Hydromorphone

Generic Name: Hydromorphone Hydrochloride
Dosage Form: Injection

CII

Rx only

Hydromorphone Description

Hydromorphone hydrochloride (WARNING: May be habit forming), a hydrogenated ketone of morphine, is a narcotic analgesic. HIGH POTENCYHydromorphone HYDROCHLORIDE is available in AMBER ampuls for intravenous (IV) subcutaneous (SC) or intramuscular (IM) administration. Each mL of sterile solution contains 10 mg Hydromorphone hydrochloride, 0.2% sodium citrate, and 0.2% citric acid in Water for Injection; pH 3.5 to 5.5.

It has the following structural formula:

Hydromorphone hydrochloride is 4,5α-Epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride. It has a molecular weight of 321.81 and a molecular formula of C17H19NO3• HCl

Hydromorphone - Clinical Pharmacology

Many of the effects described below are common to the class of narcotic analgesics. In some instances, data may not exist to demonstrate that Hydromorphone possesses similar or different effects than those observed with other narcotic analgesics. However, in the absence of data to the contrary, it is assumed that Hydromorphone would possess these effects.

Central Nervous System: Narcotic analgesics have multiple actions but exert their primary effects on the central nervous system and organs containing smooth muscle. The principal actions of therapeutic value are analgesia and sedation. A significant feature of the analgesia is that it occurs without loss of consciousness. Narcotic analgesics also suppress the cough reflex and cause respiratory depression, mood changes, mental clouding, euphoria, dysphoria, nausea, vomiting and electroencephalographic changes. The precise mode of analgesic action of narcotic analgesics is unknown. However, specific CNS opiate receptors have been identified. Narcotics are believed to express their pharmacological effects by combining with these receptors.

Narcotics depress the cough reflex by direct effect on the cough center in the medulla.

Narcotics produce 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.

Narcotics cause miosis. Pinpoint pupils are a common sign of narcotic overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings) and marked mydriasis occurs when asphyxia intervenes.

Gastrointestinal Tract and Other Smooth Muscle: Gastric, biliary and pancreatic secretions are decreased by narcotics. Narcotics cause a reduction in motility associated with an increase in tone in the antrum portion of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive penstaltic waves in the colon are decreased, and tone may be increased to the point of spasm. The end result is constipation. Narcotics can cause a marked decrease in biliary tract pressure as a result of spasm of the sphincter of Oddi.

Cardiovascular System: Certain narcotics produce peripheral vasodilation which may result in orthostatic hypotension. Release of histamine may occur with narcotics and may contribute to narcotic-induced hypotension. Other manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, and red eyes.

Effects on the myocardium after I.V. administration of narcotics are not significant in normal persons, vary with different narcotic analgesic agents and vary with the hemodynamic state of the patient, state of hydration and sympathetic drive.

Pharmacokinetics: In normal human volunteers Hydromorphone is metabolized primarily in the liver. It is excreted primarily as the glucuronidated conjugate, with small amounts of parent drug and minor amounts of 6-hydroxy reduction metabolites.

Following intravenous administration of Hydromorphone hydrochloride to normal volunteers, the mean half-life of elimination was 2.64 ± 0.88 hours. The mean volume of distribution was 91.5 liters, suggesting extensive tissue uptake. Hydromorphone is rapidly removed from the blood stream and distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. Hydromorphone also crosses the placental membranes.

In terms of area under the analgesic time-effect curve, Hydromorphone is approximately 8 times more potent than morphine (i.e., 1.3 mg of Hydromorphone produces analgesia equal to that produced by 10 mg of morphine). After intramuscular administration, Hydromorphone has a slightly more rapid onset and slightly shorter duration of action than morphine. The duration of Hydromorphone hydrochloride analgesia in the non-tolerant patient with usual doses may be up to 4 to 5 hours. However, in tolerant subjects, duration will vary substantially depending on tolerance and dose. Dose should be adjusted so that 3 to 4 hours of pain relief may be achieved.

Indications and Usage for Hydromorphone

Hydromorphone Hydrochloride Injection (High Potency) is indicated for the relief of moderate-to-severe pain in narcotic-tolerant patients who require larger than usual doses of narcotics to provide adequate pain relief. Because Hydromorphone hydrochloride injection (High Potency) contains 10 mg of Hydromorphone per mL, a smaller injection volume can be used than with other parenteral narcotic formulations. Discomfort associated with the intramuscular or subcutaneous injection of an unusually large volume of solution can therefore be avoided.

Contraindications

Hydromorphone Hydrochloride Injection (High Potency) is contraindicated in: patients who are not already receiving large amounts of parenteral narcotics, patients with known hypersensitivity to the drug, patients with respiratory depression in the absence of resuscitative equipment, and in patients with status asthmaticus. Hydromorphone hydrochloride injection (High Potency) is also contraindicated for use in obstetrical analgesia.

Warnings

Drug Dependence: Hydromorphone can produce drug dependence of the morphine type and therefore has the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration of Hydromorphone hydrochloride, and it should be prescribed and administered with the same degree of caution appropriate for the use of morphine. Since Hydromorphone hydrochloride injection (High Potency) is indicated for use in patients who are already tolerant to and hence physically dependent on narcotics, abrupt discontinuance in the administration of Hydromorphone hydrochloride injection (High Potency) is likely to result in a withdrawal syndrome. (See DRUG ABUSE AND DEPENDENCE).

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

Impaired Respiration: Respiratory depression is the chief hazard of Hydromorphone hydrochloride injection (High Potency). Respiratory depression occurs most frequently 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.

Hydromorphone hydrochloride 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 narcotic analgesics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.

Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of Hydromorphone hydrochloride 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. Narcotic analgesics including Hydromorphone hydrochloride may produce effects which can obscure the clinical course and neurologic signs of further increase in pressure in patients with head injuries.

Hypotensive Effect: Narcotic analgesics, including Hydromorphone hydrochloride, 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 also PRECAUTIONS—DRUG INTERACTIONS). Hydromorphone hydrochloride may produce orthostatic hypotension in ambulatory patients.

Hydromorphone hydrochloride injection (High Potency) should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Precautions

General:

Because of its high concentration, the delivery of precise doses of Hydromorphone hydrochloride injection (High Potency) may be difficult if low doses of Hydromorphone are required. Therefore, Hydromorphone hydrochloride injection (High Potency) should be used only if the amount of Hydromorphone required can be delivered accurately with this formulation.

In general, narcotics 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.

In the case of Hydromorphone hydrochloride injection (High Potency), however, the patient is presumed to be receiving a narcotic to which he or she exhibits tolerance and the initial dose of Hydromorphone hydrochloride injection (High Potency) selected should be estimated based on the relative potency of Hydromorphone and the narcotic previously used by the patient. See DOSAGE AND ADMINISTRATION SECTION.

The administration of narcotic analgesics including Hydromorphone hydrochloride may obscure the diagnosis or clinical course in patients with acute abdominal conditions and may aggravate preexisting convulsions in patients with convulsive disorders.

Narcotic analgesics including Hydromorphone 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.

Drug Interactions:

The concomitant use of other central nervous system depressants including sedative 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. Narcotic analgesics, including Hydromorphone hydrochloride may enhance the action of neuromuscular blocking agents and produce an increased degree of respiratory depression.

Pregnancy:

Teratogenic Effects: Pregnancy Category C.

Human: Adequate animal studies on reproduction have not been performed to determine whether Hydromorphone affects fertility in males or females. There are no well-controlled studies in women. Reports based on marketing experience do not identify any specific teratogenic risks following routine (short-term) clinical use. Although there is no clearly defined risk, such reports do not exclude the possibility of infrequent or subtle damage to the human fetus. Hydromorphone hydrochloride, should be used in pregnant women only when clearly needed (See PRECAUTIONS: Labor and Delivery and DRUG ABUSE AND DEPENDENCE).

Animal: Literature reports of Hydromorphone hydrochloride administration to pregnant Syrian hamsters show that Hydromorphone hydrochloride is teratogenic at a dose of 20 mg/kg which is 600 times the human dose. A maximal teratogenic effect (50% of fetuses affected) in the Syrian hamster was observed at a dose of 125 mg/kg.

Labor and Delivery:

Hydromorphone hydrochloride injection (High Potency) is contraindicated in Labor and Delivery (see CONTRAINDICATIONS section).

Nursing Mothers:

Low levels of narcotic analgesics have been detected in human milk. As a general rule, nursing should not be undertaken while a patient is receiving Hydromorphone hydrochloride since it, and other drugs in this class, may be excreted in the milk.

Pediatric Use:

Safety and effectiveness have not been established.

Adverse Reactions

The adverse effects of Hydromorphone hydrochloride injection (High Potency) are similar to those of other narcotic analgesics, and represent established pharmacological effects of the drug class. The major hazards 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 lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain. Some adverse reactions in ambulatory patients may be alleviated if the patient lies down.

Less Frequently Observed with Narcotic Analgesics:

General and CNS: Dysphoria, euphoria, 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 and increased intracranial pressure may occur.

*Hallucinations, although unusual with pure agonist narcotics, have been observed in one patient following both a 6 mg and a 4 mg Hydromorphone hydrochloride injection (High Potency) dose. However, the patient was receiving several concomitant medications during the second episode and a causal relationship cannot be established.

Cardiovascular: Flushing of the face, chills, tachycardia, bradycardia, palpitation, faintness, syncope, hypotension and hypertension have been reported.

Respiratory: Bronchospasm and laryngospasm have been known to occur.

Gastrointestinal: Dry mouth, constipation, biliary tract spasm, anorexia, diarrhea, cramps and taste alterations have been reported.

Genitourinary: Urinary retention or hesitancy, and antidiuretic effects have been reported.

Dermatologic: Pruritus, urticaria, other skin rashes, wheal and flare over the vein with intravenous injection, and diaphoresis have been reported with narcotic analgesics.

Other: In clinical trials, neither local tissue irritation nor induration was observed at the site of subcutaneous injection of Hydromorphone hydrochloride injection (High Potency): pain at the injection site was rarely observed. However, local irritation and induration have been seen following parenteral injection of other narcotic drug products.

Drug Abuse and Dependence

Narcotic analgesics may cause psychological and physical dependence (see WARNINGS). Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Withdrawal symptoms may also be precipitated in the patient with physical dependence by the administration of a drug with narcotic antagonist activity, e.g., naloxone (see also OVERDOSAGE). Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued narcotic usage. Tolerance, in which increasingly large doses are required in order to produce the same degree of analgesia, is initially manifested by a shortened duration of analgesic effect, and subsequently, by decreases in the intensity of analgesia. In chronic pain patients, and in narcotic tolerant cancer patients, the dose of Hydromorphone hydrochloride injection (High Potency) should be guided by the degree of tolerance manifested.

In chronic pain patients in whom narcotic analgesics including Hydromorphone are abruptly discontinued, a severe abstinence syndrome should be anticipated. This may be similar to the abstinence syndrome noted in patients who withdraw from heroin. The latter abstinence syndrome may be characterized by restlessness, lacrimation, rhinorrhea, yawning, perspiration, gooseflesh, restless sleep or "yen" and mydriasis during the first 24 hours. These symptoms may increase in severity and over the next 72 hours may be accompanied by increasing irritability, anxiety, weakness, twitching and spasms of muscles, kicking movements, severe backache, abdominal and leg pains, abdominal and muscle cramps, hot and cold flashes, insomnia, nausea, anorexia, vomiting, intestinal spasm, diarrhea, coryza and repetitive sneezing, increase in body temperature, blood pressure, respiratory rate and heart rate.

Because of excessive loss of fluids through sweating, or vomiting and diarrhea, there is usually marked weight loss, dehydration, ketosis, and disturbances in acid-base balance. Cardiovascular collapse can occur. Without treatment most observable symptoms disappear in 5 to 14 days; however there appears to be a phase of secondary or chronic abstinence which may last for 2 to 6 months characterized by insomnia, irritability, muscular aches, and autonomic instability.

In the treatment of physical dependence on Hydromorphone, the patient may be detoxified by gradual reduction of the dosage, although this is unlikely to be necessary in the terminal cancer patient. If abstinence symptoms become severe, the patient may be given methadone. Temporary administration of tranquilizers and sedatives may aid in reducing patient anxiety. Gastrointestinal disturbances or dehydration should be treated accordingly.

Overdosage

Serious overdosage with Hydromorphone 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.

Narcotic-Tolerant Patient: Since tolerance to the respiratory and CNS depressant effects of narcotics develops concomitantly with tolerance to their analgesic effects, serious respiratory depression due to an acute overdose is unlikely to be seen in narcotic-tolerant patients receiving Hydromorphone hydrochloride injection (High Potency) for chronic pain.

NOTE: In such an individual who is physically dependent on narcotics, administration of the usual dose of the antagonist will precipitate an acute withdrawal syndrome. The severity will depend on the degree of physical dependence and the dose of the antagonist administered. Use of a narcotic antagonist in such a person should be avoided. If necessary to treat serious respiratory depression in the physically-dependent the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.

Non-Tolerant Patient: The narcotic antagonist, naloxone, is a specific antidote against respiratory depression which may result from overdosage, or unusual sensitivity to Hydromorphone hydrochloride injection (High Potency). A dose of naloxone (usually 0.4 to 2 mg) should be administered intravenously, if possible, simultaneously with respiratory resuscitation. The dose can be repeated in 3 minutes. 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 injection (High Potency). In such cases, an abrupt or complete reversal of narcotic effects may precipitate an acute abstinence syndrome.

Since the duration of action of Hydromorphone hydrochloride 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.

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.

Hydromorphone Dosage and Administration

Parenteral: Hydromorphone HYDROCHLORIDE INJECTION (HIGH POTENCY) SHOULD BE GIVEN ONLY TO PATIENTS WHO ARE ALREADY RECEIVING LARGE DOSES OF NARCOTICS. Hydromorphone hydrochloride injection (High Potency) is indicated for relief of moderate-to-severe pain in narcotic-tolerant patients. Thus, these patients will already have been treated with other narcotic analgesics. If the patient is being changed from regular Hydromorphone hydrochloride to Hydromorphone hydrochloride injection (High Potency), similar doses should be used, depending on the patient"s clinical response to the drug. If Hydromorphone hydrochloride is substituted for a different narcotic analgesic, the following equivalency table should be used as a guide to determine the appropriate starting dose of Hydromorphone hydrochloride.

STRONG ANALGESICS AND STRUCTURALLY RELATED DRUGS
USED IN THE TREATMENT OF CANCER PAIN*
	IM or SC Administration
Nonproprietary Names	Dose, mg Equianalgesic to 10 mg of IM Morphine†	Duration Compared With Morphine
Morphine sulfate	10	Same
Papaveretum	20	Same
Hydromorphone	1.3	Slightly
hydrochloride		Shorter
Oxymorphone	1.1	Slightly
hydrochloride		Shorter
Nalbuphine hydrochloride	12	Same
Heroin, diamorphine	4 to 5	Slightly
hydrochloride		Shorter
Levorphanol tartrate	2.3	Same
Butorphanol tartrate	1.5 to 2.5	Same
Pentazocine lactate	60	Shorter
or hydrochloride
Meperidine, pethidine	80	Shorter
hydrochloride
Methadone hydrochloride	10	Same
*from Beaver WT
Management of cancer pain with parenteral medication
J. Am. Med. Assoc 244: 2653-2657 (1980)
† (in terms of the area under the analgesic time-effect curve.)

In open clinical trials with Hydromorphone hydrochloride injection (High Potency) in patients with terminal cancer, doses ranged from 1 to 14 mg subcutaneously or intramuscularly; one patient received 30 mg subcutaneously on two occasions. In these trials, both subcutaneous and intramuscular injections of Hydromorphone hydrochloride injection (High Potency) 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 Hydromorphone hydrochloride injection (High Potency). Subcutaneous injections of Hydromorphone hydrochloride injection (High Potency) were particularly well accepted when administered with a short, 30-gauge needle.

Experience with administration of Hydromorphone hydrochloride injection (High Potency) 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 Hydromorphone hydrochloride injection (High Potency) ampuls. No loss of potency has been demonstrated. Hydromorphone hydrochloride injection (High Potency) is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions.

How is Hydromorphone Supplied

Hydromorphone hydrochloride injection, USP (High Potency) is available as:

List	Container	Concentration	Fill	Quantity
2172	Ampul	10 mg/mL	1 mL	UNI-AMP® Pak of 25
2172	*Ampul	50 mg (10 mg/mL)	5 mL	10 ampuls per carton

*DILUTE PRIOR TO USE. FOR USE IN THE PREPARATION OF LARGE VOLUME PARENTERAL SOLUTIONS.

No added preservative.

STORAGE: Parenteral forms of Hydromorphone hydrochloride injection should be stored at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]

Protect from light.

©Hospira 2005		Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

Hydromorphone Hydrochloride (Hydromorphone Hydrochloride)

PRODUCT INFO Product Code 0409-2172 Dosage Form INJECTION, SOLUTION Route Of Administration INTRAMUSCULAR, INTRAVENOUS, SUBCUTANEOUS DEA Schedule CII

INGREDIENTS Name (Active Moiety) Type Strength Hydromorphone Hydrochloride (Hydromorphone) Active 10 MILLIGRAM  In 1 MILLILITER Sodium Citrate Inactive 2 MILLIGRAM  In 1 MILLILITER Citric Acid Inactive 2 MILLIGRAM  In 1 MILLILITER Water Inactive

IMPRINT INFORMATION Characteristic Appearance Characteristic Appearance Color Score Shape Symbol Imprint Code Coating Size

PACKAGING # NDC Package Description Multilevel Packaging 1 0409-2172-01 40 PACKET In 1 CASE contains a PACKET 1 25 AMPULE In 1 PACKET This package is contained within the CASE (0409-2172-01) and contains a AMPULE () 1 1 MILLILITER In 1 AMPULE This package is contained within a PACKET and a CASE (0409-2172-01) 2 0409-2172-05 60 CARTON In 1 CASE contains a CARTON 2 10 AMPULE In 1 CARTON This package is contained within the CASE (0409-2172-05) and contains a AMPULE () 2 5 MILLILITER In 1 AMPULE This package is contained within a CARTON and a CASE (0409-2172-05)

Revised: 09/2006