Central Nervous System

The precise mode of analgesic action of opioid analgesics is unknown. However, specific CNS opiate receptors have been identified. Opioids are believed to express their pharmacological effects by combining with these receptors.

Hydromorphone depresses the cough reflex by direct effect on the cough center in the medulla.

Hydromorphone produces respiratory depression by direct effect on brain stem respiratory centers. The mechanism of respiratory depression also involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension.

Hydromorphone causes miosis. Pinpoint pupils are a common sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of DILAUDID overdose.

Gastrointestinal Tract and Other Smooth Muscle

Gastric, biliary and pancreatic secretions are decreased by opioids such as hydromorphone. Hydromorphone causes a reduction in motility associated with an increase in tone in the gastric antrum and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, and tone may be increased to the point of spasm. The end result is constipation. Hydromorphone can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi.

Cardiovascular System

Hydromorphone may produce hypotension as a result of either peripheral vasodilation, release of histamine, or both. Other manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, and red eyes.

Effects on the myocardium after intravenous administration of opioids are not significant in normal persons, vary with different opioid analgesic agents and vary with the hemodynamic state of the patient, state of hydration and sympathetic drive.

Pharmacokinetics and Metabolism

Respiratory Depression

Respiratory depression is the chief hazard of DILAUDID-HP. Respiratory depression occurs most frequently in overdose situations, in the elderly, in the debilitated, and in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation.

DILAUDID-HP should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression. In such patients even usual therapeutic doses of opioid analgesics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.

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

Misuse, Abuse, and Diversion of Opioids

Hydromorphone is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

DILAUDID-HP can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing DILAUDID in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Prescribers should monitor all patients receiving opioids for signs of abuse, misuse, and addiction. Furthermore, patients should be assessed for their potential for opioid abuse prior to being prescribed opioid therapy. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse) or mental illness (e.g., depression). Opioids may still be appropriate for use in these patients, however, they will require intensive monitoring for signs of abuse.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain.

Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Interactions with Alcohol and Drugs of Abuse

Hydromorphone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

Neonatal Withdrawal Syndrome

Infants born to mothers physically dependent on DILAUDID-HP will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms. (see DRUG ABUSE AND DEPENDENCE).

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of DILAUDID-HP with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or preexisting increase in intracranial pressure. Opioid analgesics including DILAUDID-HP may produce effects on pupillary response and consciousness which can obscure the clinical course and neurologic signs of further increase in pressure in patients with head injuries.

Hypotensive Effect

Opioid analgesics, including DILAUDID-HP, may cause severe hypotension in an individual whose ability to maintain his blood pressure has already been compromised by a depleted blood volume, or a concurrent administration of drugs such as phenothiazines or general anesthetics (see PRECAUTIONS - Drug Interactions). DILAUDID-HP may produce orthostatic hypotension in ambulatory patients.

DILAUDID-HP should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Sulfites

Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

General

Because of its high concentration, the delivery of precise doses of DILAUDID-HP may be difficult if low doses of hydromorphone are required. Therefore, DILAUDID-HP should be used only if the amount of hydromorphone required can be delivered accurately with this formulation.

Special Risk Patients

DILAUDID-HP should be given with caution and the initial dose should be reduced in the elderly or debilitated and those with severe impairment of hepatic, pulmonary or renal function; myxedema or hypothyroidism; adrenocortical insufficiency (e.g., Addison's Disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; gall bladder disease; acute alcoholism; delirium tremens; or kyphoscoliosis, or following gastrointestinal surgery.

In the case of DILAUDID-HP, however, the patient is presumed to be receiving an opioid to which he or she exhibits tolerance and the initial dose of DILAUDID-HP selected should be estimated based on the relative potency of hydromorphone and the opioid previously used by the patient. (see DOSAGE AND ADMINISTRATION).

The administration of opioid analgesics including DILAUDID-HP may obscure the diagnosis or clinical course in patients with acute abdominal conditions and may aggravate preexisting convulsions in patients with convulsive disorders.

Reports of mild to severe seizures and myoclonus have been reported in severely compromised patients, administered high doses of parenteral hydromorphone, for cancer and severe pain. Opioid administration at very high doses is associated with seizures and myoclonus in a variety of diseases where pain control is the primary focus.

Use in Drug and Alcohol Dependent Patients

DILAUDID-HP should be used with caution in patients with alcoholism and other drug dependencies due to the increased frequency of opioid tolerance, dependence, and the risk of addiction observed in these patient populations. Abuse of DILAUDID-HP in combination with other CNS depressant drugs can result in serious risk to the patient.

Hydromorphone is an opioid with no approved use in the management of addictive disorders.

Use in Ambulatory Patients

DILAUDID-HP may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g. driving, operating machinery). Patients should be cautioned accordingly. DILAUDID may produce orthostatic hypotension in ambulatory patients.

Use in Biliary Tract Disease

Opioid analgesics, including DILAUDID-HP, should also be used with caution in patients about to undergo surgery of the biliary tract since it may cause spasm of the sphincter of Oddi.

Tolerance and Physical Dependence

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.

Drug Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been conducted in animals.

Hydromorphone was not mutagenic in the in vitro Ames reverse mutation assay, or the human lymphocytes 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 and 3-fold higher than the human dose of DILAUDID-HP when substituted for ORAL LIQUID or 8 mg TABLET, respectively, on a body surface area basis.

PREGNANCY

Labor and Delivery

DILAUDID-HP is 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 DILAUDID-HP since it, and other drugs in this class, may be excreted in the milk.

Pediatric Use

Safety and effectiveness have not been established.

Geriatric Use

Clinical studies of DILAUDID 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 PRECAUTIONS).

Less Frequently Observed Adverse Reactions

Parenteral

DILAUDID-HP SHOULD BE GIVEN ONLY TO PATIENTS WHO ARE ALREADY RECEIVING LARGE DOSES OF OPIOIDS. DILAUDID-HP is indicated for relief of moderate-to-severe pain in opioid-tolerant patients. Thus, these patients will already have been treated with other opioid analgesics. If the patient is being changed from regular DILAUDID to DILAUDID-HP, similar doses should be used, depending on the patient's clinical response to the drug. If DILAUDID-HP is substituted for a different opioid analgesic, the following equivalency table should be used as a guide to determine the appropriate dose of DILAUDID-HP (hydromorphone hydrochloride). Patients with hepatic and renal impairment should be started on a lower starting dose (See CLINICAL PHARMACOLOGY - Pharmacokinetics and Metabolism). The dosage of DILAUDID-HP 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 open clinical trials with DILAUDID-HP in patients with terminal cancer, doses ranged from 1-14 mg subcutaneously or intramuscularly; one patient received 30 mg subcutaneously on two occasions. In these trials, both subcutaneous and intramuscular injections of DILAUDID-HP were well-tolerated, with minimal pain and/or burning at the injection site. Mild erythema was rarely noted after intramuscular injection. There was no induration after either intramuscular or subcutaneous administration of DILAUDID-HP. Subcutaneous injections of DILAUDID-HP were particularly well accepted when administered with a short, 30 gauge needle.

Experience with administration of DILAUDID-HP by the intravenous route is limited. Should intravenous administration be necessary, the injection should be given slowly, over at least 2 to 3 minutes. The intravenous route is usually painless.

A gradual increase in dose may be required if analgesia is inadequate, tolerance occurs, or if pain severity increases. The first sign of tolerance is usually a reduced duration of effect.

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. A slight yellowish discoloration may develop in DILAUDID-HP ampules. No loss of potency has been demonstrated. DILAUDID injection is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions.

500 mg/50 mL Vial

To use this single dose presentation, do not penetrate the stopper with a syringe. Instead, remove both the aluminum flipseal and rubber stopper in a suitable work area such as under a laminar flow hood (or equivalent clean air compounding area). The contents may then be withdrawn for preparation of a single, large volume parenteral solution. Any unused portion should be discarded in an appropriate manner.

CAUTION: The packaging (vial stopper) of this product contains rubber latex which may cause allergic reactions.

Reconstitution of Sterile Lyophilized DILAUDID-HP 250 mg

Reconstitute immediately prior to use with 25 mL of Sterile Water for Injection USP to provide a sterile solution containing 10 mg/mL.

Storage

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature]. Protect from light.

A Schedule CS-II Narcotic. DEA Order Form Required.

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