Hydromorphone hydrochloride, a hydrogenated ketone of morphine, is an opioid analgesic. Hydromorphone hydrochloride tablets USP are indicated for the management of pain in patients where an opioid analgesic is appropriate.
Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy.
The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
In general, opioids used regularly should not be abruptly discontinued.
Patients receiving hydromorphone hydrochloride tablets or their caregivers should be given the following information by the physician, nurse, or pharmacist:
- Patients should be aware that hydromorphone hydrochloride tablets contain hydromorphone, which is a morphine-like substance and which could cause severe adverse effects including respiratory depression and even death if not taken according to the prescriber’s directions.
- Patients should be advised to report pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication.
- Patients should be advised not to adjust the dose of hydromorphone hydrochloride tablets without consulting the prescribing professional.
- Patients should be advised that hydromorphone hydrochloride tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).
- Patients should not combine hydromorphone hydrochloride tablets with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because dangerous additive effects may occur, resulting in serious injury or death.
- Women of childbearing potential who become, or are planning to become pregnant should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child.
- Patients should be advised that hydromorphone hydrochloride tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.
- Patients should be advised that if they have been receiving treatment with hydromorphone hydrochloride tablets for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the hydromorphone hydrochloride tablets dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication.
- Patients should be instructed to keep hydromorphone hydrochloride tablets in a secure place out of the reach of children. When hydromorphone hydrochloride tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet.
Drug Interactions with Other CNS Depressants – The concomitant use of other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers and alcohol may produce additive depressant effects. Respiratory depression, hypotension and profound sedation or coma may occur. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Hydromorphone hydrochloride tablets should not be taken with alcohol. Opioid analgesics, including hydromorphone hydrochloride tablets, may enhance the action of neuromuscular blocking agents and produce an excessive degree of respiratory depression.
Analgesics – Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as hydromorphone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of hydromorphone and/or may precipitate withdrawal symptoms in these patients.
No carcinogenicity studies have been conducted in animals.
Hydromorphone was not mutagenic in the in vitro Ames reverse mutation assay or the human lymphocyte chromosome aberration assay. Hydromorphone was not clastogenic in the in vivo mouse micronucleus assay.
No effects on fertility, reproductive performance, or reproductive organ morphology were observed in male or female rats given oral doses up to 7 mg/kg/day, which is equivalent to the human dose of 2.5 to 10 mg every 3 to 6 hours for oral liquid, and 3-fold higher than the human dose of 2 to 4 mg every 4 to 6 hours for the tablet on a body surface area basis.
Teratogenic Effects. Pregnancy Category C – No effects on teratogenicity or embryotoxicity were observed in female rats given oral doses up to 7 mg/kg/day, which is approximately equivalent to the human dose of 2.5 to 10 mg every 3 to 6 hours for oral liquid, and 3-fold higher than the human dose of 2 to 4 mg every 4 to 6 hours for the tablet on a body surface area basis. Hydromorphone produced skull malformations (exencephaly and cranioschisis) in Syrian hamsters given oral doses up to 20 mg/kg during the peak of organogenesis (gestation days 8 to 9). The skull malformations were observed at doses approximately 2-fold higher than the human dose of 2.5 to 10 mg every 3 to 6 hours for oral liquid, and 7-fold higher than the human dose of 2 to 4 mg every 4 to 6 hours for the tablet on a body surface area basis. There are no adequate and well-controlled studies of hydromorphone hydrochloride tablets in pregnant women.
Hydromorphone crosses the placenta, resulting in fetal exposure. Hydromorphone hydrochloride tablets should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus (see Labor and Delivery and DRUG ABUSE AND DEPENDENCE).
Nonteratogenic Effects – Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal. Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital.
Labor and Delivery – Hydromorphone hydrochloride tablets are contraindicated in Labor and Delivery (see CONTRAINDICATIONS).
Nursing Mothers – Low levels of opioid analgesics have been detected in human milk. As a general rule, nursing should not be undertaken while a patient is receiving hydromorphone hydrochloride tablets since it, and other drugs in this class, may be excreted in the milk.
Pediatric Use – Safety and effectiveness in children have not been established.
Geriatric Use – Clinical studies of hydromorphone hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see Individualization of Dosage and PRECAUTIONS).
The major hazards of hydromorphone hydrochloride tablets include respiratory depression and apnea. To a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest have occurred.
The most frequently observed adverse effects are light-headedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. These effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain.
General and CNS – Weakness, headache, agitation, tremor, uncoordinated muscle movements, alterations of mood (nervousness, apprehension, depression, floating feelings, dreams), muscle rigidity, paresthesia, muscle tremor, blurred vision, nystagmus, diplopia and miosis, transient hallucinations and disorientation, visual disturbances, insomnia, increased intracranial pressure
Cardiovascular – Flushing of the face, chills, tachycardia, bradycardia, palpitation, faintness, syncope, hypotension, hypertension
Respiratory – Bronchospasm and laryngospasm
Gastrointestinal – Constipation, biliary tract spasm, ileus, anorexia, diarrhea, cramps, taste alteration
Genitourinary – Urinary retention or hesitancy, antidiuretic effects
Dermatologic – Urticaria, other skin rashes, diaphoresis.
Serious overdosage with hydromorphone hydrochloride tablets is characterized by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia and hypotension. In serious overdosage, particularly following intravenous injection, apnea, circulatory collapse, cardiac arrest and death may occur.
In the treatment of overdosage, primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. A potentially serious oral ingestion, if recent, should be managed with gut decontamination. In unconscious patients with a secure airway, instill activated charcoal (30 to 100 g in adults, 1 to 2 g/kg in infants) via a nasogastric tube. A saline cathartic or sorbitol may be added to the first dose of activated charcoal.
Supportive measures (including oxygen, vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
The opioid antagonist, naloxone, is a specific antidote against respiratory depression which may result from overdosage, or unusual sensitivity to hydromorphone hydrochloride tablets. Therefore, an appropriate dose of this antagonist should be administered, preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression. Naloxone should be administered cautiously to persons who are known, or suspected to be physically dependent on hydromorphone hydrochloride tablets. In such cases, an abrupt or complete reversal of narcotic effects may precipitate an acute withdrawal syndrome. Since the duration of action of hydromorphone hydrochloride tablets may exceed that of the antagonist, the patient should be kept under continued surveillance; repeated doses of the antagonist may be required to maintain adequate respiration. Apply other supportive measures when indicated.
The usual starting dose for hydromorphone hydrochloride tablets USP is 2 mg to 4 mg, orally, every 4 to 6 hours. Appropriate use of hydromorphone hydrochloride tablets USP, 8 mg must be decided by careful evaluation of each clinical situation.
A gradual increase in dose may be required if analgesia is inadequate, as tolerance develops, or if pain severity increases. The first sign of tolerance is usually a reduced duration of effect.
Patients with hepatic and renal impairment should be started on a lower starting dose (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).
The dosage of opioid analgesics like hydromorphone hydrochloride should be individualized for any given patient, since adverse events can occur at doses that may not provide complete freedom from pain.
Safe and effective administration of opioid analgesics to patients with acute or chronic pain depends upon a comprehensive assessment of the patient. The nature of the pain (severity, frequency, etiology, and pathophysiology) as well as the concurrent medical status of the patient will affect selection of the starting dosage.
In non-opioid-tolerant patients, therapy with hydromorphone is typically initiated at an oral dose of 2 to 4 mg every four hours, but elderly patients may require lower doses (see PRECAUTIONS, Geriatric Use).
In patients receiving opioids, both the dose and duration of analgesia will vary substantially depending on the patient’s opioid tolerance. The dose should be selected and adjusted so that at least 3 to 4 hours of pain relief may be achieved. In patients taking opioid analgesics, the starting dose of hydromorphone hydrochloride should be based on prior opioid usage. This should be done by converting the total daily usage of the previous opioid to an equivalent total daily dosage of oral hydromorphone hydrochloride using an equianalgesic table (see below). For opioids not in the table, first estimate the equivalent total daily usage of oral morphine, then use the table to find the equivalent total daily dosage of hydromorphone hydrochloride.
Once the total daily dosage of hydromorphone hydrochloride has been estimated, it should be divided into the desired number of doses. Since there is individual variation in response to different opioid drugs, only 1/2 to 2/3 of the estimated dose of hydromorphone hydrochloride calculated from equivalence tables should be given for the first few doses, then increased as needed according to the patient’s response.
Since the pharmacokinetics of hydromorphone are affected in hepatic and renal impairment with a consequent increase in exposure, patients with hepatic and renal impairment should be started on a lower starting dose (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).
In chronic pain, doses should be administered around-the-clock. A supplemental dose of 5 to 15% of the total daily usage may be administered every two hours on an “as-needed” basis.
Periodic reassessment after the initial dosing is always required. If pain management is not satisfactory and in the absence of significant opioid-induced adverse events, the hydromorphone dose may be increased gradually. If excessive opioid side effects are observed early in the dosing interval, the hydromorphone dose should be reduced. If this results in breakthrough pain at the end of the dosing interval, the dosing interval may need to be shortened. Dose titration should be guided more by the need for analgesia than the absolute dose of opioid employed.
DILAUDID is a registered trademark of Abbott Laboratories.
Numorphan is a registered trademark of Endo Pharmaceuticals Inc.
Levo-Dromoran is a trademark of Valeant Pharmaceuticals International.
Demerol is a registered trademark of Sanofi Pharmaceuticals Inc.
Dolophine is a registered trademark of Roxane Laboratories Inc.
* Dosages, and ranges of dosages represented, are a compilation of estimated equipotent dosages from published references comparing opioid analgesics in cancer and severe pain.
| Nonproprietary |
| IM or SC |
| ORAL |
|Morphine sulfate||10 mg||40 to 60 mg|
|Hydromorphone HCl |
|1.3 to 2 mg||6.5 to 7.5 mg|
|Oxymorphone HCl |
|1 to 1.1 mg||6.6 mg|
|Levorphanol tartrate |
|2 to 2.3 mg||4 mg|
|75 to 100 mg||300 to 400 mg|
|Methadone HCl |
|10 mg||10 to 20 mg|