HYDROMORPHONEHYDROCHLORIDEINJECTION, USP(HIGH POTENCY)

HYDROMORPHONE HYDROCHLORIDE - hydromorphone hydrochloride injection, solution 
Hospira, Inc.

----------

CII

Rx only

WARNING

HYDROMORPHONE HYDROCHLORIDE INJECTION (HIGH POTENCY) IS A HIGHLY CONCENTRATED SOLUTION OF HYDROMORPHONE, A POTENT SCHEDULE II CONTROLLED OPIOID AGONIST, INTENDED FOR USE IN OPIOID-TOLERANT PATIENTS. DO NOT CONFUSE HYDROMORPHONE HYDROCHLORIDE INJECTION (HIGH POTENCY) WITH STANDARD PARENTERAL FORMULATIONS OF HYDROMORPHONE HYDROCHLORIDE OR OTHER OPIOIDS. OVERDOSE AND DEATH COULD RESULT.

SCHEDULE II OPIOID AGONISTS, INCLUDING MORPHINE, OXYMORPHONE, OXYCODONE, FENTANYL AND METHADONE, HAVE THE HIGHEST POTENTIAL FOR ABUSE AND RISK OF PRODUCING 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.

DESCRIPTION

Hydromorphone hydrochloride, a hydrogenated ketone of morphine, is an opioid analgesic. HIGH POTENCY HYDROMORPHONE HYDROCHLORIDE is available in AMBER ampuls 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, and 0.2% citric acid solution in Water for Injection; pH 3.5 to 5.5.

The chemical name of hydromorphone hydrochloride is 4,5α-Epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride and it has the following structural formula:

Hydromorphone Hydrochloride Structural Formula

M.W. 321.8                                  C17H19NO3• HCl

CLINICAL PHARMACOLOGY

Hydromorphone hydrochloride is a pure opioid agonist with the principal therapeutic activity of analgesia. A significant feature of the analgesia is that it can occur without loss of consciousness. Opioid analgesics also suppress the cough reflex and may cause respiratory depression, mood changes, mental clouding, euphoria, dysphoria, nausea, vomiting and electroencephalographic changes. Many of the effects described below are common to the class of mu-opioid analgesics which includes morphine, oxycodone, hydrocodone, codeine, and fentanyl. In some instances, data may not exist to demonstrate that hydromorphone possesses similar or different effects than those observed with other opioid analgesics. However, in the absence of data to the contrary, it is assumed that hydromorphone would possess these effects.

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 mioisis may be seen with hypoxia in the setting of hydromorphone 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 opioid 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

Distribution: At therapeutic plasma levels, hydromorphone is approximately 8-19% bound to plasma proteins. After an intravenous bolus dose, the steady state of volume of distribution [mean(%cv)] is 302.9 (32%) liters.

Metabolism: Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater than 95% of the dose metabolized to hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites.

Elimination: Only a small amount of the hydromorphone dose is excreted unchanged in the urine. Most of the dose is excreted as hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites. The systemic clearance is approximately 1.96 (20%) liters/minute. The terminal elimination half-life of hydromorphone after an intravenous dose is about 2.3 hours. 

Special Populations:

Hepatic Impairment: After oral administration of hydromorphone at a single 4 mg dose, mean exposure to hydromorphone (Cmax and AUC) is increased 4-fold in patients with moderate (Child-Pugh Group B) hepatic impairment compared with subjects with normal hepatic function. Due to increased exposure of hydromorphone, patients with moderate hepatic impairment should be started at a lower dose and closely monitored during dose titration. Pharmacokinetics of hydromorphone in severe hepatic impairment patients has not been studied. Further increase in Cmax and AUC of hydromorphone in this group is expected. As such, starting dose should be even more conservative. Use of oral liquid is recommended to adjust the dose (see DOSAGE AND ADMINISTRATION).

Renal Impairment: After oral administration of hydromorphone at a single 4 mg dose, mean exposure to hydromorphone (Cmax and AUC0-48) is increased in patients with impaired renal function by 2-fold, in moderate (CLcr = 40-60 mL/min) and 3-fold in severe (CLcr<30 mL/min) renal impairment compared with normal subjects (CLcr>80 mL/min). In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life (40 hr) compared to patients with normal renal function (15 hr). Patients with moderate renal impairment should be started on a lower dose. Starting doses for patients with severe renal impairment should be even lower. Patients with renal impairment should be closely monitored during dose titration. Use of oral liquid is recommended to adjust the dose (see DOSAGE AND ADMINISTRATION).

Pediatrics: Pharmacokinetics of hydromorphone have not been evaluated in children.

Geriatric: Age has no effect on the pharmacokinetics of hydromorphone.

Gender: Gender has little effect on the pharmacokinetics of hydromorphone. Females appear to have higher Cmax (25%) than males with comparable AUC0-24 values. The difference observed in Cmax may not be clinically relevant.

Pregnancy and nursing mothers: Hydromorphone crosses the placenta. Hydromorphone is also found in low levels in breast milk, and may cause respiratory compromise in newborns when administered during labor or delivery.

INDICATIONS AND USAGE

Hydromorphone Hydrochloride Injection (High Potency) is indicated for the relief of moderate-to-severe pain in opioid-tolerant patients who require larger than usual doses of opioids to provide adequate pain relief. Because Hydromorphone Hydrochloride Injection (High Potency) contains 10 mg of hydromorphone hydrochloride per mL, a smaller injection volume can be used than with other parenteral opioid 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 opioids, patients with known hypersensitivity to hydromorphone, 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

Respiratory Depression: Respiratory depression is the chief hazard of Hydromorphone Hydrochloride Injection (High Potency). 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.

Hydromorphone Hydrochloride Injection (High Potency) 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.

Hydromorphone Hydrochloride Injection (High Potency) 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.

Hydromorphone Hydrochloride Injection (High Potency) can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Hydromorphone 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 Hydromorphone Hydrochloride Injection (High Potency) 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 Hydromorphone Hydrochloride Injection (High Potency) 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 Hydromorphone Hydrochloride Injection (High Potency) 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 Hydromorphone Hydrochloride Injection (High Potency), 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 (High Potency) 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.

Special Risk Patients: Hydromorphone Hydrochloride Injection (High Potency) 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 Hydromorphone Hydrochloride Injection (High Potency), however, the patient is presumed to be receiving an opioid 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 opioid previously used by the patient (see DOSAGE AND ADMINISTRATION).

The administration of opioid analgesics including Hydromorphone Hydrochloride Injection (High Potency) 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: Hydromorphone Hydrochloride Injection (High Potency) 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 Hydromorphone Hydrochloride Injection (High Potency) 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: Hydromorphone Hydrochloride Injection (High Potency) 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. Hydromorphone Hydrochloride Injection (High Potency) may produce orthostatic hypotension in ambulatory patients.

Use in Biliary Tract Disease: Opioid analgesics, including Hydromorphone Hydrochloride Injection (High Potency), should 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:

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. Opioid analgesics, including Hydromorphone Hydrochloride Injection (High Potency), may enhance the action of neuromuscular blocking agents and produce an increased degree of respiratory depression.

Interactions with Mixed Agonist/Antagonist Opioid 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.

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 hydromorphone hydrochloride injection (high potency) when substituted for ORAL LIQUID or 8 mg TABLET, respectively, on a body surface area basis.

PREGNANCY-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 equivalent to and 3-fold higher than the human dose of hydromorphone hydrochloride injection (high potency), 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 8-9). The skull malformations were observed at doses approximately 2-fold and 7-fold higher than the human dose of hydromorphone hydrochloride injection (high potency) when substituted for ORAL LIQUID or 8 mg TABLET, respectively, on a body surface area basis. There are no adequate and well-controlled studies of hydromorphone in pregnant women.

Hydromorphone crosses the placenta, resulting in fetal exposures. Hydromorphone hydrochloride injection (high potency) 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 Injection (High Potency) 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 Hydromorphone Hydrochloride Injection (High Potency) 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 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 PRECAUTIONS).

ADVERSE REACTIONS

The major hazards of Hydromorphone Hydrochloride Injection (High Potency) 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, 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.

Less Frequently Observed Adverse Reactions:

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 and increased intracranial pressure.

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

Respiratory: Bronchospasm and laryngospasm.

Gastrointestinal: Constipation, biliary tract spasm, ileus, anorexia, diarrhea, cramps and taste alterations.

Genitourinary: Urinary retention or hesitancy, and antidiuretic effects.

Dermatologic: Urticaria, other skin rashes, wheal and flare over the vein with intravenous injection, and diaphoresis.

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 opioid drug products.

OVERDOSAGE

Serious overdosage with Hydromorphone Hydrochloride Injection (High Potency) 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. 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 Injection (High Potency). 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 opioid effects may precipitate an acute withdrawal syndrome.

Since the duration of action of Hydromorphone Hydrochloride Injection (High Potency) 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.

DOSAGE AND ADMINISTRATION

Parenteral: HYDROMORPHONE HYDROCHLORIDE INJECTION (HIGH POTENCY) SHOULD BE GIVEN ONLY TO PATIENTS WHO ARE ALREADY RECEIVING LARGE DOSES OF OPIOIDS. Hydromorphone Hydrochloride Injection (High Potency) 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 hydromorphone hydrochloride to high potency formulation, similar doses should be used, depending on the patient's clinical response to the drug. If Hydromorphone Hydrochloride Injection (High Potency) is substituted for a different opioid analgesic, the following equivalency table should be used as a guide to determine the appropriate starting dose of Hydromorphone Hydrochloride Injection (High Potency). Patients with hepatic and renal impairment should be started on a lower starting dose. (See CLINICAL PHARMACOLOGY: PHARMACOKINETICS AND METABOLISM.) The dosage of Hydromorphone Hydrochloride Injection (High Potency) 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.

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†

Morphine sulfate

10

Hydromorphone hydrochloride

1.3

Oxymorphone hydrochloride

1.1

Nalbuphine hydrochloride

12

Levorphanol tartrate

2.3

Butorphanol tartrate

1.5 to 2.5

Pentazocine lactate or hydrochloride

60

Meperidine, pethidine hydrochloride

80

Methadone hydrochloride

10

* 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 is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions.

DRUG ABUSE AND DEPENDENCE

HYDROMORPHONE HYDROCHLORIDE INJECTION (HIGH POTENCY) contains hydromorphone, a Schedule II controlled opioid agonist. Schedule II opioid substances which include morphine, oxycodone, oxymorphone, fentanyl, and methadone have the highest potential for abuse and risk of fatal overdose. Hydromorphone can be abused and is subject to criminal diversion.

Opioid analgesics may cause psychological and physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage, but it may occur after as little as a week of opioid use. Physical dependence and tolerance are separate and distinct from abuse and addiction.

Addiction is a chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.

“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with, forging or counterfeiting prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers, people suffering from untreated addiction and criminals seeking drugs to sell.

Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since hydromorphone hydrochloride may be diverted for non-medical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Hydromorphone hydrochloride injection (high potency) is intended for parenteral use only under the direct supervision of an appropriately licensed health care provider. Misuse or abuse of hydromorphone hydrochloride injection (high potency) poses a risk of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

SAFETY AND HANDLING INSTRUCTIONS

Hydromorphone Hydrochloride Injection (High Potency) poses little risk of direct exposure to health care personnel and should be handled and disposed of prudently in accordance with hospital or institutional policy. Patients and their families should be instructed to flush any Hydromorphone Hydrochloride Injection (High Potency) that is no longer needed.

Access to abusable drugs such as Hydromorphone Hydrochloride Injection (High Potency) presents an occupational hazard for addiction in the health care industry. Routine procedures for handling controlled substances developed to protect the public may not be adequate to protect health care workers. Implementation of more effective accounting procedures and measures to restrict access to drugs of this class (appropriate to the practice setting) may minimize the risk of self-administration by health care providers.

HOW SUPPLIED

Hydromorphone Hydrochloride Injection, USP (High Potency) is available as:

ListContainerConcentrationFillQuantity

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.

Revised: July, 2007

Printed in USA                                         EN-1554

Hospira, Inc., Lake Forest, IL 60045 USA

RL-1117

Label NDC 0409-2172-01

HYDROMORPHONE HYDROCHLORIDE 
hydromorphone hydrochloride injection, solution
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0409-2172
Route of AdministrationINTRAMUSCULAR, INTRAVENOUS, SUBCUTANEOUSDEA ScheduleCII    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
HYDROMORPHONE HYDROCHLORIDE (HYDROMORPHONE) HYDROMORPHONE HYDROCHLORIDE10 mg  in 1 mL
Inactive Ingredients
Ingredient NameStrength
SODIUM CITRATE 
CITRIC ACID MONOHYDRATE 
WATER 
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#Item CodePackage DescriptionMultilevel Packaging
1NDC:0409-2172-0125 AMPULE (25 AMPULE) in 1 CARTONcontains a AMPULE
11 mL in 1 AMPULEThis package is contained within the CARTON (0409-2172-01)
2NDC:0409-2172-0510 AMPULE (10 AMPULE) in 1 CARTONcontains a AMPULE
25 mL in 1 AMPULEThis package is contained within the CARTON (0409-2172-05)

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA07459806/19/199710/01/2011

Labeler - Hospira, Inc. (141588017)

Revised: 05/2012 Hospira, Inc.