HYDROmorphone

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]

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

Generic: 1 mg/mL (473 mL)

Solution, Injection, as hydrochloride:

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

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

Generic: 1 mg/mL (0.5 mL, 1 mL); 2 mg/mL (1 mL, 20 mL); 4 mg/mL (1 mL)

Solution, Injection, as hydrochloride [preservative free]:

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

Generic: 1 mg/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)

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 [contains sodium metabisulfite]

Dilaudid: 8 mg [DSC] [scored; contains sodium metabisulfite]

Generic: 2 mg, 4 mg, 8 mg

Tablet ER 24 Hour Abuse-Deterrent, 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

Pharmacology

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/Pharmacodynamics

Absorption

Oral: Rapidly absorbed; extensive first-pass effect

Extended release tablet: Delayed; IM: Variable and delayed

Distribution

V_d: 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%

Use in Specific Populations

Special Populations: Renal Function Impairment

Extended release: C_max 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: C_max and AUC_0-48 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

C_max 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 C_max than men.

Use: Labeled Indications

Pain management:

Immediate release:

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

Extended release: 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: Reserve for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Hydromorphone ER is not indicated as an as-needed analgesic.

Moderate to severe pain: Suppository: Relief of moderate to severe pain such as that caused by biliary colic, burns, cancer, myocardial infarction, renal colic, surgery, and trauma (soft tissue and bone).

Use: Off Label

Pain in mechanically-ventilated ICU patients (management)yes

Based on the Society of Critical Care Medicine guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the Intensive Care Unit, hydromorphone is an effective and recommended agent for management of pain in critically ill patients SCCM [Devlin 2018].

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

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, 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 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

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

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

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

Dosage and Administration

Dosing: Adult

Pain management: Note: These are a guide 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: 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 (oral solution). Start at the lower end of dosing range for opioid-naive patients; patients with prior opioid exposure may require higher initial doses.

Conversion from other opioids to hydromorphone oral immediate release: Initial: 1 to 2 mg every 4 to 6 hours as needed (tablets) or 1.25 mg to 5 mg every 3 to 6 hours as needed (oral solution).

IV: Initial: Opioid naive: 0.2 to 1 mg every 2 to 3 hours as needed. Start at the lower end of dosing range for opioid-naive patients; patients with prior opioid exposure may require higher initial doses. Hydromorphone HP should NOT be used in opioid-naive patients.

Critically ill patients (off-label):

Intermittent dosing: Loading dose: 0.5 to 2 mg; maintenance dose: 0.2 to 0.6 mg every 1 to 2 hours as needed or 0.5 mg every 3 hours as needed (SCCM [Barr 2013, Devlin 2018]; Tietze 2019).

Continuous infusion: Usual dosage range: 0.5 to 3 mg/hour (SCCM [Barr 2013, Devlin 2018]; Tietze 2019)

IM, SubQ (intermittent dosing): Note: IM administration is not recommended and should be avoided; 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. Equianalgesic doses: Morphine 10 mg SubQ = hydromorphone 1.5 mg SubQ. SubQ is a more reliable and less painful alternative route of administration compared to IM (American Pain Society 2016).

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. Hydromorphone HP should NOT be used in opioid-naive patients.

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. Hydromorphone HP or Hydromorphone HP Forte should NOT be used in opioid-naive patients.

SubQ (continuous infusion) (off label): Opioid-tolerant patients: Median doses reported from limited data: 0.167 to 4 mg/hour; however, dose should be individualized and calculated based on patient’s previous opioid intake and appropriate opioid analgesic equivalents; titrate further, if needed, based on level of pain (Miller 1999; Moulin 1991)

Patient-controlled analgesia (PCA) (off-label) (American Pain Society 2016): Note: Opioid naive: Consider lower end of dosing range. A continuous (basal) infusion is not recommended in opioid-naive patients (ISMP 2009):

Loading dose: 0.4 mg

Demand dose: Range: 0.1 to 0.4 mg

Lockout interval: 10 minutes

Epidural PCA (off-label) (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

Conversion from other opioids to hydromorphone injection:

Injection: Convert the current total daily amount(s) of opioid(s) received to an equivalent total daily dose of hydromorphone injection and reduce by 50%. Divide the new total amount by the number of doses permitted based on dosing interval (eg, 8 doses for every 3 hour dosing). Titrate dose according to patient response.

HP injection: Base the starting dose for hydromorphone HP injection on the prior dose of hydromorphone injection or on the prior dose of an alternate opioid.

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).

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, 60 mg oral hydrocodone 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 hydromorphone ER 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 hydromorphone ER: Start with the equivalent total daily dose of immediate-release hydromorphone administered once daily.

Conversion from other opioids to hydromorphone ER: 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 hydromorphone ER at 50% of the calculated total daily dose every 24 hours (see Conversion Factors to hydromorphone ER). The following conversion ratios may be used to convert from oral opioid therapy to hydromorphone ER.

Conversion factors to hydromorphone ER (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 hydromorphone ER 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 hydromorphone ER. Conversion factors in this table cannot be used to convert from hydromorphone ER 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.

Table has been converted to the following text.

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

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 hydromorphone ER: Treatment with hydromorphone ER 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 hydromorphone ER 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 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 hydromorphone ER or providing rescue medication of an immediate-release analgesic at an appropriate dose. Do not administer hydromorphone ER more frequently than every 24 hours.

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 once daily 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 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 once daily 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).

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.

Discontinuation of therapy: When discontinuing chronic opioid therapy, the dose should be gradually tapered down. An optimal universal tapering schedule for all patients has not been established (CDC [Dowell 2016]). Proposed schedules range from slow (eg, 10% reductions per week) to rapid (eg, 25% to 50% reduction every few days) (CDC 2015). Tapering schedules should be individualized to minimize opioid withdrawal while considering patient-specific goals and concerns as well as the pharmacokinetics of the opioid being tapered. An even slower taper may be appropriate in patients who have been receiving opioids for a long duration (eg, years), particularly in the final stage of tapering, whereas more rapid tapers may be appropriate in patients experiencing severe adverse events (CDC [Dowell 2016]). 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 (Berna 2015; CDC [Dowell 2016]). Continue to offer nonopioid analgesics as needed for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints, muscle spasm) as needed (Berna 2015; Sevarino 2018).

Moderate to severe pain:

Rectal:

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

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

Dosing: Geriatric

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 (AGS 2009; Galicia-Castillo 2018). 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:

Immediate-release tablets: Opioid-naive patients with persistent pain: Limited data available; based on expert opinion: Initial: 0.5 to 1 mg every 4 or 6 hours as needed or 2 mg every 4 hours as needed (Galicia-Castillo 2018). 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 (American Pain Society 2016).

Extended-release products: Opioid-tolerant patients only: Limited data available; based on expert opinion: After 3 to 7 days, divide the 24-hour dose requirement for immediate-release hydromorphone into 1 or 2 doses (depending on extended release product selected) (Galicia-Castillo 2018).

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 (American Pain Society 2016).

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 (Chang 2013).

IM: IM administration is not recommended and should be avoided (American Pain Society 2016).

Dosing: Pediatric

Acute pain, moderate to severe: Limited data available (American Pain Society 2016; Berde 2002; Kliegman 2007): 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 (Friedrichsdorf 2007; Zernikow 2009):

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) (Friedrichsdorf 2007; Zernikow 2009)

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 (Berde 2002)

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 4 to 8 hours as needed

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 (Reiter 2012)

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 (Reiter 2012)

Patient-controlled analgesia (PCA): Limited data available (American Pain Society 2016): 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 (DiGiusto 2014). 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 (ISMP 2009). 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

Administration

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 (APS 2016). 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 (APS 2016).

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, Jurnista [Canadian product]: Tablets should be swallowed whole; do not crush, break, chew, dissolve, snort, or inject. Administer 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.

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.

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: Store in refrigerator. Protect from light.

Drug Interactions

Alizapride: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

Amphetamines: May enhance the analgesic effect of Opioid Agonists. 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. 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

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

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

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

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

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

Desmopressin: Opioid Agonists may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

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

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists 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 (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Eluxadoline: Opioid Agonists 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): Opioid Agonists 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

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. Consider therapy modification

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

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

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

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

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

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. 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. Avoid combination

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

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. 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: Opioid Agonists 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: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

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

Ramosetron: Opioid Agonists 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

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. 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. Consider therapy modification

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 Opioid Agonists. 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

Tetrahydrocannabinol and Cannabidiol: 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, 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)

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.

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 sexual dysfunction, infertility, 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.
• 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.

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.
• 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 (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-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, 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 anticonvulsants 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.
• 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.

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-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]).

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]).

Pregnancy

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).

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

Patient Education

What is this drug used for?

All products:

• It is used to ease pain.

Extended-release tablets:

• This drug is only for use by people who have been taking pain drugs (opioids) and are used to their effects. Talk with the doctor.

Frequently reported side effects of this drug

• Dry mouth
• Headache
• Flushing
• Nausea
• Vomiting
• Sweating a lot
• Loss of strength and energy
• Joint pain
• Itching
• Tablet shell in stool

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Adrenal gland problems like severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss
• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea
• Slow breathing
• Shallow breathing
• Trouble breathing
• Severe dizziness
• Passing out
• Confusion
• Severe constipation
• Fast heartbeat
• Slow heartbeat
• Abnormal heartbeat
• Sensing things that seem real but are not
• Mood changes
• Seizures
• Severe abdominal pain
• Tremors
• Difficult urination
• Involuntary eye movements
• Abnormal movements
• Vision changes
• Chest pain
• Change in balance
• Trouble with memory
• Swelling of arms or legs
• Severe fatigue
• Decreased sex drive
• Trouble getting pregnant
• No menstrual period
• Sexual dysfunction (males)
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.