Introduction ⬇
AHFS Class:
Generic Name(s):
- HYDROmorphone Hydrochloride
Associated Monographs
Notification REMS: FDA approved a REMS for hydromorphone to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of hydromorphone and consists of the following: medication guide and elements to assure safe use. See the FDA REMS page ([Web]). FDA drug safety communication (4/13/2023)500- As part of its ongoing efforts to address the nation's opioid crisis, FDA is requiring several updates to the prescribing information of opioid pain medicines. The changes are being made to provide additional guidance for safe use of these drugs while also recognizing the important benefits when used appropriately. The changes apply to both immediate-release (IR) and extended-release/long-acting preparations (ER/LA).
- Updates to the IR opioids state that these drugs should not be used for an extended period unless the pain remains severe enough to require an opioid pain medicine and alternative treatment options are insufficient, and that many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine.
- Updates to the ER/LA opioids recommend that these drugs be reserved for severe and persistent pain requiring an extended period of treatment with a daily opioid pain medicine and for which alternative treatment options are inadequate.
- A new warning is being added about opioid-induced hyperalgesia (OIH) for both IR and ER/LA opioid pain medicines. This includes information describing the symptoms that differentiate OIH from opioid tolerance and withdrawal.
- Information in the boxed warning for all IR and ER/LA opioid pain medicines will be updated and reordered to elevate the importance of warnings concerning life-threatening respiratory depression, and risks associated with using opioid pain medicines in conjunction with benzodiazepines or other medicines that depress the central nervous system (CNS).
- Other changes will also be required in various other sections of the prescribing information to educate clinicians, patients, and caregivers about the risks of these drugs.
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Hydromorphone is a semisynthetic phenanthrene-derivative opiate agonist.
Uses ⬆ ⬇
Hydromorphone hydrochloride injection and conventional oral preparations of the drug (immediate-release tablets, oral solution) are used for the relief of pain that is severe enough to require an opiate analgesic.238,239 The injection containing 10 mg of the drug per mL is a highly concentrated parenteral formulation of the drug that should be used only in opiate-tolerant patients who require higher dosages of opiate analgesics; during treatment with this formulation, patients must remain on around-the-clock opiate therapy.239 Patients are considered opiate tolerant if they have been receiving at least 60 mg of oral morphine sulfate daily, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone hydrochloride daily, 60 mg of oral hydrocodone bitartrate daily, 8 mg of oral hydromorphone hydrochloride daily, 25 mg of oral oxymorphone hydrochloride daily, or an equianalgesic dosage of another opiate daily for at least 1 week.239,246 Because of the risks of addiction, abuse, and misuse associated with opiates even at recommended dosages, parenteral and conventional oral formulations of hydromorphone should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics, opiate-containing fixed combinations) have not been, or are not expected to be, adequate or tolerated.238,239
Extended-release tablets of hydromorphone hydrochloride are used orally in opiate-tolerant patients for the management of pain that is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic; because of the risks of addiction, abuse, and misuse associated with opiates even at recommended dosages, and because of the greater risks of overdosage and death associated with extended-release opiate formulations, extended-release hydromorphone should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics, immediate-release opiates) are inadequate or not tolerated.246 Extended-release hydromorphone is not intended for use on an as-needed (“prn”) basis.246
For further information on the role of opiate analgesics in the management of acute or chronic pain, see Uses: Pain, in the Opiate Agonists General Statement 28:08.08.
Dosage and Administration ⬆ ⬇
Administration 
Hydromorphone hydrochloride may be administered by subcutaneous, IM, or slow IV injection; the drug also may be administered orally as conventional (immediate-release) or extended-release tablets or as an oral solution. If rapid onset and shorter duration of analgesia are required, the drug may be given IV at a very slow rate (over at least 2-3 minutes depending on the dose) with special attention to the possibility of respiratory depression and hypotension. Hydromorphone hydrochloride has been administered as a continuous subcutaneous or IV infusion in selected opiate-tolerant patients with chronic pain conditions; extreme caution is advised when administering continuous infusions of opiates to patients with no prior exposure to opiate analgesics.240,241,242,243,244 The drug also has been administered IV via a controlled-delivery device for patient-controlled analgesia (PCA).241 Hydromorphone hydrochloride also has been administered epidurally†.240,241,244
Parenteral Administration
Parenteral preparations of hydromorphone hydrochloride are commercially available in various concentrations (0.2, 1, 2, 4, and 10 mg/mL).239,251 Preparations containing lower concentrations of the drug (0.2, 1, 2, or 4 mg/mL) should be used to initiate parenteral hydromorphone therapy in opiate-naive patients.239,251 The highly concentrated (10-mg/mL) injection is intended for use only in patients who are tolerant to and already receiving high dosages of opiate agonists.239 (See Uses and also Cautions.) Confusion between the different concentrations or between mg and mL can result in accidental overdosage and/or death.239 To avoid such dosing errors, care should be taken to ensure that correct dosages are prescribed and dispensed.239 The highly concentrated injection should be used only when the volume required for the intended dose can be accurately measured; this injection should not be used when low doses are required. The highly concentrated injection should be reserved for use in patients who require the reduced total volume and higher concentration of this formulation.239
When the single-dose 10-mg/mL vial containing 500 mg of hydromorphone hydrochloride is used for preparation of IV infusion solutions, the appropriate amount should be withdrawn for preparation of a single large-volume parenteral solution and any unused portion of the vial should be discarded.239 Hydromorphone hydrochloride has been diluted (e.g., to a concentration of 1 mg/mL) in 5% dextrose or 0.9% sodium chloride injection for continuous IV infusion in critically ill adults.242 Hydromorphone hydrochloride injection has been self-administered intermittently as needed (“prn”) via a controlled-delivery device for PCA with usual lockout intervals (minimum time between self-administered doses programmed into device) of 5-10 minutes.241
IM administration of opiate analgesics is discouraged; IM injections can cause pain and are associated with unreliable absorption, resulting in inconsistent analgesia.241,430
Standardize 4 Safety
Standardized concentrations for hydromorphone have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. Multidisciplinary expert panels were convened to determine recommended standard concentrations. Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label.249,250 For additional information on S4S (including updates that may be available), see [Web].
Table 1: Standardize 4 Safety Standards for Hydromorphone Continuous IV Infusions249,250
Patient Population | Concentration Standarda | Dosing Units |
|---|
Adults | 0.2 mg/mL | mg/hour |
| 1 mg/mL | |
| 5 mg/mL (based on high dose requirements) | |
Pediatric patients (<50 kg) | 0.2 mg/mL | mg/kg/hr |
| 1 mg/mL | |
| 5 mg/mL | |
aConcentration standard for adults is for continuous infusions not delivered by a PCA device. Concentration standard for pediatric patients also is for continuous infusions and not for delivery via PCA device.
Table 2: Standardize 4 Safety PCA Standard Concentrations for Hydromorphone252
Patient Population | Concentration Standard | Dosing Units |
|---|
Adults | 0.2 mg/mL | mg |
| 1 mg/mL(caution is advised if both hydromorphone and morphine are used to avoid confusion in selection as both have the same concentration) | |
| 10 mg/mL (sub-Q only) | |
Pediatric patients (<50 kg) | 0.05 mg/mL | mg/kg/hr |
| 0.2 mg/mL | |
| 1 mg/mL (caution is advised if both hydromorphone and morphine are used to avoid confusion in selection as both have the same concentration) | |
Table 3: Standardize 4 Safety Epidural Single Drug Standard Concentrations for Hydromorphone
Patient Population | Concentration Standard |
|---|
Adults | 10 mcg/mL |
Pediatric patients (<50 kg) | 5 mcg/mL |
| 10 mcg/mL |
Table 4: Standardize 4 Safety ADULT Epidural Combination Drug Standard Concentrations for Hydromorphone252
Drug Combinations | Anesthetic Concentration | Narcotic Concentration |
|---|
Bupivacaine with hydromorphone | 1. Bupivacaine 0.0625% | 1. Hydromorphone 10 mcg/mL |
| 2. Bupivacaine 0.125% | 2. Hydromorphone 10 mcg/mL |
Ropivacaine with hydromorphone | 1. Ropivacaine 0.2% | 1. Hydromorphone 10 mcg/mL |
Table 5: Standardize 4 Safety PEDIATRIC Epidural Combination Drug Standard Concentrations for Hydromorphone 252
Drug Combinations | Anesthetic Concentration | Narcotic Concentration |
|---|
Bupivacaine with hydromorphone | 1. Bupivacaine 0.0625% | 1. Hydromorphone 5 mcg/mL |
| 2. Bupivacaine 0.0625% | 2. Hydromorphone 10 mcg/mL |
| 3. Bupivacaine 0.125% | 3. Hydromorphone 5 mcg/mL |
| 4. Bupivacaine 0.125% | 4. Hydromorphone 10 mcg/mL |
Ropivacaine with hydromorphone | 1. Ropivacaine 0.1% | 1. Hydromorphone 5 mcg/mL |
| 2. Ropivacaine 0.1% | 2. Hydromorphone 10 mcg/mL |
| 3. Ropivacaine 0.2% | 3. Hydromorphone 5 mcg/mL |
| 4. Ropivacaine 0.2% | 4. Hydromorphone 10 mcg/mL |
Oral Administration
Commercially available conventional (immediate-release) tablets and oral solutions of hydromorphone hydrochloride are bioequivalent.238 Although food may decrease the rate and extent of absorption of hydromorphone hydrochloride conventional tablets (see Pharmacokinetics), the manufacturer states that these effects may not be clinically important.238 Patients receiving hydromorphone should avoid alcohol; concomitant use may result in profound sedation, respiratory depression, coma, and death.700
Extended-release tablets of hydromorphone hydrochloride should be prescribed only by clinicians who are knowledgeable in the use of potent opiates for the management of chronic pain.246 When therapy with extended-release hydromorphone hydrochloride is initiated, all other extended-release opiates should be discontinued.246 Extended-release tablets of hydromorphone hydrochloride should be administered once every 24 hours.246 The tablets should be swallowed intact and should not be broken, crushed, dissolved, or chewed; ingestion of broken, crushed, chewed, or dissolved tablets may result in rapid release of the drug from the preparation and absorption of a potentially fatal dose of hydromorphone hydrochloride.246 Extended-release tablets of hydromorphone hydrochloride may be administered without regard to food.246 Intake of alcohol with the extended-release tablets may result in increased peak plasma concentrations of hydromorphone and ingestion of a potentially toxic dose of the drug.246
Caution should be exercised when prescribing or dispensing oral hydromorphone hydrochloride to avoid inadvertent interchange of the 8-mg extended-release tablets and the 8-mg conventional tablets and to avoid confusion between mg and mL of the oral solution.238,246Prescriptions for the oral solution should specify the intended total dose of the drug (in mg) along with the corresponding total volume (in mL).238 To ensure accurate measurement of the dose, a calibrated measuring device should always be used to administer the oral solution; household teaspoons and tablespoons should not be used.238
Dosage
Hydromorphone hydrochloride should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient.411,413,431,432,435 Reduced dosage is indicated in geriatric or debilitated patients and in patients with hepatic or renal impairment.238,239,246 If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used.700,703
For acute pain not related to trauma or surgery, the prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opiate analgesia (generally 3 days or less and rarely more than 7 days).411,433,434,435 When opiate analgesics are used for the management of chronic noncancer pain, the US Centers for Disease Control and Prevention (CDC) recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to 50 mg or more of morphine sulfate daily (approximately 12.5 mg or more of hydromorphone hydrochloride daily) and avoid dosages equivalent to 90 mg or more of morphine sulfate daily (approximately 22.5 mg or more of hydromorphone hydrochloride daily) or carefully justify their decision to titrate the dosage to such levels.411 Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80-120 mg of morphine sulfate daily.423,431 For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.
Dosage of hydromorphone hydrochloride should be individualized to provide adequate analgesia and to minimize adverse effects.238,239,241,246 When selecting an initial dosage, consideration should be given to the severity of the patient's pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse.238,239,246 There is substantial interpatient variability in the relative potency of opiate analgesics and analgesic formulations; therefore, in patients who are being transferred to hydromorphone from other opiate therapy, it is preferable to underestimate the patient's 24-hour opiate requirements than to overestimate the requirements and manage an adverse reaction.238,239,246
Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression.238,239 Patients should be monitored closely for respiratory depression, especially during the first 24-72 hours of therapy and following any increase in dosage.238,239,246
Patients receiving opiate analgesia should be reevaluated continually for adequacy of pain control and for adverse effects, as well for the development of addiction, abuse, or misuse.238,239,246 During long-term therapy, the continued need for opiate analgesics should be periodically reevaluated.246 Frequent communication among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family is important during periods of changing analgesic requirements, including the initial dosage titration period.238,239,246 If the level of pain increases after dosage stabilization, an attempt should be made to identify the source of increased pain before increasing the hydromorphone hydrochloride dosage.238,239,246
Parenteral Dosage
The manufacturer states that the usual initial parenteral dosage of hydromorphone hydrochloride in opiate-naive adults is 1-2 mg every 2-3 hours as needed by subcutaneous or IM injection, or 0.2-1 mg every 2-3 hours by slow (i.e., over at least 2-3 minutes depending on the dose) IV injection.239 Lower initial subcutaneous or IM dosages may be appropriate in some opiate-naive patients.239 The initial IV dose should be reduced in geriatric or debilitated patients, and may be reduced to 0.2 mg.239 The dose and/or frequency of administration should be adjusted gradually based on patient response.239 In critically ill adults in an intensive care unit (ICU) setting, an IV loading dose of 0.2-0.6 mg followed by a maintenance continuous IV infusion of 0.5-3 mg/hour has been used.242 Hydromorphone hydrochloride also has been administered in intermittent IV doses of 10-30 mcg/kg every 1-2 hours or as a continuous IV infusion of 7-15 mcg/kg per hour in critically ill adults.243
To switch patients who currently are receiving other opiate therapy to therapy with parenteral hydromorphone hydrochloride, the total daily dosage of the current opiate should be converted to an equivalent daily dosage of hydromorphone hydrochloride.239 The manufacturer states that the estimated parenteral dosage of hydromorphone hydrochloride should then be reduced by one-half because of the possibility of incomplete cross-tolerance and administered in divided doses.239 Dosage of parenteral hydromorphone hydrochloride should then be adjusted based on patient response.239
The manufacturer states that when parenteral hydromorphone hydrochloride therapy is discontinued in a patient who may be physically dependent on opiates, the dosage should be reduced by 25-50% every 2-4 days.239 If manifestations of withdrawal occur, the dosage should be increased to the prior level and tapered more slowly (i.e., by increasing the interval between dosage reductions and/or reducing the amount of each incremental change in dose).239
Although safety and efficacy of parenteral hydromorphone hydrochloride have not been established in pediatric patients†, some clinicians recommend an initial parenteral dosage of 0.015 mg/kg every 3-6 hours as needed in children who weigh less than 50 kg437,438,439 and an initial parenteral dosage of 0.2-0.6 mg IV every 2-4 hours or 0.8-1 mg by IM or subcutaneous injection every 4-6 hours as needed in children and adolescents who weigh 50 kg or more.437
Oral Dosage
Conventional Preparations
The usual initial oral dosage of hydromorphone hydrochloride in non-opiate-tolerant adults is 2-4 mg as conventional (immediate-release) tablets every 4-6 hours or 2.5-10 mg as oral solution every 3-6 hours as needed.238,240 For adults with severe pain, initial oral doses of 4-8 mg have been used.241 The dose and/or frequency of administration should be adjusted gradually based on patient response.238 For management of chronic pain, conventional oral preparations of the drug should be administered at regularly scheduled intervals (“around the clock”); supplemental doses equivalent to 5-15% of the total daily dosage may be administered every 2 hours as needed for breakthrough pain.238
To switch patients who currently are receiving other opiate therapy to therapy with conventional oral preparations of hydromorphone hydrochloride, the manufacturer states that it is generally safest to initiate hydromorphone hydrochloride therapy at one-half the usual initial dose administered every 3-6 hours as oral solution or every 4-6 hours as conventional tablets.238 The dose and/or frequency of administration of oral hydromorphone hydrochloride should then be adjusted based on patient response.238
Although safety and efficacy of conventional oral preparations of hydromorphone hydrochloride have not been established in pediatric patients†, some clinicians recommend an initial oral hydromorphone hydrochloride dosage of 0.03-0.08 mg/kg every 3-4 hours as needed in children who weigh less than 50 kg245,437,438,439,440 and a usual initial oral dosage of 1-2 mg every 3-4 hours as needed in children and adolescents who weigh 50 kg or more.437,439 For children with severe pain, initial oral doses of 0.06 mg/kg have been used.241
Extended-release Tablets
When hydromorphone hydrochloride extended-release tablets are used in opiate-tolerant patients, dosage must be carefully individualized since overestimation of the initial dosage can result in fatal overdosage.246 Patients are considered opiate tolerant if they have been receiving at least 60 mg of oral morphine sulfate daily, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone hydrochloride daily, 60 mg of oral hydrocodone bitartrate daily, 8 mg of oral hydromorphone hydrochloride daily, 25 mg of oral oxymorphone hydrochloride daily, or an equianalgesic dosage of another opiate daily for at least 1 week.246 All other around-the-clock opiate analgesics should be discontinued when therapy with hydromorphone hydrochloride extended-release tablets is initiated.246
Adults being transferred from conventional (immediate-release) oral hydromorphone hydrochloride preparations to the extended-release tablets should receive the same total daily dosage administered once every 24 hours.246
When transferring adults from other oral opiates to extended-release hydromorphone hydrochloride, the approximate oral conversion factors in Table 6 may be used to calculate the estimated daily hydromorphone hydrochloride requirement.246 The recommended initial dosage is 50% of the calculated estimated daily requirement administered once daily (e.g., for a patient receiving a total daily oral oxycodone hydrochloride dosage of 60 mg, the estimated daily oral hydromorphone hydrochloride requirement would be 24 mg, and the approximate initial dosage of hydromorphone hydrochloride extended-release tablets would be 12 mg once daily).246 For patients receiving more than one opiate, the approximate oral hydromorphone hydrochloride dosage should be calculated for each opiate separately and then the totals should be summed; for patients receiving fixed-combination analgesics, only the opiate component should be considered.246 The calculated dosage should always be rounded down, when necessary, to an appropriate available tablet strength.246
Table 6 is not a table of equianalgesic doses.246 The conversion factors in the table should be used only to switch patients from one of the listed oral opiate analgesics to hydromorphone hydrochloride extended-release tablets, and cannot be used to switch patients from hydromorphone hydrochloride extended-release tablets to another opiate, as this will result in overestimation of the dosage of the new opiate and possible fatal overdosage.246
Particularly close monitoring is required when patients are switched from methadone therapy, since equianalgesic conversion ratios between methadone and other opiates vary widely depending on extent of prior methadone exposure (see Dosage and Administration: Dosage, in Methadone Hydrochloride 28:08.08).246
Table 6. Approximate Oral Conversion Factors for Determining Hydromorphone Hydrochloride Requirements When Converting from Oral Opiate Agonists to Extended-release Hydromorphone Hydrochloride246
Opiate Agonist | Approximate Oral Conversion Factor |
|---|
Hydromorphone hydrochloride | 1 |
Codeine phosphate | 0.06 |
Hydrocodone bitartrate | 0.4 |
Methadone hydrochloride | 0.6 |
Morphine sulfate | 0.2 |
Oxycodone hydrochloride | 0.4 |
Oxymorphone hydrochloride | 0.6 |
For conversion from transdermal fentanyl, the estimated equianalgesic dosage of extended-release hydromorphone hydrochloride is 12 mg every 24 hours for each 25-mcg/hour increment in fentanyl transdermal dosage.246 In general, dosage of extended-release hydromorphone hydrochloride should be initiated at 50% of the calculated total daily dosage.246 The calculated dosage should always be rounded down, when necessary, to an appropriate available tablet strength.246 Therapy with the extended-release tablets can be initiated 18 hours following removal of the fentanyl transdermal system.246
Patients who experience breakthrough pain may require dosage adjustment or supplemental analgesia (i.e., “rescue” therapy with an immediate-release analgesic).246 Dosage of hydromorphone hydrochloride extended-release tablets can be titrated in increments of 4-8 mg every 3-4 days based on patient response.246 Dosage of extended-release hydromorphone hydrochloride in clinical trials ranged from 12-64 mg daily.246
Discontinuance of Therapy
When oral hydromorphone hydrochloride therapy is discontinued in a patient who may be physically dependent on opiates, dosage generally should be reduced by no more than 10-25% daily every 2-4 weeks.238,246 Patients who have been taking opiates for briefer periods of time may tolerate a more rapid taper.238,246 If manifestations of withdrawal occur, it may be necessary to pause the taper or to increase the dosage to the prior level before tapering the dosage more slowly.238,246 When opiate dosage is tapered, patients should be monitored for adequacy of pain control, changes in mood, and emergence of suicidal thoughts, as well as for manifestation of opiate withdrawal.238,246 A multimodal approach to pain management should be in place prior to initiation of an opiate taper, particularly for patients receiving high dosages and/or long-term opiate therapy for chronic pain.238,246
Dosage in Renal and Hepatic Impairment
Because of the potential for increased drug exposure, dosage of hydromorphone hydrochloride should be reduced in patients with renal or hepatic impairment based on the degree of impairment.238,239,246 Patients with hepatic or renal impairment should be closely monitored during initiation of therapy and dosage titrations.238,239,246
Hepatic Impairment
In patients with hepatic impairment, the initial oral dosage of hydromorphone hydrochloride administered as conventional preparations (immediate-release tablets, oral solution) should be reduced to one-fourth to one-half the usual recommended dosage depending on the degree of impairment; the initial dosage should be reduced in patients with moderate hepatic impairment (Child-Pugh class B), and even more conservative initial dosages should be used in patients with severe hepatic impairment (Child-Pugh class C).238
Initial dosage of hydromorphone hydrochloride extended-release tablets in patients with moderate hepatic impairment should be reduced to one-fourth the usual recommended dosa use of alternative analgesic preparations is recommended in those with severe hepatic impairment.246
When hydromorphone hydrochloride injection is used in patients with moderate hepatic impairment, the manufacturer recommends that the initial dosage be reduced to one-fourth to one-half the usual recommended dosa the likelihood that systemic exposure to hydromorphone will be further increased in patients with severe hepatic impairment should be taken into account when selecting an initial dosage.239
Renal Impairment
In patients with renal impairment, the initial oral dosage of hydromorphone hydrochloride administered as conventional preparations (immediate-release tablets, oral solution) should be reduced to one-fourth to one-half the usual recommended dosage depending on the degree of impairment; the initial dosage should be reduced in patients with moderate renal impairment (creatinine clearance of 40-60 mL/minute) and even further reduced in those with severe renal impairment (creatinine clearance less than 30 mL/minute).238
Initial dosage of hydromorphone hydrochloride extended-release tablets in patients with moderate renal impairment should be reduced to one-half the usual recommended dosa because the extended-release preparation of the drug is intended only for once-daily administration, the manufacturer recommends that an alternative analgesic regimen with a more flexible dosing interval should be considered in patients with severe renal impairment.246
When hydromorphone hydrochloride injection is used in patients with renal impairment, the manufacturer states that the initial dosage be reduced to one-fourth to one-half the usual recommended dosage depending on the degree of renal impairment.239
Cautions ⬆ ⬇
Hydromorphone shares the toxic potentials of the opiate agonists, and the usual precautions of opiate agonist therapy should be observed. (See Cautions in the Opiate Agonists General Statement 28:08.08.) Mild to severe seizures and myoclonus have been reported in critically ill patients receiving high doses of parenterally administered hydromorphone.
Nausea, vomiting, constipation, and euphoria may be less marked with hydromorphone than with morphine.
Some commercially available preparations of hydromorphone hydrochloride contain sulfites that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.
Some packaging components of some hydromorphone hydrochloride products may contain natural latex proteins in the form of dry natural rubber and/or natural rubber latex (see the manufacturers' labeling). Some individuals may be hypersensitive to natural latex proteins found in a wide range of medical devices, including such packaging components, and the level of sensitivity may vary depending on the form of natural rubber present; rarely hypersensitivity reactions to natural latex proteins have been fatal. Therefore, while the specific risk cannot necessarily be predicted, health-care professionals should take appropriate precautions when administration of such hydromorphone preparations is considered for individuals with a history of natural latex sensitivity.
Because hydromorphone hydrochloride extended-release tablets are nondeformable and do not appreciably change shape in the GI tract, they are contraindicated in patients with GI obstruction or with severe narrowing of the GI tract due to any pathologic or iatrogenic condition (e.g., esophageal motility disorders, small bowel inflammatory disease, short-gut syndrome due to adhesions or decreased transit time, history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, Meckel's diverticulum).246 Obstructive symptoms have been reported in patients with strictures or at risk for strictures (e.g., because of prior GI surgery) who ingested nondeformable extended-release drug formulations.246
Hydromorphone hydrochloride extended-release tablets may be visible on abdominal radiographs under certain circumstances, especially when digital enhancing techniques are utilized.246
Hydromorphone hydrochloride extended-release tablets should only be used in patients who are tolerant to opiate agonists; use of this formulation in patients who are not opiate tolerant may result in fatal respiratory depression.246
Patients receiving hydromorphone should avoid alcohol;700 intake of alcohol with the extended-release tablets may result in increased peak plasma concentrations of hydromorphone and ingestion of a potentially toxic dose of the drug.246
In clinical studies, hydromorphone hydrochloride injection containing 10 mg of the drug per mL was not associated with local tissue irritation or induration at the site of subcutaneous injection but pain and/or burning occurred rarely; mild erythema occurred rarely at the site of IM injection. Because local irritation and induration have been reported with other opiate agonists, the possibility that they could occur with hydromorphone hydrochloride injection should be considered. The highly concentrated (10 mg/mL) injection should be used only in patients who are tolerant to opiate agonists (see Uses); use of this injection in patients who are not tolerant to opiate agonists may result in overdosage and/or death. Extreme caution should be taken to avoid confusing the highly concentrated injection with the less concentrated injections of the drug.
Pediatric Precautions
Safety and efficacy of hydromorphone hydrochloride in children have not been established;238,239,246 however, conventional preparations of hydromorphone have been used in children.245,437,438,439,440
Geriatric Precautions
Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, the manufacturers suggest that patients in this age group receive initial dosages of the drug in the lower end of the usual range. It may be useful to monitor renal function since hydromorphone is substantially excreted by the kidneys and the risk of adverse reactions may be increased in patients with impaired renal function.238
Pregnancy and Lactation
Pregnancy
Safe use of hydromorphone in pregnancy has not been established. Results of animal studies suggest the potential for fetal risk.246 In animal studies, neural tube defects were observed in hamsters, soft tissue and skeletal abnormalities were observed in mice, and reduced postnatal survival of pups, developmental delays, and altered behavioral responses were observed in rats following subcutaneous injection, continuous subcutaneous infusion, or oral administration of hydromorphone hydrochloride in these respective species at dosages of 4.8, 2.3, or 2.1 times, respectively, a human dosage of 32 mg daily.246 No malformations were observed in rats or rabbits at dosages of 2.1 or 17 times, respectively, this human dosage.246
The manufacturers state that hydromorphone hydrochloride should not be used during and immediately prior to labor and delivery.238,239,246
Lactation
Low concentrations of hydromorphone have been detected in human milk.246 The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for hydromorphone and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.238,239 The manufacturer states that women receiving hydromorphone hydrochloride extended-release tablets should not breast-feed infants.246
Drug Interactions ⬆ ⬇
In vitro data suggest that hydromorphone has minimal potential to inhibit the activity of hepatic cytochrome P-450 (CYP) enzymes, including CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 3A4, and 4A11, at clinically relevant concentrations.246
For further information about drug interactions involving opiate agonists (including hydromorphone), see Drug Interactions in the Opiate Agonists General Statement 28:08.08.
Other Information ⬆ ⬇
Pharmacokinetics
Absorption
Hydromorphone hydrochloride is well absorbed following oral, rectal, or parenteral administration. Hydromorphone has a more rapid onset and may have a shorter duration of action than does morphine. The onset of action of hydromorphone with conventional (immediate-release) preparations is usually 15-30 minutes and analgesia is maintained for 4-5 hours, depending on the route of administration.
Hydromorphone undergoes extensive first-pass metabolism following oral administration.238 Bioavailability following oral administration of a single 8-mg conventional tablet of the drug is approximately 24%, and peak plasma concentrations generally are attained within 0.5-1 hour following administration.238 Systemic exposure to hydromorphone is dose proportional over a hydromorphone hydrochloride dose range of 2-8 mg.238 Commercially available conventional tablets and oral solutions of hydromorphone hydrochloride are bioequivalent.238
Following oral administration of hydromorphone hydrochloride as conventional tablets given 4 times daily or as extended-release tablets given once daily at the same total daily dosage, steady-state plasma concentrations of the drug are maintained within the same concentration ran however, the extended-release preparation produces less fluctuation between peak and trough concentrations.246 Following administration of the extended-release tablets, peak plasma concentrations of hydromorphone occur about 12-16 hours after a dose.246 Steady state is reached after 3-4 days of once-daily dosing of the extended-release tablets.246
Administration of hydromorphone hydrochloride extended-release tablets with food does not alter the pharmacokinetics of the drug.246 Oral administration of a single 8-mg dose of hydromorphone hydrochloride (as conventional tablets) with food decreased peak plasma concentrations and increased systemic exposure of the drug by 25 and 35%, respectively, and delayed peak plasma concentrations by 0.8 hour.238
Distribution
At therapeutic plasma concentrations, hydromorphone is approximately 8-19% bound to plasma proteins.238
Elimination
Hydromorphone is metabolized primarily in the liver where it undergoes conjugation with glucuronic acid (more than 95% of an administered dose) and is excreted principally in the urine as the glucuronide conjugate. Minor amounts of 6-hydroxy reduction metabolites also are formed.238 The terminal elimination half-life of hydromorphone is about 2.3 hours following IV administration and 2.6-2.8 hours following oral administration as conventional preparations.238,239 The mean half-life of the extended-release formulation is approximately 11 hours (range: 8-15 hours).246
Following oral administration of a single 4-mg dose of conventional hydromorphone hydrochloride tablets, systemic exposure to the drug was increased twofold in individuals with moderate renal impairment (creatinine clearance of 40-60 mL/minute), threefold to fourfold in individuals with severe renal impairment (creatinine clearance less than 30 mL/minute), and fourfold in individuals with moderate hepatic impairment (Child-Pugh class B).238,239,246 In addition, the elimination half-life of hydromorphone was prolonged (40 hours) in patients with severe renal impairment.238
Pharmacokinetics of hydromorphone are not substantially altered by age or sex.238 In patients receiving hydromorphone hydrochloride extended-release tablets, systemic exposure to the drug was increased by approximately 11% in patients 65-75 years of age compared with those 65 years of age or younger.246 Females receiving conventional preparations of the drug reportedly have 25% higher peak concentrations compared with males, but AUC is comparable.238 Following administration as extended-release tablets, peak concentrations and AUC reportedly are increased by about 10% in females compared with males.246
Chemistry and Stability
Chemistry
Hydromorphone is a semisynthetic phenanthrene-derivative opiate agonist. The drug differs structurally from morphine in the substitution of an oxygen for the 6-hydroxyl group and hydrogenation of the 7-8 double bond of the morphine molecule. Hydromorphone is commercially available as the hydrochloride salt. Hydromorphone hydrochloride occurs as a fine, white or practically white, crystalline powder and is freely soluble in water and sparingly soluble in alcohol. Hydromorphone hydrochloride injection has a pH of 3.5-5.5.239
Stability
Hydromorphone hydrochloride is affected by light; although hydromorphone hydrochloride injection may develop a slight yellowish discoloration, this change apparently does not indicate loss of potency. Hydromorphone hydrochloride injection should be protected from light and stored at a controlled room temperature of 20-25°C, but may be exposed to temperatures ranging from 15-30°C.239 Hydromorphone hydrochloride immediate-release tablets and oral solution should be protected from light and stored at 20-25°C.238 The extended-release tablets should also be stored at 20-25°C.246
Hydromorphone hydrochloride injection reportedly is physically and chemically stable for at least 24 hours in most common IV infusion solutions when protected from light at 25°C. Specialized references should be consulted for specific solution and drug compatibility information.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Preparations ⬆ ⬇
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Hydromorphone hydrochloride preparations are subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drugs.
HYDROmorphone Hydrochloride
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|
Bulk | Powder | | | |
Oral | Solution | 5 mg/5 mL* | Dilaudid® (C-II) | Rhodes |
| | | HYDROmorphone Hydrochloride Solution (C-II) | |
| Tablets | 2 mg* | Dilaudid® (C-II) | Rhodes |
| | | HYDROmorphone Hydrochloride Tablets (C-II) | |
| | 4 mg* | Dilaudid® (C-II) | Rhodes |
| | | HYDROmorphone Hydrochloride Tablets (C-II) | |
| | 8 mg* | Dilaudid® (C-II; scored) | Rhodes |
| | | HYDROmorphone Hydrochloride Tablets (C-II) | |
| Tablets, extended-release | 8 mg* | HYDROmorphone Hydrochloride Extended-release Tablets (C-II) | |
| | 12 mg* | HYDROmorphone Hydrochloride Extended-release Tablets (C-II) | |
| | 16 mg* | HYDROmorphone Hydrochloride Extended-release Tablets (C-II) | |
| | 32 mg* | HYDROmorphone Hydrochloride Extended-release Tablets (C-II) | |
Parenteral | Injection | 0.2 mg/mL | Dilaudid® (C-II) | Fresenius Kabi |
| | 1 mg/mL* | Dilaudid® (C-II) | Fresenius Kabi |
| | | HYDROmorphone Hydrochloride Injection (C-II) | |
| | 2 mg/mL* | Dilaudid® (C-II) | Fresenius Kabi |
| | | HYDROmorphone Hydrochloride Injection (C-II) | |
| | 4 mg/mL* | HYDROmorphone Hydrochloride Injection (C-II) | |
| | 10 mg/mL (10, 50, or 500 mg)* | HYDROmorphone Hydrochloride High-Potency Formulation Injection (C-II) | |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Copyright ⬆ ⬇
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
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