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HYDROmorphone

Pronunciation

Pronunciation

(hye droe MOR fone)

Index Terms

  • Dihydromorphinone
  • Hydromorphone HCl
  • Hydromorphone Hydrochloride
  • Palladone

Dosage Forms

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; sweet flavor]

Generic: 1 mg/mL (473 mL)

Solution, Injection, as hydrochloride:

Dilaudid: 1 mg/mL (1 mL [DSC]); 2 mg/mL (1 mL [DSC]); 4 mg/mL (1 mL [DSC])

Dilaudid-HP: 10 mg/mL (1 mL [DSC], 5 mL [DSC], 50 mL [DSC])

Generic: 1 mg/mL (0.5 mL, 0.5 mL, 1 mL); 2 mg/mL (1 mL, 20 mL); 4 mg/mL (1 mL); 10 mg/mL (1 mL); 50 mg/5 mL (5 mL); 500 mg/50 mL (50 mL)

Solution, Injection, as hydrochloride [preservative free]:

Generic: 10 mg/mL (1 mL); 50 mg/5 mL (5 mL); 500 mg/50 mL (50 mL)

Solution, Intravenous, as hydrochloride:

Generic: 6 mg/30 mL (30 mL)

Solution Prefilled Syringe, Intravenous, as hydrochloride:

Generic: 10 mg/50 mL (50 mL); 15 mg/30 mL (30 mL)

Solution Prefilled Syringe, Intravenous, as hydrochloride [preservative free]:

Generic: 12 mg/60 mL (60 mL)

Solution Reconstituted, Injection, as hydrochloride:

Dilaudid-HP: 250 mg (1 ea [DSC])

Suppository, Rectal, as hydrochloride:

Generic: 3 mg (6 ea)

Tablet, Oral, as hydrochloride:

Dilaudid: 2 mg, 4 mg [contains fd&c yellow #10 aluminum lake, sodium metabisulfite]

Dilaudid: 8 mg [scored; contains sodium metabisulfite]

Generic: 2 mg, 4 mg, 8 mg

Tablet ER 24 Hour Abuse-Deterrent, Oral, as hydrochloride:

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

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

Brand Names: U.S.

  • Dilaudid
  • Dilaudid-HP [DSC]
  • Exalgo

Pharmacologic Category

  • Analgesic, Opioid

Pharmacology

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

Absorption

Oral: Rapidly absorbed; extensive first-pass effect

Extended release tablet: Delayed; IM: Variable and delayed

Distribution

Vd: 4 L/kg

Metabolism

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

Excretion

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

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)

Time to Peak

Plasma:

Immediate-release tablet: ≤1 hour

Extended-release tablet: 12 to 16 hours

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

Duration of Action

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

Extended release tablet: ~13 hours (Angst 2001)

Half-Life Elimination

Immediate-release formulations: 2 to 3 hours

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

Protein Binding

~8% to 19%

Special Populations: Renal Function Impairment

Extended release: Cmax and AUC are increased 2-fold in patients with moderate (CrCl 40 to 60 mL/minute) and 4-fold in patients with severe (CrCl <30 mL/minute) renal impairment.

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.

Special Populations: Hepatic Function Impairment

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

Special Populations: Elderly

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

Special Populations: Gender

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

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

Use: Labeled Indications

Pain:

Immediate-release formulations:

Tablet, liquid, injection: Management of pain in patients where an opioid analgesic is appropriate

HP injection: Management of moderate to severe pain in opioid-tolerant patients who require higher doses of opioids

Suppository: Management of moderate to severe pain

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

Limitations of use: Not indicated as an as-needed analgesic. Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve for use in patients for whom alternative treatment options (eg, nonopioid analgesics, immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain

Contraindications

US labeling: Hypersensitivity to hydromorphone, or any component of the formulation; acute or severe asthma, respiratory depression (in absence of resuscitative equipment or ventilatory support)

Additional product-specific contraindications:

Dilaudid liquid and tablets: Obstetrical analgesia

Dilaudid injection, Dilaudid-HP injection: Opioid-nontolerant patients (Dilaudid-HP injection only); patients with risk of developing GI obstruction, especially paralytic ileus

Exalgo: Opioid-nontolerant patients, paralytic ileus (known or suspected), preexisting GI surgery and/or diseases resulting in narrowing of GI tract, blind loops in the GI tract, or GI obstruction

Suppository: Intracranial lesion associated with increased intracranial pressure; whenever ventilatory function is depressed (eg, COPD, cor pulmonale, emphysema, kyphoscoliosis, status asthmaticus)

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

Dilaudid, Hydromorph Contin, Jurnista: 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 breast-feeding

Hydromorphone HP, Hydromorphone HP Forte: Patients not already receiving high doses or high concentrations of opioids; respiratory depression in the absence of resuscitative equipment; severe CNS depression; status asthmaticus; obstetrical analgesia; mild or moderate pain

Suppository, 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 (unless GI function is normal)

Jurnista: Prior surgical procedures and/or underlying disease that may result in narrowing of the GI tract, blind loops of the GI tract, or GI obstruction; acute asthma or other obstructive airway and status asthmaticus; management of acute or perioperative pain

Dosing: Adult

Acute pain (moderate to severe): Note: These are guidelines and do not represent the maximum doses that may be required in all patients. Doses should be titrated to provide adequate pain relief. 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: Immediate release: Initial: Opioid naive: 2 to 4 mg every 4 to 6 hours as needed (tablets) or 2.5 mg to 10 mg every 3 to 6 hours as needed (liquid); elderly/debilitated patients may require lower doses; patients with prior opioid exposure may require higher initial doses. Note: In adults with severe pain, the American Pain Society recommends an initial dose of 4 to 8 mg.

Therapy discontinuation (Canadian labeling): Decrease the previous daily dose by 50% (administered every 6 hours) for 2 days then decrease daily dose by 25% every 2 days.

IV: Initial: Opioid naive: 0.2 to 1 mg every 2 to 3 hours as needed; patients with prior opioid exposure may require higher initial doses. Dilaudid HP should NOT be used in opioid-naive patients.

Critically ill patients (off-label dosing): 0.2 to 0.6 mg every 1 to 2 hours as needed or 0.5 mg every 3 hours as needed (Barr 2013)

Continuous infusion: Usual dosage range: 0.5 to 3 mg/hour (Barr 2013)

Patient-controlled analgesia (PCA) (off-label dosing) (American Pain Society 2008): Note: Opioid naive: Consider lower end of dosing range. A continuous (basal) infusion is not recommended in opioid-naive patients (ISMP 2009):

Usual concentration: 0.2 mg/mL

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

Lockout interval: 5 to 10 minutes

Epidural PCA (off-label dosing) (de Leon-Casasola 1996; Liu 2010; Smith 2009):

Usual concentration: 0.01 mg/mL

Bolus dose: 0.4 to 1 mg

Infusion rate: 0.03 to 0.3 mg/hour

Demand dose: 0.02 to 0.05 mg

Lockout interval: 10 to 15 minutes

IM, SubQ: Note: IM use may result in variable absorption and lag time to peak effect; IM route not recommended for use (American Pain Society 2008). Equianalgesic doses: Morphine 10 mg IM = hydromorphone 1.5 mg IM.

US labeling: Initial: 1 to 2 mg every 2 to 3 hours as needed; lower initial doses may be used in opioid-naive patients. Patients with prior opioid exposure may require higher initial doses.

Canadian labeling: Opioid naive: 2 mg every 4 to 6 hours as needed; for severe pain, may administer 3 to 4 mg every 4 to 6 hours as needed. When discontinuation of therapy is necessary, decrease the previous daily dose by 50% (administered every 6 hours) for 2 days then decrease daily dose by 25% every 2 days. Hydromorphone HP or Hydromorphone HP Forte should NOT be used in opioid-naive patients.

Rectal:

US labeling: 3 mg (1 suppository) every 6 to 8 hours as needed

Canadian labeling: 3 mg (1 suppository) at bedtime as needed

Chronic pain: Note: Patients taking opioids chronically may become tolerant and require doses higher than the usual dosage range to maintain the desired effect. Tolerance can be managed by appropriate dose titration. There is no optimal or maximal dose for hydromorphone in chronic pain. The appropriate dose is one that relieves pain throughout its dosing interval without causing unmanageable side effects.

Controlled-release capsule (Hydromorph Contin [Canadian product]): Oral: Note: A patient's hydromorphone requirement should be established using prompt release formulations; conversion to long-acting products may be considered when chronic, continuous treatment is required. Higher dosages should be reserved for use only in opioid-tolerant patients. Capsule strengths ≥18 mg or a single dose >12 mg should be reserved for use only in opioid-tolerant patients requiring hydromorphone equivalent dosages ≥36 mg daily.

Opioid naive or receiving low intermittent doses of weak opioids: Initial: 3 mg every 12 hours.

Current therapy with other oral hydromorphone formulations: Initial: Initiate at same total daily hydromorphone dosage divided in 2 equal doses every 12 hours

Current therapy with other opioids: Initial: Determine equivalent oral hydromorphone daily dosage and initiate in 2 equally divided doses every 12 hours. See table below for examples of equivalent dosing (refer to manufacturer labeling for additional equivalency dosing information).

Approximate Opioid Analgesic Equivalent Dosing (Oral)

Hydromorphone

1 mg

Morphine

8 mg (5 to 7.5 mg with chronic dosing of morphine)

Oxycodone

4 mg

Codeine

~27 mg

Table has been converted to the following text.

Approximate Opioid Analgesic Equivalent Dosing (Oral)

Hydromorphone: 1 mg

Morphine: 8 mg (5 to 7.5 mg with chronic dosing of morphine)

Oxycodone: 4 mg

Codeine: ~27 mg

Dose titration: Titrate dosage at 48-hour intervals to obtain satisfactory pain relief; lowest effective dose should be used. Consider increasing the dose for patients experiencing pain at the end of the dosing interval (do not administer more frequently than every 12 hours). Rescue medication with immediate-release pain medication may also be necessary. For patients with adequate pain relief, periodic dose reductions should be attempted. If attempting to discontinue hydromorphone therapy, decrease previous daily dose by 50% for the first 2 days then decrease daily dose by 25% every two days (daily dose administered in 2 divided doses every 12 hours) or as otherwise directed.

Extended-release tablet (Exalgo): Note: For use in opioid-tolerant patients only. Patients considered opioid tolerant are those who are receiving, for 1 week or longer, at least 60 mg of oral morphine daily, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone daily, 8 mg of oral hydromorphone daily, 25 mg of oral oxymorphone daily, or an equianalgesic dose of another opioid.

Opioid-tolerant patients: Discontinue or taper all other extended-release opioids when starting therapy.

Individualization of dose: Suggested recommendations for converting to Exalgo from other analgesics are presented, but when selecting the initial dose, other characteristics (eg, patient status, 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.

Conversion from other oral hydromorphone formulations to Exalgo: Start with the equivalent total daily dose of immediate-release hydromorphone administered once daily.

Conversion from other opioids to Exalgo: Discontinue all other around-the-clock opioids when therapy is initiated. Substantial interpatient variability exists in relative potency. Therefore, it is safer to underestimate a patient’s daily oral hydromorphone requirement and provide breakthrough pain relief with rescue medication (eg, immediate release opioid) than to overestimate requirements. In general, start Exalgo at 50% of the calculated total daily dose every 24 hours (see Conversion Factors to Exalgo). The following conversion ratios may be used to convert from oral opioid therapy to Exalgo.

Conversion factors to Exalgo (see table): Select the opioid, sum the current total daily dose, multiply by the conversion factor on the table to calculate the approximate oral hydromorphone daily dose, then calculate the approximate starting dose for Exalgo at 50% of the calculated oral hydromorphone daily does; administer every 24 hours. Round down, if necessary, to the nearest strength available. For patients on a regimen of more than one opioid, calculate the approximate oral hydromorphone dose for each opioid and sum the totals to obtain the approximate total hydromorphone daily dose. For patients on a regimen of fixed-ratio opioid/nonopioid analgesic medications, only the opioid component of these medications should be used in the conversion. Note: The conversion factors in this conversion table are only to be used for the conversion from current oral opioid therapy to Exalgo. Conversion factors in this table cannot be used to convert from Exalgo to another oral opioid (doing so may lead to fatal overdose due to overestimation of the new opioid). This is not a table of equianalgesic doses.

Conversion Factors to Exalgo1

Previous Oral Opioid

Oral Conversion Factor

1The conversion factors are only to be used for the conversion from current opioid therapy to Exalgo.

2Monitor closely; ratio between methadone and other opioid agonists may vary widely as a function of previous drug exposure. Methadone has a long half-life and may accumulate in the plasma.

Hydromorphone

1

Codeine

0.06

Hydrocodone

0.4

Methadone2

0.6

Morphine

0.2

Oxycodone

0.4

Oxymorphone

0.6

Table has been converted to the following text.

Conversion factors to Exalgo (The conversion factors are only to be used for the conversion from current opioid therapy to Exalgo.)

Previous oral opioid:

Hydromorphone:

Oral conversion ratio: 1

Codeine:

Oral conversion ratio: 0.06

Hydrocodone:

Oral conversion ratio: 0.4

Methadone:

Oral conversion ratio: 0.6

Monitor closely; ratio between methadone and other opioid agonists may vary widely as a function of previous drug exposure. Methadone has a long half-life and may accumulate in the plasma.

Morphine:

Oral conversion ratio: 0.2

Oxycodone:

Oral conversion ratio: 0.4

Oxymorphone:

Oral conversion ratio: 0.6

Conversion from transdermal fentanyl to Exalgo: Treatment with Exalgo can be started 18 hours after the removal of the transdermal fentanyl patch. For every fentanyl 25 mcg/hour transdermal dose, the equianalgesic dose of Exalgo is 12 mg every 24 hours. An appropriate starting dose is 50% of the calculated total daily dose given every 24 hours. If necessary, round down to the appropriate Exalgo tablet strength available.

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 Exalgo or providing rescue medication of an immediate-release analgesic at an appropriate dose. Do not administer Exalgo more frequently than every 24 hours.

Discontinuing Exalgo: Taper by gradually decreasing the dose by 25% to 50% every 2 to 3 days to a dose of 8 mg every 24 hours before discontinuing therapy.

Extended-release tablet: Jurnista [Canadian product]: Note: May be used in conjunction with usual doses of nonopioid analgesics and analgesic adjuvants. If appropriate, initiate therapy with an immediate-release opioid formulation to establish a safe and effective dosage, then convert to an equivalent daily dose of extended-release hydromorphone. Tablets ≥16 mg are intended only for opioid-tolerant patients requiring hydromorphone equivalent dosages ≥16 mg daily.

Initial:

Patients who are opioid naive or receiving low intermittent doses of weak opioid analgesics (eg, < 40 mg daily oral morphine equivalents): Initial: 4 mg once daily (if clinically indicated, an initial dose of 8 mg may be used; maximum initial dose: 8 mg once daily); titrate dose in increments of 4 or 8 mg as needed but no sooner than every fourth dose (eg, if first dose is administered on Tuesday, increase no sooner than on Friday).

Patients receiving opioids regularly: Discontinue all other around-the-clock opioid analgesics; initial Jurnista dose is based on previous daily opioid dose. For opioids other than morphine, estimate the equivalent daily dose of morphine then determine the equivalent total daily dose of Jurnista by multiplying the equivalent morphine dose by a factor of 0.2. For example, morphine 60 mg daily multiplied by 0.2 is equivalent to hydromorphone 12 mg daily. If necessary, round down to nearest Jurnista dose available and administer once daily.

Maintenance: Dose is individualized based on response. May consider dose increases of 25% to 75% of current daily dose made no sooner than every 4th dose (eg, if first dose is administered on Tuesday, increase no sooner than on Friday). Reassess the need for around-the clock pain control periodically. Supplemental analgesia for breakthrough pain should typically not exceed 10% to 25% of the equivalent daily Jurnista dose.

Discontinuing Jurnista: Taper by gradually decreasing the dose by 50% every 2 days until lowest possible dose is reached and then discontinue. If signs of withdrawal occur during taper, stop taper and increase dose slightly until signs of withdrawal are no longer present. May then resume taper but with longer periods of time between each dose reduction, or before switching to an equianalgesic dose of another opioid to continue tapering.

Dosing: Geriatric

Doses should be titrated 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.

Acute pain, opioid-naive:

Oral: Use with caution; initiation at the low end of dosage range is recommended. For patients >70 years, the American Pain Society recommends consideration to lowering initial doses by 25% to 50% followed by upward or downward titration (APS 2008).

IM, SubQ: Refer to adult dosing. Reduce initial doses as necessary.

IV: Reduce initial dose to 0.2 mg

Dosing: Renal Impairment

Injectable:

US labeling: 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.

Canadian labeling: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, a reduced initial dose is recommended for severe renal impairment. Use with caution and monitor closely for respiratory and CNS depression.

Oral (immediate release):

US labeling: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, a reduced initial dose is recommended for moderate impairment (CrCl ≤ 60 mL/minute) and an even lower initial dose is recommended for severe impairment (CrCl <30 mL/minute). Use with caution and monitor closely for respiratory and CNS depression.

Canadian labeling: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, a reduced initial dose is recommended for severe renal impairment. Use with caution and monitor closely for respiratory and CNS depression.

Oral (extended-release tablet):

Exalgo:

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

Moderate impairment (CrCl ≤60 mL/minute): Initiate with 50% of the usual starting dose for patients with normal renal function. Use with caution and monitor closely for respiratory and CNS depression.

Severe impairment (CrCl <30 mL/minute): Initiate with 25% of the usual starting dose for patients with normal renal function. Use with caution and monitor closely for respiratory and CNS depression. Consider use of an alternate analgesic with better dosing flexibility.

Jurnista [Canadian product]:

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

Moderate impairment: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, an initial dosage reduction is recommended. Use with caution and monitor closely for respiratory and CNS depression.

Severe impairment: There are no specific dosage adjustments provided in the manufacturer’s labeling. Reduce initial dose and consider extending the dosing interval. Use with caution and monitor closely for respiratory and CNS depression.

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 closely for respiratory and CNS depression.

Moderate impairment: Initiate at 50% of initial dose for normal renal function; titrate cautiously. Monitor closely for respiratory and CNS depression following initiation of therapy and during titration.

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

Rectal suppository:

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution and monitor closely for respiratory and CNS depression.

Canadian labeling: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, an initial dosage reduction is recommended for severe renal impairment. Use with caution and monitor closely for respiratory and CNS depression

Dosing: Hepatic Impairment

Injectable:

US labeling:

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

Moderate impairment: Initiate therapy with 25% to 50% of the usual initial dose. Use with caution and monitor closely for respiratory and CNS depression.

Severe impairment: There are no specific dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, further dose reductions (compared with those recommended for moderate impairment) are recommended. Use with caution and monitor closely for respiratory and CNS depression.

Canadian labeling: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, a reduced initial dose is recommended in severe hepatic impairment. Use with caution and monitor closely for respiratory and CNS depression.

There are no specific dosage adjustments provided in the manufacturer’s labeling; however, an initial dosage reduction is recommended. Use with caution and monitor closely for respiratory and CNS depression.

Oral (immediate release):

US labeling:

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

Moderate impairment: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, an initial dosage reduction is recommended. Use with caution and monitor closely for respiratory and CNS depression.

Severe impairment: There are no specific dosage adjustments provided in the manufacturer’s labeling (has not been studied); initial dose reduction is recommended. Use with caution and monitor closely for respiratory and CNS depression.

Canadian labeling: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, a reduced initial dose is recommended in severe hepatic impairment. Use with caution and monitor closely for respiratory and CNS depression.

Oral (extended-release tablet):

Exalgo:

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.

Jurnista [Canadian product]:

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

Moderate impairment: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, a reduced initial dosage is recommended. Use with caution and monitor closely for respiratory and CNS depression.

Severe impairment: There are no specific dosage adjustments provided in the manufacturer’s labeling; reduce initial dose and use with caution. Monitor closely for respiratory and CNS depression.

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.

Rectal suppository:

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution and monitor closely for respiratory and CNS depression.

Canadian labeling: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, an initial dosage reduction is recommended for severe hepatic impairment. Use with caution and monitor closely for respiratory and CNS depression.

Administration

Parenteral: Note: Vial stopper may contain latex. May be given SubQ or IM; IM route is not recommended (APS 2008).

IV: For IVP, must be given slowly over 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.

Exalgo, Jurnista [Canadian product]: Tablets should be swallowed whole; do not crush, break, chew, dissolve or inject. May be taken with or without food.

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.

Compatibility

Stable in D5LR, D5W, D51/2NS, D5NS, LR, 1/2NS, NS.

Y-site administration: Incompatible with amphotericin B cholesteryl sulfate complex, gallium nitrate, hyaluronidase, minocycline, pantoprazole, phenytoin, sargramostim, thiopental.

Compatibility in syringe: Incompatible with ampicillin, diazepam, heparin, hyaluronidase, pantoprazole, phenobarbital, phenytoin.

Storage

Injection: Store at 15°C to 30°C (59°F to 86°F). Protect from light. A slightly yellowish discoloration has not been associated with a loss of potency. Stable for at least 24 hours when protected from light and stored at 25°C in most common large volume parenteral solutions.

Oral dosage forms: Store at 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F). Protect tablets from light.

Suppository:

US labeling: Store in refrigerator. Protect from light.

Canadian labeling: Store at 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

Alvimopan: Analgesics (Opioid) 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. Consider therapy modification

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Monitor therapy

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics 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. Consider therapy modification

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

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

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

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

CNS Depressants: May enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics 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. Consider therapy modification

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dimethindene (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Diuretics: Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics. Analgesics (Opioid) may diminish the therapeutic effect of Diuretics. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Eluxadoline: Analgesics (Opioid) may enhance the constipating effect of Eluxadoline. Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

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

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone 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. Consider therapy modification

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

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

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

MAO Inhibitors: May enhance the adverse/toxic effect of HYDROmorphone. Avoid combination

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

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

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mixed Agonist / Antagonist Opioids: May diminish the analgesic effect of Analgesics (Opioid). 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. Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Naltrexone: May diminish the therapeutic effect of Analgesics (Opioid). Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

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

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. Consider therapy modification

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

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

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

Ramosetron: Analgesics (Opioid) may enhance the constipating effect of Ramosetron. Monitor therapy

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

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

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

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin Modulators: Analgesics (Opioid) may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). 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. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol 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. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

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. Consider therapy modification

Test Interactions

Some quinolones may produce a false-positive urine screening result for opioids using commercially-available immunoassay kits. This has been demonstrated most consistently for levofloxacin and ofloxacin, but other quinolones have shown cross-reactivity in certain assay kits. Confirmation of positive opioid screens by more specific methods should be considered.

Adverse Reactions

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, seizure, 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 perforation (large intestine; Exalgo), nausea, paralytic ileus, 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 (Limited to important or life-threatening): Angioedema, hypersensitivity

ALERT: U.S. Boxed Warning

Addiction, abuse, and misuse:

Immediate-release: Hydromorphone is a potent Schedule II controlled opioid agonist. Schedule II agonists, including morphine, oxymorphone, oxycodone, fentanyl, and methadone, have the highest potential for abuse and risk of producing respiratory depression. Alcohol, other opioids and central nervous system depressants (sedative-hypnotics) potentiate the respiratory depressant effects of hydromorphone, increasing the risk of respiratory depression that might result in death.

Extended-release: Hydromorphone extended-release (ER) 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 ER and monitor all patients regularly for the development of these behaviors or conditions

Life-threatening respiratory depression (extended-release):

Serious, life-threatening, or fatal respiratory depression may occur with use of hydromorphone ER. 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 (extended-release):

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

Neonatal withdrawal syndrome (extended-release):

Prolonged use of hydromorphone ER 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.

Medication errors (injection):

High-potency hydromorphone (10 mg/mL) is for use in opioid-tolerant patients only.

Patients considered opioid tolerant are those who are taking at least 60 mg/day of oral morphine, 25 mcg/h of transdermal fentanyl, 30 mg/day of oral oxycodone, 8 mg/day of oral hydromorphone, 25 mg/day of oral oxymorphone, or an equianalgesic dose of another opioid for 1 week or longer.

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.

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. 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 [MI]), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Avoid use in patients with circulatory shock; vasodilatory effects may further reduce cardiac output and blood pressure.

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

• Respiratory depression: Extended-release tablets: [US Boxed Warning]: May cause serious, life-threatening, or fatal respiratory depression. Monitor closely for respiratory depression, especially during initiation or dose escalation. Patients should swallow 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.

• Seizures: Myoclonus and seizures have been reported with high doses; use with caution in patients with a history of seizure disorder. Some Canadian product labels specifically contraindicate use in patients with seizure disorder (refer to Contraindications).

Disease-related concerns:

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

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

• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction. Hydromorphone may increase biliary tract pressure following spasm in sphincter of Oddi. Use caution in patients with inflammatory or obstructive bowel disorder, acute pancreatitis secondary to biliary tract disease, and patients undergoing biliary surgery.

• Cardiovascular disease: Use with caution in patients with cardiovascular disease.

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

• Delirium tremens: Use with caution in patients with delirium tremens. The Canadian labeling contraindicates use of some dosage forms in patients with delirium tremens (refer to contraindications).

• Drug abuse: Use opioids for chronic pain with caution in patients at increased risk for misuse; factors associated with increased risk include previous substance use disorder, 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 (Dowell [CDC 2016]).

• GI narrowing: Exalgo and Jurnista [Canadian product] 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. The Canadian labeling contraindicates use of some dosage forms in patients with head trauma and increased cerebrospinal or ICP (refer to Contraindications).

• Hepatic impairment: Use with caution in patients with hepatic 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 (Dowell [CDC 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.

• Psychoses: Use with caution in patients with toxic psychoses.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or preexisting respiratory depression, particularly when initiating therapy and titrating with hydromorphone; even therapeutic doses may decrease respiratory drive to the point of apnea. The Canadian labeling contraindicates use of some dosage forms in acute respiratory depression, hypercarbia and cor pulmonale (refer to Contraindications). Consider the use of alternative nonopioid analgesics in these patients.

• Sleep-disordered breathing: Use opioids with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing, including HF and obesity. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

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

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Sedatives: Effects may be potentiated when used with other CNS depressants (eg, sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). In the setting of chronic pain, avoid prescribing opioids and benzodiazepines concurrently whenever possible; epidemiologic studies suggest there is an increased risk for potentially fatal overdose with concurrent use (Dowell [CDC 2016]).

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.

• Elderly: 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 (Dowell [CDC 2016]).

• Neonates: Neonatal withdrawal syndrome: Extended-release tablets: [US Boxed Warning]: Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn patient of risk to the neonate. 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.

• Perioperative patients: Use immediate-release formulations with caution in the perioperative setting; severe pain may antagonize the respiratory depressant effects of hydromorphone. The Canadian labeling (immediate-release formulations) recommends withholding hydromorphone within 24 hours of procedures that interfere with pain transmission pathways (eg, cordotomy); postoperative dose adjustments should be made as clinically indicated. The Canadian labeling for extended-release formulations contraindicates use in the perioperative setting (Hydromorph Contin may be used in this setting only if GI function is normal).

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.

• Immediate-release formulations: [US Boxed Warning]: High potential for abuse and risk of producing respiratory depression. Alcohol, other opioids, and CNS depressants potentiate the respiratory depressant effects of hydromorphone, increasing the risk of respiratory depression that might result in death.

• Injection: [US Boxed Warning]: Extreme caution should be taken to avoid confusing the highly concentrated (Dilaudid-HP) injection with the less-concentrated (Dilaudid) injectable product. Dilaudid-HP should only be used in patients who are opioid tolerant. Highly concentrated products available in Canada (Hydromorphone HP and Hydromorphone HP Forte) are for use only in opioid-tolerant patients with severe pain.

• Lactose: Some formulations may contain lactose; consider lactose content prior to initiating therapy in patients with hereditary diseases of galactose intolerance (eg, galactosemia, glucose-galactose malabsorption).

• 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:

• Abuse/misuse/diversion: [US Boxed Warning]: Users are exposed 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. Risk of opioid abuse is increased in patients with a history or family history of alcohol or drug abuse or mental illness.

• Accidental exposure: Extended-release tablets: [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-assisted treatment for opioid use disorder) 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, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg. NSAIDs, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and non-opioid 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 (Dowell [CDC 2016]).

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

• 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.

• Withdrawal: Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms.

Monitoring Parameters

Pain relief, respiratory and mental status, blood pressure; signs 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-assisted treatment for opioid use disorder): 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]).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Hydromorphone crosses the placenta. Some dosage forms are specifically contraindicated for use in obstetrical analgesia. The Canadian labeling contraindicates use of some dosage forms during pregnancy and/or labor and delivery.

When used for pain relief during labor, opioids may temporarily affect the heart rate of the fetus (ACOG 2002). Monitor the neonate for respiratory depression if hydromorphone is used during labor.

[US Boxed Warning]: Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn patient of risk to the neonate. If chronic opioid exposure occurs in pregnancy, adverse events in the newborn (including withdrawal) may occur; monitoring of the neonate is recommended. The minimum effective dose should be used if opioids are needed (Chou 2009). Neonatal abstinence syndrome following opioid exposure may present with autonomic (eg, fever, temperature instability), GI (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, increased muscle tone, irritability, seizure, tremor) symptoms (Dow 2012; Hudak 2012). Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility (Brennan 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dry mouth, flushing, sweating a lot, loss of strength and energy, joint pain, itching, or tablet shell in stool. Have patient report immediately to prescriber slow breathing, shallow breathing, trouble breathing, severe dizziness, passing out, illogical thinking, severe nausea, vomiting, severe constipation, tachycardia, bradycardia, arrhythmia, hallucinations, mood changes, seizures, severe headache, severe abdominal pain, tremors, difficult urination, involuntary eye movements, abnormal movements, vision changes, angina, change in balance, memory impairment, suicidal ideation, swelling of arms or legs, or severe fatigue (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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