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Hydromorphone Hydrochloride Injection, USP
10mg/mL
High Potency Formulation

HMEN53-00

CII
Rx Only

WARNING

HYDROMORPHONE HYDROCHLORIDE INJECTION, USP 10 mg/mL IS A HIGHLY CONCENTRATED SOLUTION OF HYDROMORPHONE INTENDED FOR USE IN NARCOTIC-TOLERANT PATIENTS. DO NOT CONFUSE HYDROMORPHONE HYDROCHLORIDE INJECTION, USP WITH STANDARD PARENTERAL FORMULATIONS OF HYDROMORPHONE HYDROCHLORIDE OR OTHER NARCOTICS. OVERDOSE AND DEATH COULD RESULT.

DESCRIPTION

Hydromorphone Hydrochloride Injection, USP, a hydrogenated ketone of morphine, is a narcotic analgesic. Chemically it is 4, 5 α-Epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride. HIGH POTENCY hydromorphone hydrochloride is available in AMBER single dose vials for intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration. Each 1 mL of sterile solution contains 10 mg hydromorphone hydrochloride with 0.2% sodium citrate, 0.2% citric acid solution.

The structural formula of hydromorphone hydrochloride is:

    M.W. 321.8

The molecular formula is C17H19NO3• HCl

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 Hydrochloride Injection 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 Hydrochloride Injection 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 peristaltic 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 increase 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 pruritis, 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 Injection 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 Hydrochloride Injection is rapidly removed from the blood stream and distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. Hydromorphone Hydrochloride Injection 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 Injection 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

Hydromorphone Hydrochloride Injection, USP 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 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 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 is also contraindicated for use in obstetrical analgesia.

WARNINGS

Drug Dependence

Hydromorphone Hydrochloride Injection 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 Injection and it should be prescribed and administered with the same degree of caution appropriate for the use of morphine. Since Hydromorphone Hydrochloride Injection 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 is likely to result in a withdrawal syndrome. (See Drug Abuse and Dependence).

Infants born to mothers physically dependent on Hydromorphone Hydrochloride Injection 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. 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 Injection 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 Injection 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 Injection 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 Injection, 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 Injection may produce orthostatic hypotension in ambulatory patients.

Hydromorphone Hydrochloride Injection 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 may be difficult if low doses of hydromorphone are required. Therefore, Hydromorphone Hydrochloride Injection 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, 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 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 Injection 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.

Narcotic analgesics including Hydromorphone Hydrochloride Injection 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 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. Narcotic analgesics, including Hydromorphone Hydrochloride Injection may enhance the action of neuromuscular blocking agents and produce an increased degree of respiratory depression.

Pregnancy

Labor and Delivery

Hydromorphone Hydrochloride Injection 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 Injection 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 Injection 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).

ADVERSE REACTIONS

The adverse effects of Hydromorphone Hydrochloride Injection 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 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 - Pruritis, 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; 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 should be guided by the degree of tolerance manifested.

In chronic pain patients in whom narcotic analgesics including Hydromorphone Hydrochloride Injection 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 back-ache, 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 Hydrochloride Injection, 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 Hydrochloride Injection 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 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 patient, 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. A dose of naloxone (usually 0.4 to 2.0 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. 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 Injection 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.

DOSAGE AND ADMINISTRATION

Parenteral

HYDROMORPHONE HYDROCHLORIDE INJECTION, USP 10 mg/mL SHOULD BE GIVEN ONLY TO PATIENTS WHO ARE ALREADY RECEIVING LARGE DOSES OF NARCOTICS. Hydromorphone Hydrochloride Injection 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 injection to high-potency Hydromorphone Hydrochloride Injection, similar doses should be used, depending on the patient’s clinical response to the drug. If Hydromorphone Hydrochloride Injection is substituted for a different narcotic analgesic, the following equivalency table should be used as a guide to determine the appropriate dose of Hydromorphone Hydrochloride Injection.

STRONG ANALGESICS AND STRUCTURALLY RELATED DRUGS USED IN THE TREATMENT OF CANCER PAIN*




Nonproprietary
Names
IM OR SC ADMINISTRATION

Dose, mg
Equianalgesic
To 10 mg of
IM Morphine



Duration
Compared
With Morphine
*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.)
Morphine sulfate10Same
Papaveretum20Same
Hydromorphone Hydrochloride 1.3 Slightly Shorter
Oxymorphone Hydrochloride1.1Slightly Shorter
Nalbuphine hydrochloride12Same
Heroine, diamorphine Hydrochloride4 to 5Slightly Shorter
Levorphanol tartrate2.3Same
Butorphanol tartrate1.5 to 2.5Same
Pentazocine lactate or hydrochloride60Shorter
Meperidine, pethidine hydrochloride 80 Shorter
Methadone hydrochloride10Same

In open clinical trials with Hydromorphone Hydrochloride Injection 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 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. Subcutaneous injections of Hydromorphone Hydrochloride Injection were particularly well accepted when administered with a short, 30 gauge needle.

Experience with administration of Hydromorphone Hydrochloride Injection 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 vials. No loss of potency has been demonstrated. Hydromorphone Hydrochloride 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 spans may then be withdrawn for preparation of a single, large volume parenteral solution. Any unused portion should be discarded in an appropriate manner.

HOW SUPPLIED

Hydromorphone Hydrochloride Injection, USP 10 mg/mL single dose amber vials contain 10 mg hydromorphone hydrochloride per mL in 0.2% sodium citrate and 0.2% citric acid solution. No added preservative.

High Potency:

NDC 61703-243-45 10 mg/1 mL single dose vials

                                 10 mg/mL

                                 Package of 10

NDC 61703-243-53 *50 mg/5 mL single dose vials

                                10 mg/mL

                                 Package of 10

NDC 61703-243-50 *500 mg/50 mL Single dose vial

                                 10 mg/mL

                                 Packaged Individually

*FOR USE IN THE PREPARATION OF LARGE VOLUME PARENTERAL SOLUTIONS

STORAGE

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

A Schedule CII narcotic. DEA order Form Required.

Manufactured for:

Mayne Pharma ( USA) Inc.

Paramus, NJ  07652

Rev. April 2006         HMEN53-00