Hydromorphone Hydrochloride

Class: Opiate Agonists
VA Class: CN101
CAS Number: 71-68-1
Brands: Dilaudid, Dilaudid-HP

Introduction

Opiate agonist; semisynthetic phenanthrene derivative.^a

Uses for Hydromorphone Hydrochloride

Acute Pain

A strong analgesic used in the relief of moderate to severe pain.^{a f}

Usually, temporary relief of moderate to severe pain such as that associated with acute and some chronic medical disorders including renal or biliary colic, acute trauma, postoperative pain, and cancer.^f

Used to provide analgesia during diagnostic and orthopedic procedures.^f

Highly concentrated 10-mg/mL injection is used for relief of moderate to severe pain in opiate-tolerant patients requiring large doses for adequate pain relief; smaller volume may be injected IM or sub-Q, and discomfort of larger volumes avoided.^e

IV route (including patient-controlled administration) is preferred for administration of opiate agonists after major surgery since repeated IM injections may cause pain and trauma.^f

Consider around-the-clock dosing of analgesics in the initial stages of acute pain to avoid wide swings in pain and sedation often associated with as-needed dosing regimens.^f

Chronic Pain

For relief of malignant (cancer) pain and chronic nonmalignant pain.^f

In the management of severe, chronic pain associated with a terminal illness such as cancer, the principal goal of analgesic therapy is to make the patient relatively pain-free while maintaining as good a quality of life as possible.^f

Analgesic therapy must be individualized and titrated according to patient response and tolerance.^f

Although consideration of the dependence potential of opiate agonists has often limited their effective use by many clinicians in terminally ill patients with severe, chronic pain, such consideration is irrelevant in the context of terminal illness.^f

As tolerance to initial dosage develops, larger doses may be given as necessary.^f

Alternative analgesic adjuncts such as tricyclic antidepressants or anticonvulsants also should be considered in the treatment of chronic nonmalignant pain (e.g., neurogenic pain).^f

During prolonged use, especially when opiate agonists are self-administered, precautions should be taken to prevent unnecessary increases in dosage.^f

Hydromorphone Hydrochloride Dosage and Administration

Administration

Administer orally or by sub-Q, IM, or slow IV injection or infusion.^{a b c d e} May be administered rectally as suppositories (no longer commercially available in US).^d

Oral Administration

Use highly potent 8-mg tablets only after careful evaluation of the clinical situation.^{a c}

IV Administration

For solution and drug compatibility, see Compatibility under Stability.

Administer by direct IV injection or IV infusion.^a Also administered IV via a controlled-delivery device for patient-controlled analgesia (PCA).ⁱ

Reconstitution

Add 25 mL of sterile water for injection to lyophilized powder in the 250-mg vial to provide 10-mg/mL solution.^{a e}

Dilution

For IV infusion, use 10-mg/mL injection (from the 50-mg ampul, 500-mg single-use vial, or 250-mg vial) for preparation of IV infusion solutions.^e

If the 500-mg single-use (10-mg/mL) vial is used, remove container seal and rubber stopper in a laminar flow hood or equivalent clean air compounding area; do not penetrate with a syringe.^e

Withdraw appropriate amount and then discard any unused portion in an appropriate manner.^e

Rate of Administration

If rapid onset and shorter duration of analgesia are required, may give IV at slow rate (over at least 2–3 minutes), with special attention to the possibility of respiratory depression and hypotension.^a

Experience with IV administration of the highly concentrated 10-mg/mL injection is limited; if administered IV, inject slowly over at least 2–3 minutes.^a

IV injection for PCA: self-administered intermittently as needed (“prn”) via controlled-delivery device, with usual lockout intervals (minimum time between self-administered doses programmed into device) of 6–12 minutes.ⁱ

IM Administration

IM injection is discouraged for any analgesic (e.g., the injection itself is painful, delayed onset).ⁱ

Use 10-mg/mL injection only in patients tolerant to and receiving high dosages of opiates; do not use when low doses are required.^a

Use 10-mg/mL injection only when required volume can be accurately measured.^{a e}

Sub-Q Administration

Use 10-mg/mL injection only in patients tolerant to and receiving high dosages of opiate agonists; do not use when low doses are required.^a

Use 10-mg/mL injection only when required volume can be accurately measured.^a

Inject 10-mg/mL injection sub-Q with a short 30-gauge needle to minimize local adverse reactions.^{a e}

Dosage

Available as hydromorphone hydrochloride; dosage expressed in terms of the salt.^{b c d e}

Give the smallest effective dose as infrequently as possible to minimize the development of tolerance and physical dependence.^a

Reduce dosage in poor-risk patients, in pediatric or geriatric patients, and in patients receiving other CNS depressants.^a

In patients who are tolerant to opiate agonists and who require high dosages (e.g., patients with severe chronic pain associated with cancer), individualize dosage of highly potent preparations based on response and tolerance.^a

Avoid abrupt withdrawal from relatively high dosages (e.g., in chronic pain patients) since precipitation of severe abstinence syndrome is likely.^{a c d e}

Pediatric Patients

Pain†

Oral

Children 6–12 years of age: 0.03–0.08 mg/kg every 4–6 hours as needed.^h

Children >12 years of age: 1–4 mg every 4–6 hours as needed.^h

IV, IM, or Sub-Q

Children 6–12 years of age: 0.015 mg/kg every 4–6 hours as needed.^h

Children >12 years of age: 1–4 mg every 4–6 hours as needed.^h

Adults

Pain

Oral

Usually, 2 mg every 4–6 hours as necessary.^a

For severe pain, 4 mg (or more) every 3–6 hours as indicated and tolerated.^a

IV or IM

1–2 mg every 3–6 hours as necessary.^{a m}

For severe pain, 3–4 mg every 4–6 hours may be given.^a

Pain associated with terminal cancer: individual doses of 1–14 mg.^a

Sub-Q

1–2 mg every 4–6 hours as necessary.^{a m}

For severe pain, 3–4 mg every 4–6 hours.^a

Pain associated with terminal cancer: individual doses of 1–14 mg; occasionally, individual 30-mg doses (60 mg total) in opiate-tolerant patients.^a

Special Populations

Geriatric and Debilitated Patients

Select dosage with caution, and use lower than usual initial dosages.^{a d}

Cautions for Hydromorphone Hydrochloride

Contraindications

• Known hypersensitivity to hydromorphone or any ingredient in the formulation.^{b c d e}

• Respiratory depression in the absence of resuscitative equipment.^{b c d e}

• Acute or severe asthma.^{c d e}

• Obstetrical analgesia.^{c d e}

• 10-mg/mL injection is contraindicated in patients not already receiving large doses of parenteral opiate agonists.^e

Warnings/Precautions

Warnings

Shares the toxic potentials of the opiate agonists; observe the usual precautions of opiate agonist therapy.^a

Dependence and Abuse

Physical and psychic dependence and tolerance may develop with repeated administration, and abuse potential exists; use with caution.^{a b c d e}

Abrupt cessation of therapy or sudden reduction in dosage after prolonged use may result in withdrawal symptoms.^{b c d e} After prolonged exposure to opiate analgesics, if withdrawal is necessary, it must be undertaken gradually.^{b c d e}

Increased risk of tolerance, dependence, or addiction in patients with alcoholism or other drug dependency.^{c d e} Use with caution.^{c d e}

Hydromorphone abuse in combination with other CNS depressants may result in serious risk. (See Specific Drugs under Interactions.)^{c d e}

Use of Highly Concentrated Injection

Use 10-mg/mL injection only in patients who are tolerant to opiate agonists; overdosage and/or death may result if confused with less concentrated formulations and used in patients who are not tolerant to opiate agonists.^{a e}

Use extreme caution to avoid confusing the highly concentrated injection with the less concentrated injections.^a

Respiratory Depression

Causes dose-related respiratory depression; also affects respiratory rhythm and may cause irregular and periodic breathing.^b

The major toxicity associated with hydromorphone.^{c d e}

Occurs most frequently in geriatric or debilitated patients, and in those with conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic opiate dosages may dangerously decrease pulmonary ventilation.^{c d e}

Use with extreme caution in patients with COPD or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression.^{c d e} In such patients, even therapeutic hydromorphone doses may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.^{c d e}

Head Injury and Increased Intracranial Pressure

Respiratory depressant effects and ability of opiates to increase CSF pressure may be markedly exaggerated in patients with head injury, other intracranial lesions, or preexisting elevation in intracranial pressure; opiate effects may produce cerebral hypoxia and obscure clinical course of patients with head injuries.^{b c d e} Use with extreme caution, if at all.^f

Hypotension

Possible severe hypotension in individuals whose ability to maintain their BP is compromised by depleted blood volume or concomitant drugs that compromise vascular tone (e.g., phenothiazines, general anesthetics).^{c d e} (See Specific Drugs under Interactions.)

May produce orthostatic hypotension in ambulatory patients.^{c d e}

Use with caution in patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and BP.^{c d e}

Acute Abdominal Conditions

May obscure diagnosis or clinical course of patients with acute abdominal conditions.^{b c d e}

Sensitivity Reactions

Sulfite Sensitivity

Some formulations contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.^{a c d e}

Latex Sensitivity

Packaging components for some formulations (e.g., 2-mg/mL 40-mg vial, 10-mg/mL 500-mg vial) contain natural latex proteins in the form of dry natural rubber and/or natural rubber latex; take appropriate precautions for patients with a history of natural latex sensitivity.^{a d e}

General Precautions

Cough Reflex

Suppresses cough reflex; use with caution postoperatively and in pulmonary disease.^{b d}

CNS Effects

May impair mental alertness or physical coordination; warn patient to use caution when driving or operating machinery.^{b c d}

Concomitant use of another CNS depressant may have additive effects; decrease dosage of one or both drugs.^{b c d e} (See Specific Drugs under Interactions.)

Seizures

May aggravate preexisting seizures in patients with seizure disorders.^{c d e}

Mild to severe seizures and myoclonus have been reported in critically ill patients receiving high parenteral doses of hydromorphone.^{a c d e}

Debilitated and Special-risk Patients

Use with caution in debilitated patients, patients with myxedema or hypothyroidism, Addison’s disease, prostatic hypertrophy, urethral stricture, gall bladder disease, CNS depression or coma, toxic psychosis, acute alcoholism, delirium tremens, kyphoscoliosis, or following GI surgery.^{b c d e}

Biliary Surgery

Use with caution immediately before biliary tract surgery; may cause sphincter of Oddi spasm.^{c d e}

Use of Concentrated Injection

Consider possibility of local irritation and induration with IM or sub-Q use of 10-mg/mL injection.^a

Specific Populations

Pregnancy

Category C.^{b c d e}

Administration during labor may cause neonatal respiratory depression, especially with high doses.^{a c} Use for obstetrical analgesia is contraindicated.^{c d e}

Infants born to women regularly taking opiates during pregnancy will be physically dependent; intensity of withdrawal syndrome does not always correlate with maternal opiate dosage or duration of use.^{b c d e} Irritability, excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever are signs of neonatal withdrawal.^{b c d e}

Lactation

Distributed into milk in low concentrations.^c Women receiving hydromorphone generally should not nurse.^{c d e}

Pediatric Use

Safety and efficacy not established in children;^{c d e} however, hydromorphone has been used in children.^{b h} (See Pediatric Patients under Dosage and Administration.)

Geriatric Use

Use with caution.^{b c d e}

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution, and use lower than usual initial dosages.^{a c d e}

Hepatic Impairment

Use with caution.^{b c d e}

Renal Impairment

Use with caution.^{b c d e}

Common Adverse Effects

Light-headedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, pruritus.^{c e}

Interactions for Hydromorphone Hydrochloride

Not known whether hydromorphone is metabolized by CYP isoenzymes.^j

Hydromorphone is a poor inhibitor of CYP isoenzymes 1A2, 2A6, 2C8, 2D6, and 3A4.^j

Specific Drugs

Drug	Interaction	Comments
Amphetamine	Dextroamphetamine may enhance opiate agonist analgesiaf
Antidepressants, MAO inhibitors and tricyclics	Potentiation of the effects of the antidepressantf	Use concomitantly with caution; dosage adjustment may be necessaryf
CNS depressants (e.g., other opiate agonists, general anesthetics, tranquilizers, sedatives and hypnotics, alcohol)	Additive CNS effectsc d e f	Reduce dosage of one or both agentsc d e f Avoid use of alcoholc d
Diuretics	Opiate agonists may decrease effects of diuretics used in CHFf
Opiate partial agonists (butorphanol, nalbuphine, pentazocine)	Possible reduced analgesic effect and/or withdrawal symptomsf	Caution advisedf
Phenothiazines	Some tranquilizers, especially phenothiazines, may antagonize opiate agonist analgesiaf Possible severe hypotensionc d e
Skeletal muscle relaxants	May enhance the neuromuscular blocking action of skeletal muscle relaxantsc d e f

Hydromorphone Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral, rectal, or parenteral administration.^a

Onset

Usually 15–30 minutes; more rapid than morphine.^{a d}

Duration

Maintained for 4–5 hours, depending on the route; may have shorter duration of action than morphine.^e

Food

Effects of food have not been studied.^c

Distribution

Extent

Crosses the placenta.^{c e}

Plasma Protein Binding

8–19%.^c

Elimination

Metabolism

Principally in the liver via glucuronic acid conjugation to hydromorphone-3-glucuronide (95%); minor amounts of 6-hydroxy reduction metabolites.^{a c}

Elimination Route

Excreted principally in the urine as hydromorphone-3-glucuronide.^{a c}

Half-life

Approximately 2.3–2.6 hours.^{c d e}

Stability

Storage

Oral

Tablets

Tight, light-resistant container, usually at 25°C (may be exposed to 15–30°C).^{c d}

One manufacturer of 4-mg tablets states to store in tight, light-resistant container at 20–25°C.^b

Solution

Tight, light-resistant container at 25°C (may be exposed to 15–30°C).^c

Parenteral

Affected by light and injection may develop a slight yellowish discoloration; this change apparently does not indicate loss of potency.^{a d e}

Powder for Injection, for IV Infusion

25° C (may be exposed to 15–30° C).^e Protect from light.^e

Injection

25° C (may be exposed to 15–30° C).^{d e} Protect from light.^{d e} Do not freeze.^a

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Injection reported physically and chemically stable for at least 24 hours in most common IV infusion solutions when protected from light at 25°C.^a

Solution Compatibility^HID

Compatible
Amino acids 7, 8, or 8.5%
Amino acids 8.5% with electrolytes
Amino acids, essential, 5.4%
Dextrose 5% in Ringer’s injection
Dextrose 5% in Ringer’s injection, lactated
Dextrose 5% in water
Dextrose 5% in sodium chloride 0.45 or 0.9%
Fructose 10% in water
Ringer’s injection
Ringer’s injection, lactated
Sodium chloride 0.45 or 0.9%
Sodium lactate (1/6) M

Drug Compatibility

Admixture CompatibilityHID

Compatible
Bupivacaine HCl
Clonidine HCI
Fluorouracil
Heparin sodium
Midazolam HCl
Ondansetron HCl
Potassium chloride
Promethazine HCl
Verapamil HCl
Incompatible
Sodium bicarbonate
Thiopental sodium

Y-Site CompatibilityHID

Compatible
Acyclovir sodium
Allopurinol sodium
Amifostine
Amikacin sulfate
Amsacrine
Atropine sulfate
Aztreonam
Bivalirudin
Cefepime HCl
Cefotaxime sodium
Cefoxitin sodium
Ceftazidime
Ceftizoxime sodium
Cefuroxime sodium
Chloramphenicol sodium succinate
Cisplatin
Cladribine
Clindamycin phosphate
Co-trimoxazole
Cyclophosphamide
Cytarabine
Dexamethasone sodium phosphate
Dexmedetomidine HCl
Diltiazem HCl
Diphenhydramine HCl
Dobutamine HCl
Docetaxel
Dopamine HCl
Doxorubicin HCl
Doxorubicin HCl liposome injection
Doxycycline hyclate
Epinephrine HCl
Erythromycin lactobionate
Etoposide phosphate
Famotidine
Fenoldopam mesylate
Fentanyl citrate
Filgrastim
Fludarabine phosphate
Foscarnet sodium
Furosemide
Gemcitabine HCl
Gentamicin sulfate
Granisetron HCl
Haloperidol lactate
Heparin sodium
Hetastarch in lactated electrolyte injection (Hextend)
Hydroxyzine HCl
Kanamycin sulfate
Ketorolac tromethamine
Labetalol HCl
Linezolid
Lorazepam
Magnesium sulfate
Melphalan HCl
Methotrexate sodium
Metoclopramide HCI
Metronidazole
Midazolam HCl
Milrinone lactate
Morphine sulfate
Nafcillin sodium
Nicardipine HCl
Nitroglycerin
Norepinephrine bitartrate
Ondansetron HCl
Oxacillin sodium
Oxaliplatin
Paclitaxel
Pemetrexed disodium
Penicillin G potassium
Piperacillin sodium–tazobactam sodium
Propofol
Ranitidine HCl
Remifentanil HCl
Scopolamine HBr
Tacrolimus
Teniposide
Thiotepa
Tobramycin sulfate
Vancomycin HCl
Vecuronium bromide
Vinorelbine tartrate
Incompatible
Amphotericin B cholesteryl sulfate complex
Gallium nitrate
Lansoprazole
Phenytoin sodium
Sargramostim
Thiopental sodium
Variable
Ampicillin sodium
Cefazolin sodium
Diazepam
Phenobarbital sodium

Actions

• A potent analgesic; shares actions of the opiate agonists.^{a c e}

• Opiate agonists alter perception of and emotional response to pain.^f

• Precise mechanism of action has not been fully elucidated; opiate agonists act at several CNS sites, involving several neurotransmitter systems to produce analgesia.^{c e f}

• Pain perception is altered in the spinal cord and higher CNS levels (e.g., substantia gelatinosa, spinal trigeminal nucleus, periaqueductal gray, periventricular gray, medullary raphe nuclei, hypothalamus).^f

• Opiate agonists do not alter the threshold or responsiveness of afferent nerve endings to noxious stimuli, nor peripheral nerve impulse conduction.^f

• Opiate agonists act at specific receptor binding sites in the CNS and other tissues; opiate receptors are concentrated in the limbic system, thalamus, striatum, hypothalamus, midbrain, and spinal cord.^f

• Agonist activity at the opiate μ- or κ-receptor can result in analgesia, miosis, and/or decreased body temperature.^f

• Agonist activity at the μ-receptor can also result in suppression of opiate withdrawal (and antagonist activity can result in precipitation of withdrawal).^f

• Respiratory depression may be mediated by μ-receptors, possibly μ₂-receptors (which may be distinct from μ₁-receptors involved in analgesia); κ- and δ-receptors may also be involved in respiratory depression.^f

• May depress the cough reflex by a direct effect on the cough centers in the medulla; cough-suppressant opiate receptors have also been suggested.^f

• Nausea, vomiting, constipation, and euphoria may be less marked with hydromorphone than with morphine.^f

Advice to Patients

• Potential for drug to impair mental alertness or physical coordination; use caution when driving or operating machinery until effects on individual are known.^{b c d e f}

• Importance of informing patients that hydromorphone should not be combined with alcohol or other CNS depressants (e.g., sleep medications, tranquilizers).^{c d e}

• Importance of informing patients that this is a drug of potential abuse and should also be protected from theft.^{c d e}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^{c d e f}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{a c d e}

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drugs.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Hydromorphone Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Bulk	Powder*		Hydromorphone Hydrochloride Powder for Prescription Compounding (C-II)
Oral	Solution	5 mg/5 mL	Dilaudid (C-II)	Purdue Pharma
			Hydromorphone Hydrochloride Solution (C-II)
	Tablets	2 mg*	Dilaudid (C-II)	Purdue Pharma
			Hydromorphone Hydrochloride Tablets (C-II)
		4 mg*	Dilaudid (C-II)	Purdue Pharma
			Hydromorphone Hydrochloride Tablets (C-II)
		8 mg*	Dilaudid (C-II; scored)	Purdue Pharma
			Hydromorphone Hydrochloride Tablets (C-II)
Parenteral	For injection, for preparation of IV infusion	250 mg	Dilaudid-HP Lyophilized (C-II)	Purdue Pharma
	Injection	1 mg/mL*	Dilaudid (C-II)	Purdue Pharma
			Hydromorphone Hydrochloride Injection (C-II)
		2 mg/mL*	Dilaudid (C-II)	Purdue Pharma
			Hydromorphone Hydrochloride Injection (C-II)
		4 mg/mL*	Dilaudid (C-II)	Purdue Pharma
			Hydromorphone Hydrochloride Injection (C-II)
		10 mg/mL*	Dilaudid-HP (C-II)	Purdue Pharma
			Hydromorphone Hydrochloride Injection (C-II)
	Injection, for preparation of IV infusion	10 mg/mL (50 or 500 mg)*	Dilaudid-HP (C-II)	Purdue Pharma
			Hydromorphone Hydrochloride Injection (C-II)

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Dilaudid 2MG Tablets (PURDUE PHARMA L.P.): 20/$23.99 or 30/$35.99

Dilaudid 4MG Tablets (PURDUE PHARMA L.P.): 20/$35.99 or 30/$47.97

Dilaudid 8MG Tablets (PURDUE PHARMA L.P.): 20/$53.99 or 30/$80.99

Dilaudid-5 1MG/ML Liquid (PURDUE PHARMA L.P.): 473/$180.00 or 1419/$539.99

HYDROmorphone HCl 2MG Tablets (MALLINCKRODT PHARM): 20/$15.33 or 30/$22.99

HYDROmorphone HCl 4MG/ML Solution (HOSPIRA): 20/$42.99 or 30/$64.97

HYDROmorphone HCl 4MG Tablets (ROXANE): 20/$16.01 or 30/$24.01

HYDROmorphone HCl 8MG Tablets (MALLINCKRODT PHARM): 20/$29.51 or 30/$44.27