continuous infusion with an initial dose of 0.5 to 2 mg/hour; titrate to clinical effect (ie, pain control and/or sedation); usual dosage range: 0.25 to 4 mg/hour (Ref).

Acute postoperative pain, postoperative recovery/postanesthesia care unit

Acute postoperative pain, postoperative recovery/postanesthesia care unit:

Note: Optimize multimodal perioperative pain management (eg, regional or local anesthesia, nerve blocks, nonopioid analgesics, and other adjuvants) to minimize opioid use (Ref). Refer to institutional protocols.

Initial pain control:

IV: Initial: 0.2 to 0.5 mg given as frequently as every 5 minutes until adequate pain relief or adverse effects (eg, respiratory depression, oxygen desaturation, hypotension) occur (Ref). Refer to institution-specific protocols as appropriate.

Ongoing pain control:

IV, SUBQ: 0.2 to 0.5 mg every 3 to 4 hours as needed. If usual dose and frequency is insufficient, reassess patient and reconsider pain management strategies. Note: If IV access is difficult, may administer SUBQ (Ref). Although SUBQ absorption is ~80% of the IV route, some experts use a 1:1 (SUBQ:IV) ratio for dosing (Ref).

Note: If patient-controlled analgesia is needed, refer to "Example Hydromorphone IV Patient-Controlled Analgesia Initial Dose Ranges for Patients Who Are Opioid Naive" table.

Patient-controlled analgesia:

Note: Reserve for use in patients who are alert and have the capacity to repeatedly press a button to titrate analgesia (eg, postoperatively). Initiate patient-controlled analgesia only after initial pain control is achieved (Ref).

Example Hydromorphone IV Patient-Controlled Analgesia Initial Dose Ranges for Patients Who Are Opioid Naive

a May adjust dosing and provide rescue bolus doses (eg, 0.1 to 0.4 mg) if analgesia is inadequate (Mariano 2021).

b The use of a continuous basal infusion for patient-controlled analgesia is generally not recommended for most patients because of the risk of respiratory depression, and use should be limited to carefully selected patients who are opioid tolerant and/or receiving care in an ICU (Carr 2021; Mariano 2021).

Usual concentration

0.2 mg/mL

Demand dose

Usual range: 0.1 to 0.4 mga

Basal dose

In general, a continuous (basal) infusion is not recommended in an opioid-naive patient (ISMP 2009)b

Lockout interval

10 to 15 minutes

Maximum cumulative dose

~1.5 mg within 1 hour (or 6 mg within a 4-hour period)

Acute vaso-occlusive pain in sickle cell disease

Acute vaso-occlusive pain in sickle cell disease:

Note: Dosing presented is for patients who do not have a pain treatment plan on file and whose previous opioid dose for prior episodes is unknown. Refer to the individual's personal pain protocol or institutional pain protocol for dosing if available. If opioid dose given for a prior episode is known, choose initial dose based on intensity of pain in comparison with previous episode and previous effective dose (Ref).

Unknown pain treatment plan:

Patient weight ≥50 kg:

IV: Initial: 1.5 mg, given once within 30 to 60 minutes of presentation; if severe pain continues, repeat with ~20% to 50% of the original dose every ~30 minutes; monitor for sedation/respiratory depression (Ref).

Patient weight <50 kg:

IV: Initial: 0.02 to 0.05 mg/kg (maximum initial dose: 1.5 mg), given once within 30 to 60 minutes of presentation; if severe pain continues, repeat with ~20% to 50% of the original dose every ~30 minutes; monitor for sedation/respiratory depression (Ref).

Note: If IV access is difficult, may administer SUBQ (Ref). Although SUBQ absorption is ~80% of the IV route, some experts use a 1:1 (SUBQ:IV) ratio for dosing (Ref).

Neuraxial analgesia

Neuraxial analgesia: Note: Reserve use for severe pain (eg, after surgery). Must be administered by health care providers skilled in the care of patients receiving intraspinal opioids (Ref). Use a preservative-free formulation intended for neuraxial use (Ref).

Epidural:

Note: Example regimens and usual doses are provided; specific regimens and doses vary based on type of surgery, comorbidities, and institutional policies and practices.

Single dose: Opioid-naive patients: Epidural: Usual dosage range: 0.4 to 1.5 mg (Ref).

Continuous infusion: Opioid-naive patients: Epidural: Usual dosage range: 20 to 300 mcg/hour (Ref). May be given alone or usually in combination with local anesthetics (eg, bupivacaine, ropivacaine); when combined with local anesthetic, analgesic effect is increased due to synergy (Ref).

Intrathecal:

Note: Intrathecal dose is usually 1/10 (one-tenth) that of epidural dosage (Ref).

Single dose: Intrathecal: Dosage range: 50 to 200 mcg (Ref). Note: Doses vary depending on the clinical scenario and other medications administered as part of multimodal analgesia.

Chronic pain, noncancer and cancer pain

Chronic pain, noncancer and cancer pain:

Note: Before starting opioid therapy for chronic pain, establish realistic goals for pain and function, and consider how therapy will be discontinued if benefits do not outweigh risks (Ref). Opioids, including hydromorphone, are not the preferred therapy for chronic noncancer pain due to insufficient evidence of benefit and risk of serious harm; nonpharmacologic treatment and nonopioid analgesics are preferred, with the exception of chronic pain from active cancer, sickle cell disease, and end-of-life care. Consider opioids, including hydromorphone, only in patients who experience clinically meaningful improvement in pain and function that outweighs patient safety risks (Ref).

Opioid-naive patients: Noncancer or cancer pain:

Note: In general, for noncancer pain, establish hydromorphone requirement using IR formulations (Ref). In patients with cancer pain, may switch to a long-acting formulation earlier in the course of therapy (Ref).

Immediate release: Oral: Initial: 1 to 2 mg every 3 to 4 hours as needed or scheduled around the clock (eg, cancer pain); adjust dose according to patient response (see "Titration" below). Usual dosage range: 1 to 4 mg every 3 to 4 hours as needed or scheduled around the clock. If usual dose and frequency is insufficient, reassess patient and reconsider pain management strategies (Ref).

Titration:

Noncancer pain: Adjust dose according to patient response. If needed, increase the dose slowly in increments of no more than 25% to 50% of the total daily dose (Ref). Note: To reduce risk of overdose in noncancer pain (excluding patients with sickle cell disease and palliative care), use caution when increasing opioid dosage to ≥50 MME/day orally (equivalent to ≥12.5 mg oral hydromorphone/day) and avoid increasing dosage to ≥90 MME/day orally (equivalent to ≥22.5 mg oral hydromorphone/day) (Ref).

Cancer pain: Adjust dose according to patient response. If needed, increase the fixed scheduled dose by 30% to 100% of the total dose taken in the prior 24-hour period, while taking into consideration the total amount of rescue medication used (Ref).

Extended release: Oral:

Note: Do not use in opioid-naive, noncancer patients with chronic pain until treated for at least 1 week with IR form. Unless pain is associated with cancer, palliative care, or sickle cell disease, the CDC recommends that ER opioids be reserved for patients who have received IR opioids daily for ≥1 week yet continue to experience severe, continuous pain (Ref).

Capsules, controlled release, 12 hour (Hydromorph Contin [Canadian product]): Oral: Initial: 3 mg every 12 hours; increase dose every 48 hours as needed; maximum total daily dose: 18 mg/day for noncancer, nonpalliative pain.

IV, SUBQ:

Note: Typically reserved for acute exacerbations or for patients who cannot tolerate oral administration. For progressive illnesses (eg, cancer), a continuous IV or SUBQ infusion, with or without a patient-controlled analgesia option, can also be used as pain requirements increase. In general, SUBQ dose is equivalent to IV dose (Ref). Individualize dose based on patient's previous opioid intake and appropriate opioid analgesic equivalents; titrate further, if needed, based on level of pain.

IV, SUBQ: Initial: 0.2 to 0.4 mg every 2 to 4 hours as needed; adjust dose according to patient response. Usual maintenance dosage range: 0.2 to 1 mg every 2 to 4 hours as needed (Ref). If usual dose and frequency is insufficient, reassess patient and reconsider pain management strategies. Refer to institutional protocols; reported dosing varies widely based on practice and patient needs (Ref).

Opioid-tolerant patients: Noncancer or cancer pain (also refer to the section "Dose Conversions for Pain Management" ):

Oral: Extended release:

Note: Do not use in opioid-naive, noncancer patients with chronic pain until treated for at least 1 week with IR form. Unless pain is associated with cancer, palliative care, or sickle cell disease, the CDC recommends that ER opioids be reserved for patients who have received IR opioids daily for ≥1 week yet continue to experience severe, continuous pain (Ref).

Capsules, controlled release, 12 hour (Hydromorph Contin [Canadian product]):

Note: Capsule strengths ≥18 mg or a single dose >12 mg should be reserved for use only in patients who are opioid tolerant requiring oral hydromorphone dosages ≥36 mg daily (or equivalent).

Individualization of dose: Oral: Administer total daily oral hydromorphone dose in 2 divided doses (every 12 hours).

Tablets, extended release, 24 hour (Exalgo): Oral:

Individualization of dose: See "Dose Conversions for Pain Management." Discontinue or taper all other ER and around-the-clock opioids when starting therapy. Refer to published equianalgesic opioid conversion data for guidance (or refer to institutional protocols), then administer estimated total daily oral hydromorphone dose once daily. Note: When selecting the initial dose, other characteristics (eg, patient condition; degree of opioid tolerance; concurrent medications; type of pain; risk factors for addiction, abuse, and misuse) should also be considered. Pain relief and adverse events should be assessed frequently.

Initial sample dose: Estimated total daily oral hydromorphone dose once daily (eg, 8 mg once daily).

Titration and maintenance: Dose adjustments in 4 to 8 mg increments may occur every 3 to 4 days. In patients experiencing breakthrough pain, consider increasing the dose of ER hydromorphone or providing rescue medication of an IR analgesic at an appropriate dose. Do not administer ER hydromorphone more frequently than once every 24 hours. To reduce risk of overdose in noncancer and nonpalliative pain, use caution when increasing opioid dosage ≥50 MME/day orally (equivalent to ≥12.5 mg oral hydromorphone/day) and avoid increasing dosage to ≥90 MME/day (equivalent to ≥22.5 mg of oral hydromorphone/day) (Ref).

Dose conversions to/from IR products for pain management:

Note: Equianalgesic conversions serve only as a general guide to estimate opioid dose equivalents. Multiple factors must be considered for safely individualizing conversion of opioid analgesia. In general, for noncancer pain, the decision to convert from an IR to an ER formulation should be individualized and reserved for those with severe, continuous pain who have been taking opioids for ≥1 week (Ref).

Converting from oral IR hydromorphone to parenteral hydromorphone: Approximate equivalency: 7.5 mg (oral hydromorphone): 1.5 mg (IV/SUBQ hydromorphone) (Ref).

Converting from oral IR hydromorphone to rectal hydromorphone: The bioavailability of rectal hydromorphone is ~33% of oral hydromorphone; however, absorption is variable and may be higher or lower than expected. Therefore, when switching from oral to rectal dosing, an increase in rectal dose and decrease in frequency (eg, every 6 to 8 hours) may be necessary (Ref).

Converting to/from hydromorphone (parenteral or oral) to/from a different opioid (parenteral or oral): It is safer to underestimate a patient's daily oral requirement and provide breakthrough pain relief with IR formulations rather than risk overestimating daily requirements. When switching to a new opioid (except to/from methadone), reduce initial daily calculated equianalgesic dose of the new opioid by 25% to 50% to adjust for lack of complete mu receptor cross-tolerance (conversions to/from methadone are highly variable and require extreme caution) (Ref).

Dose conversions to ER products for pain management:

Individualization of dose: Refer to published equianalgesic opioid conversion data for guidance (or refer to institutional protocols). When selecting the initial dose, other characteristics (eg, patient condition; degree of opioid tolerance; concurrent medications; type of pain; risk factors for addiction, abuse, and misuse) should also be considered. Pain relief and adverse events should be assessed frequently.

Converting from oral IR hydromorphone to oral ER hydromorphone preparations:

Hydromorph Contin: Total daily oral hydromorphone dose may be administered in 2 divided doses (every 12 hours).

Exalgo: Total daily oral hydromorphone dose administered once daily.

Converting from transdermal fentanyl to hydromorphone ER 24 hour (Exalgo): Treatment with hydromorphone ER 24 hour can be started 18 hours after the removal of the transdermal fentanyl patch. For every fentanyl 25 mcg/hour transdermal dose, the estimated equianalgesic dose of hydromorphone ER is 12 mg every 24 hours. Due to incomplete cross-tolerance, an appropriate starting dose is 50% of the calculated total daily dose given every 24 hours (Example: fentanyl 50 mcg/hour transdermal dose = hydromorphone ER 24 mg/day, then divide in half the calculated hydromorphone ER dose: patient hydromorphone ER dose is 12 mg/day). If necessary, round down to the appropriate hydromorphone ER tablet strength available.

Converting from other opioids to hydromorphone ER (Exalgo): Refer to published equianalgesic opioid conversion data for guidance (or refer to institutional protocols). Conversion ratios are only approximations and substantial interpatient variability exists; therefore, it is safer to underestimate a patient's daily oral requirement and provide breakthrough pain relief with IR formulations rather than risk overestimating daily requirements. When switching to a new opioid (except to/from methadone), reduce initial daily calculated equianalgesic dose of the new opioid by 25% to 50% to adjust for lack of complete mu receptor cross-tolerance (conversions to/from methadone are highly variable and require extreme caution) (Ref).

Discontinuation or tapering of therapy:

When reducing the dose, discontinuing, or tapering long-term opioid therapy, the dose should be gradually tapered. An optimal tapering schedule has not been established (Ref). Proposed schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of long-term therapy) to rapid (eg, 25% to 50% reduction every few days) (Ref). Individualize dosing based on discussions with patient to minimize withdrawal while considering patient-specific goals and concerns, as well as the opioid's pharmacokinetics. Slower tapers may be appropriate after long-term use (eg, years), particularly in the final stage of tapering, whereas more rapid tapers may be appropriate in patients experiencing severe adverse effects (Ref). During tapering, patients may be at an increased risk of overdose if they return to their original (or higher) opioid dose or use illicit opioids, due to rapid loss of tolerance; consider prescribing naloxone (Ref). Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt withdrawal symptoms (Ref). Continue to offer nonopioid analgesics as needed for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI symptoms, muscle spasm) as needed (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: Approximately 37% of hydromorphone is metabolized to hydromorphone-3-glucuronide, a potentially neuroexcitatory metabolite, which can accumulate with kidney impairment (Ref). Careful titration of dosing with close monitoring of response and adverse reactions (eg, CNS depression, respiratory depression, neuroexcitation) due to drug and metabolite accumulation is important with all degrees of kidney impairment.

Injection, oral, rectal:

Altered kidney function (expert opinion derived from manufacturer’s labeling) (Ref):

CrCl ≥60 mL/minute: No dosage adjustment necessary.

CrCl 30 to <60 mL/minute: Administer 50% of usual initial dose.

CrCl <30 mL/minute:

Immediate release: Administer 25% of usual initial dose and extend dosing interval by 25% to 50%.

Extended release: ER opioids are preferably avoided due to increased risk of adverse effects and toxicity (Ref). If necessary, administer 25% of usual initial dose. Alternatively, as hydromorphone ER tablets are only intended for once daily administration, consider switching to IR tablets or another analgesic that will permit more flexibility with the dosing interval (Ref).

Hemodialysis, intermittent (thrice weekly): Dialyzable (both hydromorphone [~55%] (Ref) and its hydromorphone-3-glucuronide metabolite [exact % removed unknown] (Ref)):

Immediate release: Administer 25% of usual initial dose and extend dosing interval by 25% to 50% (Ref).

Extended release: Avoid use (Ref).

Peritoneal dialysis:

Immediate release: Administer 25% of usual initial dose and extend dosing interval by 25% to 50% (Ref).

Extended release: Avoid use (Ref).

CRRT: Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted.

Immediate release: Administer 25% to 50% of usual initial dose and extend the dosing interval by 25% to 50% (Ref).

Extended release: Avoid use (Ref).

PIRRT (eg, sustained, low-efficiency diafiltration): Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement.

Immediate release: Administer 25% to 50% of the usual initial dose and extend the dosing interval by 25% to 50% (Ref).

Extended release: Avoid use (Ref).

Dosing: Hepatic Impairment: Adult

Injectable, oral (immediate release), rectal: Mild to severe impairment: Initiate with 25% to 50% of the usual starting dose depending on the degree of impairment. Use with caution and monitor closely for respiratory and CNS depression.

Oral (extended-release tablet): Hydromorphone ER:

Mild impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Moderate impairment: Initiate with 25% of the usual starting dose for patients with normal hepatic function. Use with caution and monitor closely for respiratory and CNS depression.

Severe impairment: Use alternate analgesic.

Oral (extended-release capsule): Hydromorph Contin [Canadian product]:

Mild impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution and monitor for respiratory and CNS depression.

Moderate impairment: Initiate at 25% of initial dose for normal hepatic function; titrate cautiously. Monitor closely for respiratory and CNS depression following initiation of therapy and during titration.

Severe impairment: Use is not recommended (has not been studied); consider alternative analgesics. If therapy with hydromorphone is initiated, the manufacturer recommends a more conservative dose than that recommended for moderate impairment but does not provide specific dosing recommendations. Monitor closely for respiratory and CNS depression.

Dosing: Pediatric

(For additional information see "Hydromorphone: Pediatric drug information")

Acute pain, moderate to severe

Acute pain, moderate to severe: Limited data available (Ref): Note: Doses should be titrated to appropriate analgesic effects, while minimizing adverse effects; when changing routes of administration, note that oral doses are less than one-half as effective as parenteral doses (may be only 1/5 as effective):

Infants >6 months weighing >10 kg (Ref):

Oral: Immediate release: Usual initial: 0.03 mg/kg/dose every 4 hours as needed; usual range: 0.03 to 0.06 mg/kg/dose.

IV: Usual initial: 0.01 to 0.015 mg/kg/dose every 3 to 6 hours as needed.

Continuous IV infusion: Usual initial: 0.003 to 0.005 mg/kg/hour.

Children weighing <50 kg and Adolescents weighing <50 kg:

Oral: Immediate release: 0.03 to 0.08 mg/kg/dose every 3 to 4 hours as needed; Note: The American Pain Society (2016) recommends an initial oral dose of 0.06 mg/kg for severe pain in children.

IV: 0.015 mg/kg/dose every 3 to 6 hours as needed.

Continuous IV infusion: Usual initial: 0.003 to 0.005 mg/kg/hour (maximum initial rate: 0.2 mg/hour) (Ref).

Children weighing ≥50 kg and Adolescents weighing ≥50 kg:

Oral: Immediate release: Initial: Opioid-naive: 1 to 2 mg every 3 to 4 hours as needed; patients with prior opioid exposure may tolerate higher initial doses; usual adult dose: 2 to 4 mg; doses up to 8 mg have been used in adults.

IV: Initial: Opioid-naive: 0.2 to 0.6 mg every 2 to 4 hours as needed; patients with prior opioid exposure may tolerate higher initial doses.

Continuous IV infusion: Usual infusion: 0.3 mg/hour (Ref).

IM, SubQ: Note: IM use may result in variable absorption and a lag time to peak effect. Initial: Opioid-naive: 0.8 to 1 mg every 4 to 6 hours as needed; patients with prior opioid exposure may require higher initial doses; usual dosage range: 1 to 2 mg every 3 to 6 hours as needed.

Rectal: 3 mg (1 suppository) every 6 to 8 hours as needed (Ref).

Continuous analgesia/sedation; mechanically ventilated

Continuous analgesia/sedation; mechanically ventilated: Limited data available: Not routinely used first-line: Infants, Children, and Adolescents: Continuous IV infusion: Initial rate: 0.018 mg/kg/hour; titrate carefully to effect; maximum reported rate: 0.043 mg/kg/hour (Ref).

Continuous analgesia/sedation; mechanically ventilated and during ECMO

Continuous analgesia/sedation; mechanically ventilated and during ECMO: Very limited data available: Not routinely used first-line: Infants and Children: Continuous IV infusion: Reported initial rate: 0.064 mg/kg/hour; titrate carefully to effect; maximum reported rate: 0.14 mg/kg/hour; dosing based on retrospective data from experience in 12 patients reported significantly higher requirements in those receiving ECMO than non-ECMO patients (Ref).

Patient-controlled analgesia

Patient-controlled analgesia (PCA): Limited data available (Ref): Opioid-naive: Note: PCA has been used in children as young as 4 years of age; however, clinicians need to assess children 4 to 8 years of age to determine if they are able to use the PCA device correctly (Ref). All patients should receive an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Use lower end of dosing range for opioid-naive; a continuous (basal) infusion is not recommended in opioid-naive patients (Ref). Assess patient and pain control at regular intervals and adjust settings if needed:

Children ≥5 years weighing <50 kg and Adolescents weighing <50 kg:

Usual concentration: 0.2 mg/mL.

Demand dose: Usual initial: 0.003 to 0.004 mg/kg/dose; usual range: 0.003 to 0.005 mg/kg/dose.

Lockout: Usual initial: 5 doses/hour.

Lockout interval: Range: 6 to 10 minutes.

Usual basal rate: 0 to 0.004 mg/kg/hour.

Children weighing ≥50 kg and Adolescents weighing ≥50 kg:

Usual concentration: 0.2 mg/mL.

Demand dose: Usual initial: 0.1 to 0.2 mg; usual range: 0.05 to 0.4 mg.

Lockout interval: Usual initial: 6 minutes; usual range: 5 to 10 minutes.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

There are no pediatric-specific recommendations; based on experience in adult patients, dosage adjustment is suggested.

Dosing: Hepatic Impairment: Pediatric

There are no pediatric-specific recommendations; based on experience in adult patients, dosage adjustment is suggested.

Dosing: Older Adult

Pain management: Note: Opioids should always be used with caution in older adults due to the potential for drug accumulation and increased sensitivity to CNS active medications; monitor closely for opioid-induced adverse effects (eg, respiratory depression, hypotension, sedation) during use, particularly during treatment initiation and dose titration (Ref). Initiate doses at a low dose and titrate slowly to appropriate analgesic effects. When changing routes of administration, oral doses and parenteral doses are NOT equivalent; parenteral doses are up to 5 times more potent. Therefore, when administered parenterally, one-fifth of the oral dose will provide similar analgesia.

Oral:

IR tablets: Opioid-naive patients with persistent pain: Initial: 1 to 2 mg every 3 to 4 hours as needed (Ref). In patients >70 years of age, the American Pain Society suggests lowering initial doses by 25% to 50%, followed by upward or downward titration (Ref).

ER products: Opioid-tolerant patients only: Limited data available; based on expert opinion: After 3 to 7 days, divide the 24-hour dose requirement for IR hydromorphone into 1 or 2 doses (depending on ER product selected) (Ref).

IV:

Opioid-naive patients with persistent pain: Initial: IV: 0.2 mg every 2 to 3 hours as needed (manufacturer's labeling) or 0.25 to 0.5 mg every 3 to 4 hours as needed (limited data available; based on expert opinion). In patients >70 years of age, the American Pain Society recommends giving consideration to lowering initial doses by 25% to 50%, followed by upward or downward titration (Ref).

Opioid-naive patients in acute, severe pain: Emergency Department (ED) setting: Limited data available; one trial used the following study protocol: 0.5 mg IV given as a single dose, followed by an optional repeat dose of 0.5 mg IV 15 minutes later if patient still in pain (Ref).

IM: IM administration is not recommended and should be avoided (Ref).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Liquid, Oral, as hydrochloride:

Dilaudid: 1 mg/mL (473 mL) [contains methylparaben, propylparaben, sodium metabisulfite]

Generic: 1 mg/mL (473 mL)

Solution, Injection, as hydrochloride:

Generic: 1 mg/mL (0.5 mL); 2 mg/mL (1 mL [DSC], 20 mL)

Solution, Injection, as hydrochloride [preservative free]:

Dilaudid: 0.2 mg/mL (1 mL); 1 mg/mL (0.5 mL, 1 mL); 2 mg/mL (1 mL)

Generic: 1 mg/mL (0.5 mL, 1 mL); 2 mg/mL (1 mL); 4 mg/mL (1 mL); 10 mg/mL (1 mL, 5 mL, 50 mL); 50 mg/5 mL (5 mL); 500 mg/50 mL (50 mL)

Solution, Intravenous, as hydrochloride:

Generic: 0.2 mg/mL (2 mL, 10 mL, 25 mL, 50 mL)

Suppository, Rectal, as hydrochloride:

Generic: 3 mg (6 ea)

Tablet, Oral, as hydrochloride:

Dilaudid: 2 mg, 4 mg [contains quinoline (d&c yellow #10) aluminum lake, sodium metabisulfite]

Dilaudid: 8 mg [contains sodium metabisulfite]

Generic: 2 mg, 4 mg, 8 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Exalgo: 8 mg [DSC], 12 mg [DSC], 16 mg [DSC], 32 mg [DSC] [contains sodium metabisulfite]

Generic: 8 mg, 12 mg, 16 mg, 32 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Extended Release 12 Hour, Oral:

Hydromorph Contin: 3 mg [contains quinoline yellow (d&c yellow #10)]

Hydromorph Contin: 4.5 mg [contains fd&c blue #1 (brilliant blue)]

Hydromorph Contin: 6 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10)]

Hydromorph Contin: 9 mg [contains fd&c blue #1 (brilliant blue)]

Hydromorph Contin: 12 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10)]

Hydromorph Contin: 18 mg, 24 mg

Hydromorph Contin: 30 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]

Generic: 3 mg, 4.5 mg, 6 mg, 9 mg, 12 mg, 18 mg, 24 mg, 30 mg

Solution, Injection:

Generic: 20 mg/mL (50 mL); 50 mg/mL (1 mL, 50 mL); 100 mg/mL (10 mL)

Solution, Injection, as hydrochloride:

Generic: 1 mg/mL (1 mL); 2 mg/mL (1 mL, 2 mL); 10 mg/mL (1 mL, 5 mL, 10 mL, 50 mL)

Solution, Intravenous, as hydrochloride:

Generic: 20 mg/50 mL in NaCl 0.9% (50 mL); 40 mg/100 mL (100 mL)

Syrup, Oral:

Generic: 1 mg/mL (500 mL)

Tablet, Oral:

Dilaudid: 1 mg [contains fd&c blue #1 (brill blue) aluminum lake, quinoline yellow (d&c yellow #10)]

Generic: 1 mg

Tablet, Oral, as hydrochloride:

Dilaudid: 2 mg, 4 mg [contains quinoline yellow (d&c yellow #10)]

Dilaudid: 8 mg

Generic: 2 mg, 4 mg, 8 mg

Controlled Substance

C-II

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Dilaudid: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/019891s029,019892s037lbl.pdf#page=30.

Exalgo: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021217s025lbl.pdf#page=31. Medication guides are also available at http://www.exalgorems.com.

Hydromorphone hydrochloride extended-release tablets:https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204278Orig1s000MG.pdf.

Administration: Adult

Parenteral: Note: Vial stopper may contain latex.

Extreme caution should be taken to avoid confusing the highly concentrated injectable product (hydromorphone HP) containing 10 mg/mL with the standard parenteral formulations containing hydromorphone 1, 2, or 4 mg/mL. Hydromorphone HP is for use in opioid-tolerant patients only; confusion could result in overdose and death.

IM, SubQ: May be given SubQ or IM; however, IM administration is not recommended and should be avoided (Ref). IM administration is painful and may result in variable absorption, a lag time to peak effect, a rapid fall of action compared to oral administration, and may lead to nerve injury. SubQ administration is a more reliable and less painful alternative route of administration compared to IM (Ref).

IV: For IVP, must be given slowly over at least 2 to 3 minutes (rapid IVP has been associated with an increase in side effects, especially respiratory depression and hypotension)

Oral: Hydromorphone is available in an 8 mg immediate-release tablet and an 8 mg extended-release tablet. Extreme caution should be taken to avoid confusing dosage forms.

Hydromorphone ER: Tablets should be swallowed whole; do not crush, break, chew, dissolve, snort, or inject. Administer with or without food.

Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Switch to IR tablet or oral solution.

Hydromorph Contin [Canadian product]: For oral use only. Capsule should be swallowed whole; do not crush or chew. Contents may be sprinkled on a tablespoon of applesauce (stored at room temperature or under refrigeration) or custard (stored at room temperature) and swallowed without chewing as soon as possible (discard if not consumed within 30 minutes); patient should then rinse mouth with water to ensure entire contents are swallowed.

Oral solution: Ensure accuracy when prescribing, dispensing, and administering. Dosing errors due to confusion between mg and mL can result in accidental overdose and death. A calibrated oral syringe/dosing cup that can measure and deliver the prescribed dose accurately should be used; do not use a household teaspoon or tablespoon to measure dose.

Administration: Pediatric

Oral: Note: Hydromorphone is available in an 8 mg immediate-release tablet and an 8 mg extended-release tablet. Extreme caution should be taken to avoid confusing dosage forms.

Immediate release: Administer with food or milk to decrease GI upset.

Parenteral: Note: Vial stopper may contain latex.

Injectable formulation is available in multiple strengths. Extreme caution should be taken to avoid confusing the highly concentrated injectable product (hydromorphone HP) containing 10 mg/mL with the standard parenteral formulations containing hydromorphone ≤4 mg/mL. Hydromorphone HP is for use in opioid-tolerant patients only; confusion could result in overdose and death.

IV: Administer via slow IV injection over at least 2 to 3 minutes; rapid IV administration has been associated with an increase in side effects, especially respiratory depression and hypotension.

IM: May be administered IM, but not recommended due to variable absorption and a lag time to peak effect (Ref).

Rectal: Insert suppository rectally and retain

Use: Labeled Indications

Pain management:

Immediate release:

Tablet, oral solution, injection, suppository: Management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

HP injection: Management of pain severe enough to require an opioid analgesic in opioid-tolerant patients who require higher doses of opioids and for which alternative treatments are inadequate.

Extended release: Management of pain in opioid-tolerant patients that is severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Use: Off-Label: Adult

Critically ill patients in the ICU, analgesia and sedation

Medication Safety Issues
Sound-alike/look-alike issues:

Dilaudid may be confused with Demerol, Dilantin

HYDROmorphone may be confused with buprenorphine, diamorphine, oxyMORphone

HYDROmorphone may be confused with morphine; significant overdoses have occurred when hydromorphone products have been inadvertently administered instead of morphine sulfate. Commercially available prefilled syringes of both products looks similar and are often stored in close proximity to each other. Note: Hydromorphone 1 mg oral is approximately equal to morphine 4 mg oral; hydromorphone 1 mg IV is approximately equal to morphine 5 mg IV

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Administration issues:

Dilaudid, Dilaudid-HP: Extreme caution should be taken to avoid confusing the highly-concentrated (Dilaudid-HP) injection with the less-concentrated (Dilaudid) injectable product.

Exalgo: Extreme caution should be taken to avoid confusing the extended release Exalgo 8 mg tablets with immediate release hydromorphone 8 mg tablets.

Significant differences exist between oral and IV dosing. Use caution when converting from one route of administration to another.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not defined.

Cardiovascular: Bradycardia, extrasystoles, flushing (facial), hypertension, hypotension, palpitations, peripheral edema, peripheral vasodilation, syncope, tachycardia

Central nervous system: Abnormal dreams, abnormal gait, abnormality in thinking, aggressive behavior, agitation, apprehension, ataxia, brain disease, burning sensation of skin (Exalgo), central nervous system depression, chills, cognitive dysfunction, confusion, decreased body temperature (Exalgo), depression, disruption of body temperature regulation (Exalgo), dizziness, drowsiness, drug dependence, dysarthria, dysphoria, equilibrium disturbance, euphoria, fatigue, hallucination, headache, hyperesthesia, hyperreflexia, hypoesthesia, hypothermia, increased intracranial pressure, insomnia, lack of concentration, lethargy, malaise, memory impairment, mood changes, myoclonus, nervousness, painful defecation, panic attack, paranoia, paresthesia, psychomotor agitation, restlessness, sedation, sleep disorder (Exalgo), suicidal ideation, uncontrolled crying, vertigo

Dermatologic: Diaphoresis, erythema (Exalgo), hyperhidrosis, pruritus, skin rash, urticaria

Endocrine & metabolic: Antidiuretic effect, decreased amylase, decreased libido, decreased plasma testosterone, dehydration, fluid retention, hyperuricemia, hypokalemia, weight loss

Gastrointestinal: Abdominal distention, anal fissure, anorexia, bezoar formation (Exalgo), biliary tract spasm, constipation, decreased appetite, decreased gastrointestinal motility (Exalgo), delayed gastric emptying, diarrhea, diverticulitis, diverticulosis, duodenitis, dysgeusia, dysphagia, eructation, flatulence, gastroenteritis, gastroesophageal reflux disease (aggravated; Exalgo), hematochezia, increased appetite, intestinal obstruction, intestinal perforation (large intestine; Exalgo), nausea, stomach cramps, vomiting, xerostomia

Genitourinary: Bladder spasm, decreased urine output, difficulty in micturition, dysuria, erectile dysfunction, hypogonadism, sexual disorder, ureteral spasm, urinary frequency, urinary hesitancy, urinary retention

Hematologic & oncologic: Oxygen desaturation

Hepatic: Increased liver enzymes

Hypersensitivity: Histamine release

Local: Pain at injection site, post-injection flare

Neuromuscular & skeletal: Arthralgia, dyskinesia, laryngospasm, muscle rigidity, muscle spasm, myalgia, tremor, weakness

Ophthalmic: Blurred vision, diplopia, dry eye syndrome, miosis, nystagmus

Otic: Tinnitus

Respiratory: Apnea, bronchospasm, dyspnea, flu-like symptoms (Exalgo), hyperventilation, hypoxia, respiratory depression, respiratory distress, rhinorrhea

Postmarketing and/or case reports: Angioedema, hypersensitivity, increased serum prolactin (Molitch 2008; Vuong 2010)

Contraindications

US labeling: Hypersensitivity (eg, anaphylaxis) to hydromorphone, hydromorphone salts, or any component of the formulation; significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment or ventilatory support; gastrointestinal obstruction, including paralytic ileus (known or suspected).

Additional product-specific contraindications:

Dilaudid-HP injection: Opioid-nontolerant patients.

Hydromorphone ER tablets: Opioid-nontolerant patients; preexisting GI surgery and/or diseases resulting in narrowing of GI tract or blind loops in the GI tract.

Suppository: Hypersensitivity (eg, anaphylaxis) to sulfite-containing medications.

Documentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Hypersensitivity to hydromorphone or any component of the formulation.

Dilaudid, Hydromorph Contin: Known or suspected mechanical GI obstruction (eg, bowel obstruction or strictures) or any disease that affects bowel transit (eg, ileus of any type); suspected surgical abdomen (eg, acute appendicitis or pancreatitis); mild, intermittent, or short-duration pain that can be managed with other pain medications; acute respiratory depression, hypercarbia and cor pulmonale; acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure, and head injury; coadministration with monoamine oxidase inhibitors (concomitant use or within 14 days); women during pregnancy, labor and delivery, or breastfeeding.

Dilaudid HP: Patients not already receiving high doses or high concentrations of opioids.

Hydromorphone HP, Hydromorphone HP Forte, Hydromorphone 0.4 mg/mL injection: Patients not already receiving high doses or high concentrations of opioids; known or suspected mechanical gastrointestinal obstruction (eg, bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (eg, ileus of any type); suspected surgical abdomen (eg, acute appendicitis or pancreatitis); mild pain that can be managed with other pain medications; acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus; acute respiratory depression, elevated carbon dioxide levels in the blood and cor pulmonale; acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure, and head injury; coadministration with monoamine oxidase inhibitors (concomitant use or within 14 days); women during pregnancy, labor and delivery, or breastfeeding.

Syrup: Respiratory depression in the absence of resuscitative equipment; status asthmaticus.

Additional product-specific contraindications:

Dilaudid: Hypersensitivity to other opioid analgesics; acute asthma or other obstructive airway and status asthmaticus.

Hydromorph Contin: Hypersensitivity to other opioid analgesics; acute asthma or severe bronchial asthma or status asthmaticus; management of acute pain, including use in outpatient or day surgeries; management of perioperative pain.

Hydromorphone HP, Hydromorphone HP Forte: Signs of intoxication, including due to centrally acting sedatives and/or stimulants, or in any other acute clinical condition that would increase risk of an adverse event when used for supervised injectable opioid agonist therapy.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Constipation: May cause constipation which may be problematic in patients with unstable angina and patients post-myocardial infarction. Consider preventive measures to reduce the potential for constipation. Use with extreme caution in patients with chronic constipation.

• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute myocardial infarction), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.

• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists (codeine, hydrocodone, levorphanol, oxycodone, oxymorphone).

• Respiratory depression: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely for respiratory depression, especially during initiation or dose escalation. Swallow ER tablets whole; crushing, chewing, or dissolving can cause rapid release and a potentially fatal dose. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Patients and caregivers should be educated on how to recognize respiratory depression and the importance of getting emergency assistance immediately (eg, calling 911) in the event of known or suspected overdose.

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.

• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).

• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; opioids may cause constriction of sphincter of Oddi.

• CNS depression/coma: Avoid use in patients with impaired consciousness or coma, as these patients are susceptible to intracranial effects of CO2 retention.

• Delirium tremens: Use with caution in patients with delirium tremens.

• GI narrowing: Hydromorphone ER tablets are nondeformable; do not administer to patients with preexisting severe GI narrowing (eg, esophageal motility, small bowel inflammatory disease, short gut syndrome, history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, Meckel's diverticulum); obstruction may occur.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage reduction recommended in moderate to severe impairment. ER tablets are not recommended in severe impairment.

• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2016]).

• Obesity: Use with caution in patients who are morbidly obese.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis: Use with caution in patients with toxic psychosis.

• Renal impairment: Use with caution in patients with renal impairment; dosage reduction recommended. ER tablets are not recommended in severe impairment.

• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Seizures: Use with caution in patients with a history of seizure disorders; may cause or exacerbate preexisting seizures.

• Sleep-related disorders: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell2016]).

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Benzodiazepines or other CNS depressants: [US Boxed Warning]: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of hydromorphone and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosage and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation. Consider prescribing naloxone for emergency treatment of opioid overdose in patients taking benzodiazepines or other CNS depressants concomitantly with opioids.

Special populations:

• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Older adult: Use with caution in the elderly; may be more sensitive to adverse effects. Decrease initial dose. Use opioids for chronic pain with caution in this age group; monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (CDC [Dowell 2016]). Consider the use of alternative nonopioid analgesics in these patients.

• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

Dosage form specific issues:

• Extended-release tablets: Therapy should only be prescribed by health care professionals familiar with the use of potent opioids for chronic pain. Tablets may be visible on abdominal x-rays, especially when digital enhancing techniques are used. The tablet shell may appear in the excreted stool.

• Oral solution: [US Boxed Warning]: Ensure accuracy when prescribing, dispensing, and administering hydromorphone oral solution. Dosing errors due to confusion between mg and mL can result in accidental overdose and death.

• Injection: [US Boxed Warning]: High-potency hydromorphone (10 mg/mL) is a more concentrated solution of hydromorphone than hydromorphone 1, 2, or 4 mg/mL, and is for use in opioid-tolerant patients only. Do not confuse high-potency hydromorphone with standard parenteral formulations of hydromorphone or other opioids, as overdose and death could result.

• Lactose: Some formulations may contain lactose.

• Latex: Vial stoppers of single-dose injectable vials may contain latex.

• Sodium metabisulfite: Some dosage forms may contain trace amounts of sodium metabisulfite, which may cause allergic reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible individuals.

Other warnings/precautions:

• Abrupt discontinuation/withdrawal: Abrupt discontinuation in patients who are physically dependent on opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances and provide care as needed. Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists.

• Abuse/misuse/diversion: [US Boxed Warning]: Hydromorphone exposes patients and other users to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors or conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk for misuse include younger age, concomitant depression (major), and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (CDC [Dowell 2016]).

• Accidental exposure: [US Boxed Warning]: Accidental ingestion of even one dose, especially in children, can result in a fatal overdose of hydromorphone.

• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, myocardial infarction, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, nonsteroidal anti-inflammatory drugs, acetaminophen, certain antiseizure medications and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (CDC [Dowell 2016]).

• IM administration: Variable absorption and a lag time to peak effect may result from IM use.

• IV administration: Administer IV very slowly; rapid IV injection of opioid analgesics increases the possibility of side effects such as hypotension and respiratory depression.

• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of), or have experienced a previous opioid overdose. Additionally, health care providers should consider prescribing naloxone to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help.

• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

• REMS program: [US Boxed Warning]: To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, a REMS is required. Drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are encouraged to complete a REMS-compliant education program; counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist; and consider other tools to improve patient, household, and community safety.

• Surgery: Use immediate-release formulations with caution in the perioperative setting; severe pain may antagonize the respiratory depressant effects of hydromorphone. Opioids decrease bowel motility; monitor for decreased bowel motility in postop patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

Warnings: Additional Pediatric Considerations

Prolonged use of any hydromorphone product during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification

Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Desmopressin: Opioid Agonists may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of HYDROmorphone. Risk X: Avoid combination

Nalfurafine: Opioid Agonists may enhance the adverse/toxic effect of Nalfurafine. Opioid Agonists may diminish the therapeutic effect of Nalfurafine. Risk C: Monitor therapy

Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Samidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combination

Serotonergic Agents (High Risk): Opioid Agonists may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification

Somatostatin Analogs: Opioid Agonists may diminish the analgesic effect of Somatostatin Analogs. Opioid Agonists may enhance the analgesic effect of Somatostatin Analogs. Risk C: Monitor therapy

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Reproductive Considerations

Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility in men and women (Brennan 2013).

Pregnancy Considerations

Hydromorphone crosses the placenta (Alexander 2018).

According to some studies, maternal use of opioids may be associated with birth defects (including neural tube defects, congenital heart defects, and gastroschisis), poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2016]).

[US Boxed Warning]: Prolonged use of hydromorphone during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. If chronic opioid exposure occurs in pregnancy, adverse events in the newborn (including withdrawal) may occur (Chou 2009). Symptoms of neonatal abstinence syndrome (NAS) following opioid exposure may be autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, hyperactivity, increased muscle tone, increased wakefulness/abnormal sleep pattern, irritability, sneezing, seizure, tremor, yawning) (Dow 2012; Hudak 2012). Mothers who are physically dependent on opioids may give birth to Infants who are also physically dependent. Opioids may cause respiratory depression and psycho-physiologic effects in the neonate; newborns of mothers receiving opioids during labor should be monitored.

Hydromorphone is not commonly used to treat pain during labor and immediately postpartum (ACOG 209 2019) or chronic noncancer pain in pregnant women or those who may become pregnant (CDC [Dowell 2016]; Chou 2009).

Breastfeeding Considerations

Hydromorphone is present in breast milk (Edwards 2003).

The half-life of hydromorphone was 10.5 ± 5.2 hours in breast milk following a single intranasal dose of hydromorphone 2 mg (Edwards 2003).

Progressive lethargy requiring treatment with naloxone was noted in a 6-day old infant exposed to hydromorphone via breast milk (Schultz 2019). Withdrawal symptoms may occur when maternal use is discontinued or breastfeeding is stopped.

Nonopioid analgesics are preferred for breastfeeding females who require pain control peripartum or for surgery outside of the postpartum period (ABM [Martin 2018]; ABM [Reece-Stremtan 2017]). Limited use of hydromorphone may be considered; delivery by PCA or via the epidural route will help limit infant exposure (Sachs 2013).

When opioids are needed in breastfeeding women, the lowest effective dose for the shortest duration of time should be used to limit adverse events in the mother and breastfeeding infant. In general, a single, occasional dose of an opioid analgesic may be generally compatible with breastfeeding (WHO 2002). Note: Extended release formulations are not indicated for intermittent pain control. Breastfeeding women using opioids for postpartum pain or for the treatment of chronic maternal pain should monitor their infants for drowsiness, sedation, feeding difficulties, or limpness (ACOG 209 2019).

Monitoring Parameters

Pain relief, respiratory and mental status, blood pressure; bowel function; signs/symptoms of misuse, abuse, and addiction; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013)

Alternate recommendations: Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (Dowell [CDC 2016]).

Critically ill: The Numeric Rating Scale should be used in patients who are able to self-report pain. In patients who are unable to self-report pain, the Behavioral Pain Scale and the Critical-Care Pain Observational Tool can be used in intubated or nonintubated patients (SCCM [Devlin 2018]).

Mechanism of Action

Binds to opioid receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; causes cough suppression by direct central action in the medulla; produces generalized CNS depression

Pharmacokinetics

Onset of action: Analgesic:

Immediate-release formulations:

Oral: 15 to 30 minutes; Peak effect: 30 to 60 minutes

IV: 5 minutes; Peak effect: 10 to 20 minutes

Extended-release tablet: 6 hours; Peak effect: ~9 hours (Angst 2001)

Duration:

Immediate-release formulations: Oral, IV: 3 to 4 hours; suppository may provide longer duration of effect

Extended-release tablet: ~13 hours (Angst 2001)

Absorption: Oral: Rapidly absorbed; extensive first-pass effect; Extended-release tablet: Delayed; IM: Variable and delayed

Distribution: Vd: 4 L/kg

Protein binding: ~8% to 19%

Metabolism: Hepatic via glucuronidation; to inactive metabolites; >95% is metabolized to hydromorphone-3-glucuronide; minor amounts as 6-hydroxy reduction metabolites

Bioavailability: Oral, immediate release: ~24%

Half-life elimination:

Immediate-release formulations: 2 to 3 hours

Extended-release tablets: Apparent half-life: ~11 hours (range: 8 to 15 hours)

Time to peak, plasma:

Immediate-release tablet: ≤1 hour

Extended-release tablet: 12 to 16 hours

Extended-release capsule [Canadian product]: ~5 hours

Excretion: Urine (primarily as glucuronide conjugates); minimal unchanged drug is excreted in urine (~7%) and feces (1%)

Pharmacokinetics: Additional Considerations

Altered kidney function:

Immediate release: Cmax and AUC0-48 are increased 2-fold in patients with moderate (CrCl 40 to 60 mL/minute) and 3-fold in patients with severe (CrCl <30 mL/minute) renal impairment.

Hepatic function impairment: Cmax and AUC is increased 4-fold in patients with moderate (Child-Pugh class B) hepatic impairment.

Older adult: Extended release: Average 11% AUC increase in the elderly.

Sex:

Extended release: Women appear to have ~10% higher mean systemic exposure.

Immediate release: Women appear to have a 25% higher Cmax than men.

Pricing: US

Liquid (Dilaudid Oral)

1 mg/mL (per mL): $1.21

Liquid (HYDROmorphone HCl Oral)

1 mg/mL (per mL): $0.40 - $0.60

Solution (Dilaudid Injection)

0.2 mg/mL (per mL): $3.60

1 mg/mL (per 0.5 mL): $4.98

2 mg/mL (per mL): $4.98

Solution (HYDROmorphone HCl Injection)

1 mg/mL (per mL): $2.68 - $4.86

2 mg/mL (per mL): $1.90 - $6.52

4 mg/mL (per mL): $3.12

Solution (HYDROmorphone HCl PF Injection)

1 mg/mL (per mL): $4.32

2 mg/mL (per mL): $4.32

4 mg/mL (per mL): $4.48

10 mg/mL (per mL): $3.00 - $5.64

Suppository (HYDROmorphone HCl Rectal)

3 mg (per each): $12.27

Tablet, 24-hour (HYDROmorphone HCl ER Oral)

8 mg (per each): $7.73 - $9.24

12 mg (per each): $11.54 - $13.81

16 mg (per each): $15.41 - $18.41

32 mg (per each): $20.49 - $24.35

Tablets (Dilaudid Oral)

2 mg (per each): $2.79

4 mg (per each): $4.56

8 mg (per each): $8.30

Tablets (HYDROmorphone HCl Oral)

2 mg (per each): $0.11 - $0.48

4 mg (per each): $0.15 - $0.72

8 mg (per each): $0.61 - $1.38

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Dilaudid (AT, AU, BB);
  • Dilid (KR);
  • Dolonovag (AR);
  • Himop (CR, DO, GT, HN, NI, PA, SV);
  • Hydal (AT);
  • Jurnista (AT, AU, CR, DE, DK, DO, EE, EG, ES, GT, HN, HU, ID, IT, NI, PA, PT, SA, SG, SI, SV, TW, ZW);
  • JURNISTA (CH);
  • jURNISTA (ZA);
  • Jurnista IR (KR);
  • Jurnista SR (KR);
  • Liberaxim (CR, DO, GT, HN, MX, NI, PA, SV);
  • Narurapid (JP);
  • Narusus (JP);
  • Paliadon Retardkaps (DE);
  • Palladon (CH, DK, FI, IS, NL, NO, SE, SI);
  • Palladone (BE, CZ, EE, ES, GB, GR, HN, IE, IL, LU);
  • Palladone SR (GB, SK)


For country code abbreviations (show table)
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