Hydromorphone Hydrochloride

Akorn, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use hydromorphone hydrochloride injection [high potency formulation (HPF)] safely and effectively. See full prescribing information for Hydromorphone Hydrochloride Injection [high potency formulation (HPF)]Hydromorphone Hydrochloride Injection[high potency formulation (HPF)] CIIFor intravenous, intramuscular and subcutaneous use Initial U.S. Approval: January 1984 BOXED WARNING WARNING: RISK OF RESPIRATORY DEPRESSION, ABUSE, AND MEDICATION ERRORS HYDROMORPHONE HYDROCHLORIDE INJECTION [high potency formulation (HPF)] IS FOR USE IN OPIOID-TOLERANT PATIENTS ONLY See full prescribing information for complete boxed warning. Do not confuse Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] with standard parenteral formulations of hydromorphone hydrochloride or other opioids, as overdose and death could result. (5) Hydromorphone is a potent Schedule II opioid agonist. Schedule II opioid agonists have the highest potential for abuse and risk of producing respiratory depression. Ethanol, other opioids, and other central nervous system depressants can potentiate the respiratory-depressant effects of hydromorphone and increase the risk of adverse outcomes, including death. (5.1, 7.1) INDICATIONS AND USAGE Hydromorphone Hydrochloride Injection (high potency formulation) is indicated for the management of moderate-to-severe pain in opioid-tolerant patients who require higher doses of opioids. (1) DOSAGE AND ADMINISTRATION Hydromorphone Hydrochloride Injection (high potency formulation) should be used only if the amount of hydromorphone required can be delivered accurately with this formulation. (2.5) For patients already receiving opioids, use standard conversion ratio estimates. (2.4) The dose should be adjusted according to the severity of pain, as well as the patient's underlying disease state and age. (2.1, 2.2) Should intravenous administration be necessary, the injection should be given slowly, over at least 2 to 3 minutes and the usual starting dose is 0.2 to 1 mg. (2.3.2) DOSAGE FORMS AND STRENGTHS Hydromorphone Hydrochloride Injection (HPF): 10 mg/mL in 1 mL or 5 mL ampule or 50 mL single-dose vial. (3) CONTRAINDICATIONS Known hypersensitivity to hydromorphone, hydromorphone salts, any components of the product, or in any situation where opioids are contraindicated (4) Patients with respiratory depression in the absence of resuscitative equipment or in unmonitored settings; patients with status asthmaticus (4) Gastrointestinal obstruction, especially paralytic ileus (4) Hydromorphone Hydrochloride Injection (HPF): Patients who are not opioid tolerant (4) WARNINGS AND PRECAUTIONS Hydromorphone Hydrochloride Injection (HPF) is a concentrated formulation of hydromorphone. Do NOT confuse Hydromorphone Hydrochloride Injection (HPF) with Hydromorphone Hydrochloride Injection. Overdose and death could result. (5.1) May cause respiratory depression, use with extreme caution in patients at risk of respiratory depression, elderly and debilitated patients. (5.2) Abuse of Hydromorphone Hydrochloride Injection (HPF), poses a hazard of overdose and death. (5.3) Risk of medication errors: Morphine does not convert to hydromorphone on a milligram per milligram basis. Use Table 1 to convert. (5.1) Alcohol, other opioids and central nervous system depressants potentiate the respiratory depressant effects of hydromorphone. (5.4) Infants born to mothers physically dependent on Hydromorphone Hydrochloride Injection (HPF) will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms. (5.5) Respiratory depression may be markedly increased in patients with head injury, other intracranial lesions, or preexisting increase in intracranial pressure. (5.6) May cause hypotension, use with caution in patients at increased risk of hypotension and in patients in circulatory shock. (5.7) Hydromorphone Hydrochloride Injection (HPF) contain sodium metabisulfite. There is a risk of anaphylactic symptoms and life-threatening asthmatic episodes in susceptible people. (5.8) Use with caution in patients with biliary tract disease including pancreatitis. (5.9) Use with caution and in reduced initial doses in the elderly, debilitated, or other patient populations with increased risk of adverse reactions from opioids. (5.10) Use with caution in patients with alcoholism or other drug dependencies. (5.11) May impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. (5.12) Side EffectsMost common adverse reactions are lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. (6) To report Suspected Adverse Reactions, contact Akorn, Inc. at 1-800-932-5676 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . DRUG INTERACTIONS Concurrent use of other CNS depressants may cause respiratory depression, hypotension, and profound sedation or coma. (7.1) Mixed agonist/antagonist analgesics may reduce the analgesic effect of hydromorphone and may precipitate withdrawal symptoms in these patients. (7.2) USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. (8.1) Labor and Delivery: Use with caution during labor. (8.2) Nursing Mothers: Nursing should not be undertaken while a patient is receiving Hydromorphone Hydrochloride Injection (HPF). (8.3) Pediatrics: Safety and effectiveness in pediatric patients have not been established. (8.4) Geriatrics: Use with caution in elderly patients, initiate dose at low end of dosing range. (8.5) Hepatic and Renal Impairment: Patients with hepatic and renal impairment should be started on a lower starting dose. (8.6, 8.7, 12.2)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: RISK OF RESPIRATORY DEPRESSION, ABUSE, AND MEDICATION ERRORS
• 1 HYDROMORPHONE HYDROCHLORIDE INDICATIONS AND USAGE
• 2 HYDROMORPHONE HYDROCHLORIDE DOSAGE AND ADMINISTRATION
  • 2.1 General Dosing Considerations
  • 2.2 Individualization of Dosing
  • 2.4 Conversion From Prior Opioid
  • 2.5 Hydromorphone Hydrochloride Injection (HPF) (for use in opioid-tolerant patients only)
  • 2.6 Administration and Reconstitution
• 3 DOSAGE FORMS AND STRENGTHS
• 4 HYDROMORPHONE HYDROCHLORIDE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Risk of Medication Errors
  • 5.2 Respiratory Depression
  • 5.3 Misuse, Abuse and Diversion of Opioids
  • 5.4 Interactions with Alcohol and other CNS Depressants
  • 5.5 Neonatal Withdrawal Syndrome
  • 5.6 Use in Increased Intracranial Pressure or Head Injury
  • 5.7 Hypotensive Effect
  • 5.8 Sulfites
  • 5.9 Use in Pancreatic/Biliary Tract Disease and Other Gastrointestinal Conditions
  • 5.10 Special Risk Patients
  • 5.11 Use in Drug and Alcohol Dependent Patients
  • 5.12 Use in Ambulatory Patients
  • 5.13 Parenteral Administration
• 6 HYDROMORPHONE HYDROCHLORIDE ADVERSE REACTIONS
• 7 DRUG INTERACTIONS
  • 7.1 Drug Interactions with other CNS Depressants
  • 7.2 Interactions with Mixed Agonist/Antagonist Opioid Analgesics
  • 7.3 Monoamine Oxidase Inhibitors (MAOIs)
  • 7.4 Anticholinergics
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic Impairment
• 9 DRUG ABUSE AND DEPENDENCE
  • 9.1 Controlled Substance
  • 9.2 Abuse
  • 9.3 Dependence
• 10 OVERDOSAGE
  • 10.1 Signs and Symptoms
  • 10.2 Treatment
• 11 HYDROMORPHONE HYDROCHLORIDE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 Safety And Handling Instructions
  • 16.2 How Supplied
  • 16.3 Storage

FULL PRESCRIBING INFORMATION

Hydromorphone Hydrochloride Injection [high potency formulation (HPF)], CII

For intravenous, intramuscular and subcutaneous use

1 INDICATIONS AND USAGE

Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] is indicated for the management of moderate-to-severe pain in opioid-tolerant patients who require higher doses of opioids.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Considerations

Take care when prescribing and administering Hydromorphone Hydrochloride Injection (HPF) to avoid dosing errors due to confusion between the different concentrations and between mg and mL, which could result in accidental overdose and death. Take care to ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total volume of the dose.

Selection of patients and administration of hydromorphone hydrochloride injection (HPF) should be governed by the same principles that apply to the use of similar opioid analgesics to treat patients with acute or chronic pain, and depends upon a comprehensive assessment of the patient. Individualize treatment in every case, using non-opioid analgesics, opioids on an as needed basis and/or combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality, and the American Pain Society.

The nature of the pain (severity, frequency, etiology, and pathophysiology), as well as the medical status of the patient, will affect selection of the starting dosage. Opioid analgesics, including hydromorphone hydrochloride injection (HPF), have a narrow therapeutic index in certain patient populations, especially when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks.

2.2 Individualization of Dosing

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment. Give attention to the following:

• the age, general condition, and medical status of the patient;
• the patient's degree of opioid tolerance;
• the daily dose, potency, and specific characteristics of the opioid the patient has been taking previously;
• concurrent medications
• the type and severity of the patient's pain
• risk factors for abuse or addiction; including whether the patient has a previous or current substance abuse problem, a family history of substance abuse, or a history of mental illness or depression;
• the balance between pain control and adverse reactions.

Periodic reassessment after the initial dosing of hydromorphone hydrochloride injection (HPF) is required. If pain management is not satisfactory, and opioid-induced adverse events are tolerable, the hydromorphone dose may be increased gradually. If excessive opioid side effects are observed early in the dosing interval, reduce the hydromorphone hydrochloride dose. If this results in breakthrough pain at the end of the dosing interval, the dosing interval may need to be shortened. Dose titration should be guided more by the need for analgesia and the severity of adverse events than the absolute dose of opioid employed.

2.4 Conversion From Prior Opioid

Use the equianalgesic dose table below (Table 1) as a guide to determine the appropriate dose of hydromorphone hydrochloride injection (HPF). Convert the current total daily amount(s) of opioid(s) received to an equivalent total daily dose of hydromorphone hydrochloride injection (HPF) and reduce by one-half due to the possibility of incomplete cross tolerance. Divide the new total amount by the number of doses permitted based on dosing interval (e.g., 8 doses for every-three-hour dosing). Titrate the dose according to the patient's response. For opioids not in Table 1, first estimate the daily amount of morphine that is equivalent to the current total daily amount of other opioid(s) received, then use Table 1 to find the approximate equivalent total daily dose of hydromorphone hydrochloride injection (HPF).

2.5 Hydromorphone Hydrochloride Injection (HPF) (for use in opioid-tolerant patients only)

Do not use Hydromorphone Hydrochloride Injection (HPF) for patients who are not tolerant to the respiratory depressant or sedating effects of opioids. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer.

Use Hydromorphone Hydrochloride Injection (HPF) ONLY for patients who require the higher concentration and lower total volume of Hydromorphone Hydrochloride Injection (HPF).

Because of its high concentration, the delivery of precise doses of hydromorphone hydrochloride injection (HPF) may be difficult if low doses of hydromorphone are required. Therefore, use hydromorphone hydrochloride injection (HPF) only if the amount of hydromorphone required can be delivered accurately with this formulation.

Base the starting dose for hydromorphone hydrochloride injection (HPF) on the prior dose of hydromorphone hydrochloride injection or on the prior dose of an alternate opioid as described above in Section 2.4 Conversion From Prior Opioid and Table 1.

2.6 Administration and Reconstitution

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. A slight yellowish discoloration may develop in hydromorphone hydrochloride injection (HPF) ampules. No loss of potency has been demonstrated. Hydromorphone hydrochloride injection (HPF) are 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. Discard any unused portion in an appropriate manner.

3 DOSAGE FORMS AND STRENGTHS

Hydromorphone Hydrochloride Injection (high potency formulation) (for use in opioid-tolerant patients only): Each amber ampule and amber single-dose vial contains 10 mg/mL of hydromorphone hydrochloride in a sterile, aqueous solution and is available in 1 mL or 5 mL ampules or in 50 mL single-dose vials^†.

^† The Stoppers Of These Product Does Not Contain Natural Rubber Latex.

4 CONTRAINDICATIONS

Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] is contraindicated:

• In patients with known hypersensitivity to hydromorphone, hydromorphone salts, any other components of the product, or sulfite-containing medications [see WARNINGS AND PRECAUTIONS, Sulfites (5.8)].
• In any situation where opioids are contraindicated, e.g., in patients with respiratory depression in the absence of resuscitative equipment or in unmonitored settings; or patients with acute or severe bronchial asthma.
• In patients with, or at risk of developing, gastrointestinal obstruction, especially paralytic ileus because hydromorphone diminishes the propulsive peristaltic wave in the gastrointestinal tract and may prolong the obstruction.

Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] is contraindicated in patients who are not opioid tolerant [see WARNINGS AND PRECAUTIONS (5.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Risk of Medication Errors

Hydromorphone HCl Injection (HPF) is a 10 mg/mL concentrated solution of hydromorphone, and is intended for use in opioid-tolerant patients only. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer.

Do not confuse Hydromorphone HCl Injection (HPF) with standard parenteral formulations of Hydromorphone HCl Injection (1 mg/mL, 2 mg/mL, 4 mg/mL) or other opioids, as overdose and death could result.

Morphine does not convert to hydromorphone on a mg per mg basis. Use Table 1 when converting a patient from morphine to hydromorphone to avoid errors that can lead to overdose or death.

5.2 Respiratory Depression

Respiratory depression is the chief hazard of Hydromorphone HCl injection (HPF). Respiratory depression occurs most frequently in the elderly, in the debilitated, and in those suffering from conditions accompanied by hypoxia or hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may dangerously decrease pulmonary ventilation. Respiratory depression is also a particular problem following large initial doses in non opioid-tolerant patients or when opioids are given in conjunction with other agents that depress respiration.

Use Hydromorphone HCl Injection (HPF) 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. Consider using non-opioid analgesics, and administer Hydromorphone HCl Injection only under careful medical supervision at the lowest effective dose in such patients.

5.3 Misuse, Abuse and Diversion of Opioids

Hydromorphone HCl Injection (HPF) contain hydromorphone, an opioid agonist with an abuse liability similar to morphine, and a Schedule II, controlled substance. Hydromorphone has the potential for being abused, is sought by drug abusers and people with addiction disorders, and is subject to criminal diversion. Diversion of Schedule II products is an act subject to criminal penalty.

Abuse of Hydromorphone HCl Injection (HPF), poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol or other substances. Schedule II opioid agonists have the highest potential for abuse and risk of fatal respiratory depression.

Hydromorphone HCl Injection (HPF) can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Hydromorphone HCl Injection (HPF) in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.

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.

5.4 Interactions with Alcohol and other CNS Depressants

The concurrent use of Hydromorphone HCl Injection (HPF) with other central nervous system (CNS) depressants, including but not limited to, other opioids, illicit drugs, sedatives, hypnotics, general anesthetics, phenothiazines, muscle relaxants, other tranquilizers, and alcohol, increases the risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. Use with caution and in reduced dosages in patients taking CNS depressants.

5.5 Neonatal Withdrawal Syndrome

Infants born to mothers physically dependent on Hydromorphone HCl Injection (HPF) will also be physically dependent and may exhibit signs of withdrawal. 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. Neonatal opioid withdrawal syndrome may be life threatening and should be treated according to protocols developed by neonatology experts [see DRUG ABUSE AND DEPENDENCE (9.3)].

5.6 Use in Increased Intracranial Pressure or Head Injury

The respiratory depressant effects of Hydromorphone HCl Injection (HPF) promote carbon dioxide retention which results in elevation of cerebrospinal fluid pressure. This increase in intracranial pressure may be markedly exaggerated in the presence of head injury, intracranial lesions, or other conditions that predispose patients to increased intracranial pressure.

Hydromorphone HCl Injection (HPF) 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.

5.7 Hypotensive Effect

Hydromorphone HCl Injection (HPF) may cause severe hypotension in patients whose ability to maintain blood pressure is compromised by a depleted blood volume, or a concurrent administration of drugs such as phenothiazines, general anesthetics, or other agents which compromise vasomotor tone [see DRUG INTERACTIONS (7.1)].

Hydromorphone HCl Injection (HPF) may produce orthostatic hypotension in ambulatory patients.

Administer Hydromorphone HCl Injection (HPF) with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

5.8 Sulfites

Hydromorphone HCl Injection (HPF) contain 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.

5.9 Use in Pancreatic/Biliary Tract Disease and Other Gastrointestinal Conditions

The administration of Hydromorphone HCl Injection (HPF) may obscure the diagnosis or clinical course in patients with acute abdominal conditions [see CONTRAINDICATIONS (4.0)].

Use Hydromorphone HCl Injection (HPF) with caution in patients who are at risk of developing ileus.

Use Hydromorphone HCl Injection (HPF) with caution in patients with biliary tract disease, including acute pancreatitis, as hydromorphone may cause spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions.

5.10 Special Risk Patients

Give Hydromorphone HCl Injection (HPF) 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; acute alcoholism; delirium tremens; or kyphoscoliosis associated with respiratory depression.

The administration of opioid analgesics including Hydromorphone HCl Injection (HPF) may aggravate preexisting convulsions in patients with convulsive disorders.

Hydromorphone HCl Injection (HPF), as with other opioids, may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings.

Reports of mild to severe seizures and myoclonus have been reported in severely compromised patients, administered high doses of parenteral hydromorphone.

5.11 Use in Drug and Alcohol Dependent Patients

Use Hydromorphone HCl Injection (HPF) 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 HCl Injection (HPF) in combination with other CNS depressant drugs can result in serious risk to the patient.

Hydromorphone HCl Injection (HPF) contain hydromorphone, an opioid with no approved use in the management of addiction disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission, is for the management of pain requiring opioid analgesia.

5.12 Use in Ambulatory Patients

Hydromorphone HCl Injection (HPF) 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 HCl Injection (HPF) may produce orthostatic hypotension in ambulatory patients.

5.13 Parenteral Administration

Hydromorphone HCl Injection may be given intravenously, but the injection should be given very slowly. Rapid intravenous injection of opioid analgesics increases the possibility of side effects such as hypotension and respiratory depression [see DOSAGE AND ADMINISTRATION (2.3)].

6 ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Serious adverse reactions associated with Hydromorphone HCl Injection (HPF) include respiratory depression and apnea and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest.

The following serious adverse reactions described elsewhere in the labeling include:

• Respiratory depression and secondary effects on intracranial pressure [see WARNINGS AND PRECAUTIONS (5.2, 5.6)]
• Hypotension [see WARNINGS AND PRECAUTIONS (5.7)]
• Gastrointestinal effects and effects in sphincter of Oddi [see WARNINGS AND PRECAUTIONS (5.9)]
• Drug abuse, addiction, and dependence [see DRUG ABUSE AND DEPENDENCE (9.2, 9.3)]
• Effects on the ability to drive and operate machinery [see WARNINGS AND PRECAUTIONS (5.12)]

The most common 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

Cardiac disorders: tachycardia, bradycardia, palpitations

Eye disorders: vision blurred, diplopia, miosis, visual impairment

Gastrointestinal disorders: constipation, ileus, diarrhea, abdominal pain

General disorders and administration site conditions: weakness, feeling abnormal, chills, injection site urticaria

Hepatobiliary disorders: biliary colic

Metabolism and nutrition disorders: decreased appetite

Musculoskeletal and connective tissue disorders: muscle rigidity

Nervous system disorders: headache, tremor, paraesthesia, nystagmus, increased intracranial pressure, syncope, taste alteration, involuntary muscle contractions, presyncope

Psychiatric disorders: agitation, mood altered, nervousness, anxiety, depression, hallucination, disorientation, insomnia, abnormal dreams

Renal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effects

Respiratory, thoracic, and mediastinal disorders: bronchospasm, laryngospasm

Skin and subcutaneous tissue disorders: injection site pain, urticaria, rash, hyperhidrosis

Vascular disorders: flushing, hypotension, hypertension

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of hydromorphone. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylactic reactions, confusional state, convulsions, drowsiness, dyskinesia, dyspnea, erectile dysfunction, fatigue, hepatic enzymes increased, hyperalgesia, hypersensitivity reaction, injection site reactions, lethargy, myoclonus, oropharyngeal swelling, peripheral edema, and somnolence.

7 DRUG INTERACTIONS

7.1 Drug Interactions with other CNS Depressants

Hydromorphone HCl Injection (HPF) should be used with caution and in reduced dosages when administered to patients concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, centrally acting anti-emetics, tranquilizers, and alcohol because respiratory depression, hypotension, and profound sedation or coma may result.

When such combined therapy is contemplated, the dose of one or both agents should be reduced. Opioid analgesics, including Hydromorphone HCl Injection (HPF), may enhance the action of neuromuscular blocking agents and produce an increased degree of respiratory depression.

7.2 Interactions with Mixed Agonist/Antagonist Opioid Analgesics

Agonist/antagonist analgesics (e.g., pentazocine, nalbuphine, and butorphanol) and partial agonist analgesics (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 HCl Injection (HPF). In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of Hydromorphone HCl Injection (HPF) and/or may precipitate withdrawal symptoms in these patients.

7.3 Monoamine Oxidase Inhibitors (MAOIs)

MAOIs may potentiate the action of Hydromorphone HCl Injection (HPF). Allow at least 14 days after stopping treatment with MAOIs before initiating treatment with Hydromorphone HCl Injection (HPF).

7.4 Anticholinergics

Anticholinergics or other medications with anticholinergic activity when used concurrently with Hydromorphone HCl Injection (HPF) may result in increased risk of urinary retention and severe constipation, which may lead to paralytic ileus.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Hydromorphone crosses the placenta. Hydromorphone HCl Injection (HPF) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

No effects on teratogenicity or embryotoxicity were observed in pregnant rats given oral doses up to 7 mg/kg/day which is 3-fold higher than the human dose of 24 mg Hydromorphone HCl Injection (HPF) (4 mg every 4 hours), on a body surface area basis. Hydromorphone administration to pregnant Syrian hamsters and CF-1 mice during major organ development revealed teratogenic effects likely the result of maternal toxicity associated with sedation and hypoxia. In Syrian hamsters given single subcutaneous doses from 14 to 258 mg/kg during organogenesis (gestation days 8-10), doses ≥ 19 mg/kg of hydromorphone produced skull malformations (exencephaly and cranioschisis). In CF-1 mice, continuous infusion of hydromorphone (≥ 15 mg/kg over 24 hours) via implanted osmotic pumps during organogenesis (gestation days 7-10) produced soft tissue malformations (cryptorchidism, cleft palate, malformed ventricles and retina), and skeletal variations (split supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites). The malformations and variations observed in the hamsters and mice were observed at doses approximately 6-fold and 3-fold higher, respectively, than the human dose of 24 mg Hydromorphone HCl Injection (HPF) (4 mg every 4 hours), on a body surface area basis.

8.2 Labor and Delivery

Hydromorphone HCl Injection (HPF) should be used with caution during labor. Opioids cross the placenta and may produce respiratory depression and physiologic effects in neonates. Sinusoidal fetal heart rate patterns may occur with the use of opioid analgesics.

Occasionally, opioid analgesics, including Hydromorphone HCl Injection (HPF), may prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.

Opioid analgesics, including Hydromorphone HCl Injection (HPF), may cause respiratory depression in the newborn. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. Have a specific opioid antagonist, such as naloxone or nalmefene, available for reversal of opioid-induced respiratory depression in the neonate.

Neonates whose mothers have been taking opioids chronically may also exhibit withdrawal signs, either at birth or in the nursery, because they have developed physical dependence. This is not, however, synonymous with addiction [see DRUG ABUSE AND DEPENDENCE (9.3)]. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts [see WARNINGS AND PRECAUTIONS (5.3)]. The effect of Hydromorphone HCl Injection (HPF), if any, on the later growth, development, and functional maturation of the child is unknown.

8.3 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 HCl Injection (HPF) since it, and other drugs in this class, may be excreted in the milk.

8.4 Pediatric Use

The safety and effectiveness of Hydromorphone HCl Injection (HPF) in pediatric patients has not been established.

8.5 Geriatric Use

Clinical studies of Hydromorphone HCl Injection (HPF) 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. Respiratory depression is the chief risk in elderly or debilitated patients, usually the result of large initial doses in non-opioid-tolerant patients. Titration in these patients should proceed cautiously [see DOSAGE AND ADMINISTRATION (2.4) and WARNINGS AND PRECAUTIONS (5.10)].

8.6 Renal Impairment

The pharmacokinetics of hydromorphone following an oral administration of hydromorphone at a single 4 mg dose (2 mg hydromorphone immediate-release tablets) are affected by renal impairment. Mean exposure to hydromorphone (C_max and AUC_0-OC) is increased by 2-fold in patients with moderate (CLcr = 40 - 60 mL/min) renal impairment and increased by 4-fold in patients with 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 a longer terminal elimination half-life (40 hr) compared to patients with normal renal function (15 hr). Start patients with renal impairment on one-fourth to one-half the usual starting dose depending on the degree of impairment. Patients with renal impairment should be closely monitored during dose titration [see CLINICAL PHARMACOLOGY (12.2)].

8.7 Hepatic Impairment

The pharmacokinetics of hydromorphone following an oral administration of hydromorphone at a single 4 mg dose (2 mg hydromorphone immediate-release tablets) are affected by hepatic impairment. Mean exposure to hydromorphone (C_max 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 one-fourth to one-half the recommended starting dose depending on the degree of hepatic dysfunction and closely monitored during dose titration. The pharmacokinetics of hydromorphone in patients with severe hepatic impairment has not been studied. A further increase in C_max and AUC of hydromorphone in this group is expected and should be taken into consideration when selecting a starting dose [see CLINICAL PHARMACOLOGY (12.2)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Hydromorphone HCl Injection (HPF) contain hydromorphone, which is a Schedule II controlled substance with an abuse liability similar to morphine. Hydromorphone hydrochloride can be abused and is subject to criminal diversion.

9.2 Abuse

Hydromorphone HCl Injection (HPF) are intended for parenteral use only under the direct supervision of an appropriately licensed health care professional.

Abuse of Hydromorphone HCl Injection (HPF) poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol or other substances. Parenteral drug abuse is commonly associated with transmission of infectious diseases, such as hepatitis and HIV.

Hydromorphone HCl Injection (HPF) can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing, dispensing, ordering, or administering Hydromorphone HCl Injection (HPF) 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 indications of abuse.

Opioid drugs are sought by people with substance use disorders (abuse or addiction, the latter of which is also called “substance dependence”) and criminals who supply them by diverting medicines out of legitimate distribution channels. Hydromorphone HCl Injection (HPF) are targets for diversion.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include, but are not limited to, emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, altering or forging of 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 people with untreated substance use disorders and criminals who divert controlled substances.

The risks of misuse and abuse should be considered when prescribing or dispensing Hydromorphone HCl Injection (HPF). Concerns about abuse and addiction should not prevent the proper management of pain, however. Treatment of pain should be individualized, balancing the potential benefits and risks for each patient.

Addiction is defined as a chronic, neurobiological disorder with genetic, psychosocial, and environmental aspects, characterized by 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.

Abuse and addiction are separate and distinct from physical dependence and tolerance. 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 nonmedical purposes, often in combination with other psychoactive substances. Careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, proper dispensing and correct storage and handling are appropriate measures that help to limit misuse and abuse of opioid drugs. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

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.

9.3 Dependence

Tolerance to opioids is demonstrated by the need for increasing doses to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance to different effects of opioids may develop to varying degrees and at varying rates in a given individual. There is also interpatient variability in the rate and extent of tolerance that develops to various opioid effects, whether the effect is desirable (e.g., analgesia) or undesirable (e.g., nausea). In general, patients taking opioid analgesics that are appropriately titrated for pain control develop tolerance to the respiratory depressant effects fairly reliably. Conversely, tolerance to the constipating effects of opioids rarely develops, even when they are administered over long periods of time.

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, and mydriasis. Other signs and 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.

10 OVERDOSAGE

10.1 Signs and Symptoms

Signs and symptoms of acute overdosage with Hydromorphone HCl Injection (HPF) include: respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, apnea, circulatory collapse, cardiac arrest, and death.

Hydromorphone may cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis, rather than miosis, may be seen with hypoxia in overdose situations.

10.2 Treatment

In the treatment of overdosage, primary attention should be given to the reestablishment 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 HCl Injection (HPF). Therefore, an appropriate dose of this antagonist should be administered, preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on Hydromorphone HCl Injection (HPF). In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

Since the duration of action of Hydromorphone HCl Injection (HPF) 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.

11 DESCRIPTION

Hydromorphone hydrochloride, a hydrogenated ketone of morphine, is an opioid analgesic. The chemical name of hydromorphone hydrochloride is 4,5a-epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochlorid. The structural formula is:

Hydromorphone hydrochloride injection [high potency formulation (HPF)] is available as a sterile, aqueous solution in AMBER ampules and in AMBER, single-dose vials for intravenous, subcutaneous, or intramuscular administration. Each ampule and single-dose vial contains 10 mg/mL of hydromorphone hydrochloride with 0.2% sodium citrate and 0.2% citric acid added as a buffer to maintain a pH of between 3.5 and 5.5. The single dose vials are capped with stoppers containing natural rubber latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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 hydrochloride is a mu-opioid receptor agonist whose principal therapeutic action is analgesia. Other members of the class known as opioid agonists include substances such as morphine, oxycodone, fentanyl, codeine, hydrocodone, and oxymorphone.

Central Nervous System

Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, and cough suppression, as well as analgesia.

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 (pontine lesions of hemorrhagic or ischemic origin may produce similar findings).

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.

Endocrine System

Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes.

Immune System

In vitro and animal studies indicate that opioids have a variety of effects on immune functions. The clinical significance of these findings is unknown.

12.2 Pharmacokinetics

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 (2 mg hydromorphone immediate-release tablets), mean exposure to hydromorphone (C_max and AUC∞) is increased 4-fold in patients with moderate (Child-Pugh Group B) hepatic impairment compared with subjects with normal hepatic function. Patients with moderate hepatic impairment should be started at one-fourth to one-half the recommended starting dose and closely monitored during dose titration. The pharmacokinetics of hydromorphone in patients with severe hepatic impairment has not been studied. A further increase in C_max and AUC of hydromorphone in this group is expected and should be taken into consideration when selecting a starting dose [see USE IN SPECIFIC POPULATIONS (8.7)].

Renal Impairment

The pharmacokinetics of hydromorphone following an oral administration of hydromorphone at a single 4 mg dose (2 mg hydromorphone immediate-release tablets) are affected by renal impairment. Mean exposure to hydromorphone (C_max and AUC_0-∞) is increased by 2-fold in patients with moderate (CLcr = 40 - 60 mL/min) renal impairment and increased by 4-fold in patients with 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 a longer terminal elimination half-life (40 hr) compared to patients with normal renal function (15 hr). Start patients with renal impairment on one-fourth to one-half the usual starting dose depending on the degree of impairment. Patients with renal impairment should be closely monitored during dose titration [see USE IN SPECIFIC POPULATIONS (8.6)]

Pediatrics

Pharmacokinetics of hydromorphone have not been evaluated in children.

Geriatric

In the geriatric population, age has no effect on the pharmacokinetics of hydromorphone.

Gender

Gender has little effect on the pharmacokinetics of hydromorphone. Females appear to have a higher C_max (25%) than males with comparable AUC_0-24 values. The difference observed in C_max may not be clinically relevant.

Race

The effect of race on hydromorphone pharmacokinetics has not been studied.

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long term studies in animals to evaluate the carcinogenic potential of hydromorphone have not been conducted.

Mutagenesis

Hydromorphone was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay). Hydromorphone was not clastogenic in either the in vitro human lymphocyte chromosome aberration assay or the in vivo mouse micronucleus assay.

Impairment of Fertility

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 3-fold higher than the human dose of 24 mg Hydromorphone hydrochloride injection (4 mg every 4 hours), on a body surface area basis.

14 CLINICAL STUDIES

Analgesic effects of single doses of Hydromorphone Hydrochloride Oral Liquid administered to patients with post-surgical pain have been studied in double-blind controlled trials. In one study, both 5 mg and 10 mg of Hydromorphone Hydrochloride Oral Liquid provided significantly more analgesia than placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 Safety And Handling Instructions

Hydromorphone Hydrochloride Injection (HPF) pose little risk of direct exposure to health care personnel and should be handled and disposed of prudently in accordance with hospital or institutional policy. When Hydromorphone Hydrochloride Injection (HPF) is no longer needed, any unused liquid should be destroyed by flushing it down the toilet.

Access to drugs with a potential for abuse such as Hydromorphone Hydrochloride Injection (HPF) 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.

16.2 How Supplied

Hydromorphone Hydrochloride Injection (High Potency Formulation) is available in AMBER ampules, and single dose vials. Each 1 mL of sterile solution contains 10 mg of hydromorphone hydrochloride with 0.2% sodium citrate and 0.2% citric acid. No added preservative.

Hydromorphone hydrochloride injection (High Potency Formulation) is supplied as follows:

NDC 17478-540-01           Box of ten 1 mL (10 mg) ampules

NDC 17478-540-05           Box of ten 5 mL (50 mg) ampules

NDC 17478-540-50           One 50 mL (500 mg) Single-dose Vial.

^† The Stoppers Of These Product Does Not Contain Natural Rubber Latex.

16.3 Storage

Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Protect from light.

Keep covered in carton until time of use.

CAUTION: DEA Order Form Required.

AKORN

Manufactured by: Akorn, Inc.
Lake Forest, IL 60045

HM00N
Rev. 02/13

Principal Display Panel Text for Container Label:

NDC 17478-540-05 Akorn

High Potency Formulation

Hydromorphone

Hydrochloride

Injection, USP CII

50 mg/5 mL (10 mg/mL)

Rx only Sterile

5 mL Ampule

FOR USE IN THE PREPARATION OF

LARGE VOLUME PARENTERAL SOLUTIONS