Hydromorphone Hydrochloride Injection USP (Jamp Pharma) Product Monograph

RECENT MAJOR LABEL CHANGES

Not applicable.

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ................................................................................ 2

TABLE OF CONTENTS ....................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION ....................................................... 4

1 INDICATIONS............................................................................................................ 4

• 1.1 Pediatrics .........................................................................................................4
• 1.2 Geriatrics ..........................................................................................................4
• 2 CONTRAINDICATIONS............................................................................................ 4
• 3 SERIOUS WARNINGS AND PRECAUTIONS BOX............................................... 5
• 4 DOSAGE AND ADMINISTRATION ......................................................................... 6
• 4.1 Dosing Considerations ....................................................................................6
• 4.2 Recommended Dose and Dosage Adjustment..............................................7
• 4.3 Administration ................................................................................................10
• 5 OVERDOSAGE ....................................................................................................... 10
• 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............ 11
• 7 WARNINGS AND PRECAUTIONS ........................................................................ 12
• 7.1 Special Populations ...................................................................................... 19
• 7.1.1 Pregnant Women.......................................................................................... 19
• 7.1.2 Breast-feeding .............................................................................................. 20
• 7.1.3 Pediatrics (<18 years of age) ....................................................................... 20
• 7.1.4 Geriatrics (>65 years of age) ....................................................................... 20
• 7.1.5 Patients with Hepatic Impairment ................................................................ 20
• 7.1.6 Patients with Renal Impairment ................................................................... 20

8 ADVERSE REACTIONS ......................................................................................... 21

• 8.1 Adverse Reaction Overview......................................................................... 21
• 8.2 Adverse Reactions ....................................................................................... 22
• 8.3 Post-Market Adverse Reactions .................................................................. 23

9 DRUG INTERACTIONS .......................................................................................... 24

• 9.1 Serious Drug Interactions Box ..................................................................... 24
• 9.2 Overview ....................................................................................................... 25
• 9.3 Drug-Drug Interactions ................................................................................. 25
• 9.4 Drug-Food Interactions................................................................................. 25
• 9.5 Drug-Herb Interactions ................................................................................. 26
• 9.6 Drug-Laboratory Test Interactions ............................................................... 26
• 9.7 Drug-Lifestyle Interactions ........................................................................... 26

10 ACTION AND CLINICAL PHARMACOLOGY ...................................................... 26

• 10.1 Mechanism of Action .................................................................................... 26
• 10.2 Pharmacodynamics ...................................................................................... 26
• 10.3 Pharmacokinetics ......................................................................................... 27

11 STORAGE AND STABILITY .................................................................................. 28

12 SPECIAL HANDLING INSTRUCTIONS ................................................................ 28

PART II: SCIENTIFIC INFORMATION ............................................................................. 29

13 PHARMACEUTICAL INFORMATION ................................................................... 29

14 SUPPORTING PRODUCT MONOGRAPHS ......................................................... 30

PATIENT MEDICATION INFORMATION ......................................................................... 31

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

HYDROmorphone Hydrochloride Injection USP (HYDROmorphone hydrochloride) is indicated for the relief of moderate to severe pain in adults.

1.1 Pediatrics

Pediatrics (< 18 years of age): The safety and efficacy of HYDROmorphone Hydrochloride Injection USP has not been studied in the pediatric population. Therefore the use of HYDROmorphone Hydrochloride Injection USP is not recommended in patients under 18 years of age.

1.2 Geriatrics

Geriatrics (> 65 years of age ): In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, and titrated slowly, reflecting the greater frequency of decreased hepatic, renal or cardiac function, concomitant disease or other drug therapy (see 7 WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).

2 CONTRAINDICATIONS

HYDROmorphone Hydrochloride Injection USP is contraindicated in:

• Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• Patients who are hypersensitive to other opioid analgesics.
• Patients with known or suspected mechanical gastrointestinal obstruction (e.g., bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (e.g., ileus of any type).
• Patients with suspected surgical abdomen (e.g., acute appendicitis or pancreatitis).
• Patients with mild pain that can be managed with other pain medications.
• Patients with acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus.
• Patients with acute respiratory depression, elevated carbon dioxide (CO₂) levels in the blood and cor pulmonale.
• Patients with acute alcoholism, delirium tremens, and convulsive disorders.
• Patients with severe CNS depression, increased cerebrospinal or intracranial pressure, and head injury.
• Patients taking monoamine oxidase (MAO) inhibitors (or within 14 days of such therapy).
• Women who are breast-feeding, pregnant, or during labour and delivery (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX and 7 WARNINGS AND PRECAUTIONS).

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

For acute pain, it is recommended that HYDROmorphone Hydrochloride Injection USP be used for a maximum of 7 days at the lowest dose that provides adequate pain relief.

All doses of opioids carry an inherent risk of fatal or non-fatal adverse events. This risk is increased with higher doses. For the management of chronic non-cancer, non-palliative pain, it is recommended that 13.5 mg (90 morphine milligram equivalent) of HYDROmorphone Hydrochloride Injection USP not be exceeded. Each patient should be assessed for their risk prior to prescribing HYDROmorphone Hydrochloride Injection USP, as the likelihood of experiencing serious adverse events can depend upon the type of opioid, duration of treatment, level of pain as well as the patient’s own level of tolerance. In addition, the level of pain should be assessed routinely to confirm the most appropriate dose and the need for further use of HYDROmorphone Hydrochloride Injection USP (see 4 DOSAGE AND ADMINISTRATION - Adjustment or reduction of Dosage).

HYDROmorphone Hydrochloride Injection USP should only be used in patients for whom alternative treatment options (e.g., non-opioid analgesics) are ineffective, or not tolerated, or would be otherwise inadequate to provide appropriate management of pain.

Rapid intravenous injection of opioid analgesics increases the possibility of hypotension and respiratory depression.

HYDROmorphone Hydrochloride Injection USP is not indicated for rectal administration.

Sterile Solution for Injection: HYDROmorphone Hydrochloride Injection USP sterile solution for injection is to be visually inspected prior to use. Only clear solutions practically free from particles should be used. The injection should be given immediately after opening the ampoule. Once opened, any unused portion should be discarded.

4.2 Recommended Dose and Dosage Adjustment

Pediatrics (<18 years of age): Health Canada has not authorized an indication for pediatric use (see 1 INDICATIONS).

Adults (≥18 years of age): Individual dosing requirements vary considerably based on each patient’s age, weight, severity and cause of pain, and medical and analgesic history.

Patients Not Receiving Opioids at the Time of Initiation of HYDROmorphone Treatment The usual adult parenteral dose for pain relief is 2 mg by subcutaneous or intramuscular route every 4 to 6 hours as necessary. If necessary, HYDROmorphone may be given intravenously, but the injection should be given very slowly. Rapid intravenous injection of opioid analgesics increases the possibility of hypotension and respiratory depression. Severe pain can be controlled with 3 to 4 mg every 4 to 6 hours as necessary.

HYDROmorphone hydrochloride injection has been reported to be physically or chemically incompatible with solutions containing sodium bicarbonate and thiopenthal sodium.

Patients Currently Receiving Opioids

For patients who are receiving an alternate opioid, the “oral HYDROmorphone equivalent” of the analgesic presently being used, should be determined. Having determined the total daily dosage of the present analgesic, Table 1 can be used to calculate the approximate daily oral HYDROmorphone dosage that should provide equivalent analgesia. Further dose reductions should be considered due to incomplete cross- tolerance between opioids.

Opioid Rotation: Conversion ratios for opioids are subject to variations in kinetics governed by genetics and other factors. When switching from one opioid to another, consider reducing the calculated dose by 25-50% to minimize the risk of overdose. Subsequently, up-titrate the dose, as required, to reach the appropriate maintenance dose.

Table 1: Opioid Analgesics - Approximate Analgesic Equivalences ¹

Footnotes:

¹References:

Expert Advisory Committee on the Management of Severe Chronic Pain in Cancer Patients, Health and Welfare Canada. Cancer pain: A monograph on the management of cancer pain. Ministry of Supplies and Services Canada, 1987. Cat. No. H42-2/5-1984E.

Foley KM. The treatment of cancer pain. N Engl J Med 1985;313(2):84-95.

Aronoff GM, Evans WO. Pharmacological management of chronic pain: A review. In: Aronoff GM, editor.

Evaluation and treatment of chronic pain. 2nd ed. Baltimore (MD): Williams and Wilkins; 1992. p. 359-68.

Cherny NI, Portenoy RK. Practical issues in the management of cancer pain. In: Wall PD, Melzack R, editors. Textbook of pain. 3rd ed. New York: Churchill Livingstone; 1994. p. 1437-67.

² Most of this data was derived from single-dose, acute pain studies and should be considered an approximation for selection of doses when treating chronic pain. As analgesic conversion factors are approximate and patient response may vary, dosing should be individualized according to relief of pain and side effects. Because of incomplete cross-tolerance, dose reductions of 25% to 50% of the equianalgesic dose may be appropriate in some patients when converting from one opioid to another, particularly at high doses.† Upward titration may be required to reach appropriate maintenance doses.

†Levy MH. Pharmacologic treatment of cancer pain. N Engl J Med 1996;335:1124-1132.

³ For acute pain, the oral or rectal dose of morphine is six times the injectable dose. However, for chronic dosing, clinical experience indicates that this ratio is 2-3:1 (i.e., 20-30 mg of oral or rectal morphine is equivalent to 10 mg of parenteral morphine).

⁴ Based on single entity oral oxycodone in acute pain.

⁵ Clinical experience indicates that during chronic dosing the oral morphine/ oral HYDROmorphone dose ratio is 5 - 7.5:1.

⁶ Extremely variable equianalgesic dose. Patients should undergo individualized titration starting at an equivalent to 1/10 of the morphine dose.

⁷ Not recommended for the management of chronic pain.

⁸ Mixed agonist-antagonists can precipitate withdrawal in patients on pure opioid agonists.

Patients with Hepatic Impairment

Start patients on one-fourth to one-half the usual HYDROmorphone Hydrochloride Injection USP injection starting dose depending on the degree of impairment. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression during initiation of therapy with HYDROmorphone Hydrochloride Injection USP and during dose titration. Use of alternate analgesics is recommended for patients with severe hepatic impairment (see 7 WARNINGS AND PRECAUTIONS, Special Populations, Hepatic Impairment).

Patients with Renal Impairment

Start patients on one-fourth to one-half the usual HYDROmorphone Hydrochloride Injection USP injection starting dose depending on the degree of impairment. Closely monitor patients with renal impairment for respiratory and central nervous system depression during initiation of therapy with HYDROmorphone Hydrochloride Injection USP and during dose titration (see 7 WARNINGS AND PRECAUTIONS, Special Populations, Renal Impairment).

Geriatrics

Respiratory depression has occurred in the elderly following administration of large initial doses of opioids to patients who were not opioid-tolerant or when opioids were co- administered with other agents that can depress respiration. HYDROmorphone Hydrochloride Injection USP should be initiated at a low end of the dosing range and slowly titrated (see 7 WARNINGS AND PRECAUTIONS).

Use with Non-Opioid Medications

If a non-opioid analgesic is being provided, it may be continued. If the non-opioid is discontinued, consideration should be given to increasing the opioid dose to compensate for the non-opioid analgesic. HYDROmorphone Hydrochloride Injection USP can be safely used concomitantly with usual doses of other non-opioid analgesics.

Dose Titration

Dose titration is the key to success with opioid analgesic therapy. Proper optimization of doses scaled to the relief of the individual’s pain should aim at the regular administration of the lowest dose of HYDROmorphone Hydrochloride Injection USP which will achieve the overall treatment goal of satisfactory pain relief with acceptable side effects.

Dosage adjustments should be based on the patient’s clinical response.

Adjustment or Reduction of Dosage

Physical dependence with or without psychological dependence tends to occur with chronic administration of opioids, including HYDROmorphone Hydrochloride Injection USP. Withdrawal (abstinence) symptoms may occur following abrupt discontinuation of therapy. These symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning.

Following successful relief of moderate to severe pain, periodic attempts to reduce the opioid dose should be made. Smaller doses or complete discontinuation may become feasible due to a change in the patient’s condition or mental state. Patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer required for pain control. In patients who are appropriately treated with opioid analgesics and who undergo gradual withdrawal for the drug, these symptoms are usually mild (see 7 WARNINGS AND PRECAUTIONS). Tapering should be individualized and carried out under medical supervision.

Patients should be informed that reducing and/or discontinuing opioids decreases their tolerance to these drugs. If treatment needs to be re-initiated, the patient must start at the lowest dose and titrate up to avoid overdose.

Opioid analgesics may only be partially effective in relieving dysesthetic pain, postherpetic neuralgia, stabbing pains, activity-related pain and some forms of headache. That is not to say that patients with advanced cancer suffering from some of these forms of pain should not be given an adequate trial of opioid analgesics, but it may be necessary to refer such patients at an early time to other forms of pain therapy.

4.3 Administration

The usual adult parenteral dose for pain relief is 2 mg by subcutaneous or intramuscular route every 4 to 6 hours as necessary. If necessary, HYDROmorphone may be given intravenously, but the injection should be given very slowly. Rapid intravenous injection of opioid analgesics increases the possibility of hypotension and respiratory depression.

HYDROmorphone hydrochloride injection has been reported to be physically or chemically incompatible with solutions containing sodium bicarbonate and thiopenthal sodium.

5 OVERDOSAGE

Symptoms

Serious overdosage with HYDROmorphone Hydrochloride Injection USP is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), dizziness, confusion, extreme somnolence progressing to stupor or coma, pneumonia aspiration, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, toxic leukoencephalopathy, delayed post-hypoxic leukoencephalopathy and sometimes bradycardia and hypotension. In severe overdosage, particularly following intravenous injection, apnea, circulatory collapse, cardiac arrest and death may occur.

Treatment

In the treatment of overdosage, primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. It should be borne in mind that for individuals who are physically dependent on opioids and are receiving large doses of these drugs, the administration of the usual dose of opioid 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 an opioid antagonist in such persons 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, commencing with 10 to 20% of the usual recommended initial dose.

Respiratory depression which may result from overdosage, or unusual sensitivity to HYDROmorphone in a non-opioid-tolerant patient, can be managed with the opioid antagonist naloxone. 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 cardiovascular depression. Naloxone should be administered cautiously to persons who are known or suspected to be physically dependent on HYDROmorphone. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome.

Since the duration of action of HYDROmorphone 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. Other supportive measures should be applied when indicated.

Supportive measures, including oxygen and 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.

Evacuation of gastric contents may be useful in removing unabsorbed drug, in particular when an oral formulation has been taken.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 2 – Dosage Forms, Strengths, Composition and Packaging

HYDROmorphone Hydrochloride Injection USP is available as 1 mL ampoules in boxes of 5 or 10 ampoules. Each mL of sterile solution contains: 2 mg HYDROmorphone hydrochloride. Non-medicinal ingredients: 2 mg citric acid, 2 mg sodium citrate, 7.48 mg sodium chloride, hydrochloric acid to adjust pH, and water for injection.

7 WARNINGS AND PRECAUTIONS

Please see the Serious Warnings and Precautions Box at the beginning of Part I: Health Professional Information.

General

HYDROmorphone Hydrochloride Injection USP should be stored securely to avoid theft or misuse.

HYDROmorphone Hydrochloride Injection USP should only be prescribed by healthcare professionals who are knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for the treatment of pain, and in the detection and management of respiratory depression, including the use of opioid antagonists.

In diseases, such as malignant cancers, where pain control is the primary focus, opioid administration at very high doses is associated with seizures and myoclonus.

If necessary, HYDROmorphone may be given intravenously but the injection should be given very slowly. Rapid intravenous injection of narcotic analgesic agents, including HYDROmorphone, increases the possibility of adverse effects, such as hypotension and respiratory depression.

Patients should be cautioned not to consume alcohol while taking HYDROmorphone Hydrochloride Injection USP as it may increase the chance of experiencing serious adverse events, including death (see 9 DRUG INTERACTIONS).

Hyperalgesia that will not respond to a further dose increase of HYDROmorphone may occur at particularly high doses. A HYDROmorphone dose reduction or change in opioid may be required.

Addiction, Abuse and Misuse

Like all opioids, HYDROmorphone Hydrochloride Injection USP is a potential drug of abuse and misuse, which can lead to overdose and death. Therefore, HYDROmorphone Hydrochloride Injection USP should be prescribed and handled with caution. This risk is increased if HYDROmorphone Hydrochloride Injection USP is taken with alcohol or other CNS depressants.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse and abuse.

Opioids, such as HYDROmorphone Hydrochloride Injection USP, should be used with particular care in patients with a history of alcohol and illicit /prescription drug abuse. However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.

Cardiovascular Hypotension

HYDROmorphone administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquilizers, sedatives, hypnotics, tricyclic antidepressants or general anesthetics (see 9 DRUG INTERACTIONS). These patients should be monitored for signs of hypotension after initiating or titrating the dose of HYDROmorphone Hydrochloride Injection USP.

The use of HYDROmorphone Hydrochloride Injection USP in patients with circulatory shock should be avoided as it may cause vasodilation that can further reduce cardiac output and blood pressure.

Rapid intravenous injection of opioid analgesics increases the possibility of hypotension and respiratory depression and should be avoided (see 4 DOSAGE AND ADMINISTRATION).

Dependence/Tolerance

As with other opioids, tolerance and physical dependence may develop upon repeated administration of HYDROmorphone and there is a potential for development of psychological dependence. HYDROmorphone Hydrochloride Injection USP should therefore be prescribed and handled with the degree of caution appropriate to the use of a drug with abuse potential.

Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid, and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.

Patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning (see 8 ADVERSE REACTIONS, and 4 DOSAGE AND ADMINISTRATION, Adjustment or Reduction of Dosage).

Use in Drug and Alcohol Addiction

HYDROmorphone Hydrochloride Injection USP is an opioid with no approved use in the management of addictive 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. Patients with a history of addiction to drugs or alcohol may be at higher risk of becoming addicted to HYDROmorphone Hydrochloride Injection USP; extreme caution and awareness is warranted to mitigate the risk.

Driving and Operating Machinery

HYDROmorphone may impair the mental and/or physical abilities needed for certain potentially hazardous activities such as driving a car or operating machinery. Patients should be cautioned accordingly. Patients should also be cautioned about the combined effects of HYDROmorphone with other CNS depressants, including other opioids, phenothiazine, sedatives, hypnotics and alcohol.

Endocrine and Metabolism

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Gastrointestinal

HYDROmorphone and other morphine-like opioids have been shown to decrease bowel motility. HYDROmorphone may obscure the diagnosis or clinical course in patients with acute abdominal conditions and is also contraindicated in patients with paralytic ileus, appendicitis and pancreatitis. HYDROmorphone may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease for worsening symptoms (see 2 CONTRAINDICATIONS and 8 ADVERSE REACTIONS, Nausea and Vomiting and Constipation).

Neonatal Opioid Withdrawal Syndrome (NOWS)

Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life - threatening.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.

Use of HYDROmorphone Hydrochloride Injection USP is contraindicated in pregnant women (see 2 CONTRAINDICATIONS).

Neurologic

Interactions with CNS Depressants (including benzodiazepines and alcohol) HYDROmorphone should be used with caution and in a reduced dosage during concomitant administration of other opioid analgesics, general anesthetics, phenothiazines and other tranquilizers, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, benzodiazepines, centrally-active anti-emetics and other CNS depressants. Respiratory depression, hypotension and profound sedation, coma or death may result.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see 9 DRUG INTERACTIONS). If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when HYDROmorphone Hydrochloride Injection USP is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see 9 DRUG INTERACTIONS).

HYDROmorphone Hydrochloride Injection USP should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects, including death (see 2 CONTRAINDICATIONS and 8 ADVERSE REACTIONS, Sedation, and 9 DRUG INTERACTIONS).

Severe pain antagonizes the subjective and respiratory depressant actions of opioid analgesics. Should pain suddenly subside, these effects may rapidly become manifest.

Use in Patients with Convulsive or Seizure Disorders

The HYDROmorphone in HYDROmorphone Hydrochloride Injection USP may aggravate convulsions in patients with convulsive disorders and may induce or aggravate seizures in some clinical settings. Therefore, HYDROmorphone Hydrochloride Injection USP should not be used in these patients (see 2 CONTRAINDICATIONS).

Serotonin Toxicity / Serotonin Syndrome

Serotonin toxicity also known as serotonin syndrome is a potentially life-threatening condition and has been reported withHYDROmorphone, including HYDROmorphone Hydrochloride Injection USP, particularly during combined use with other serotonergic drugs (see 9 DRUG INTERACTIONS).

Serotonin toxicity is characterised by neuromuscular excitation, autonomic stimulation (e.g., tachycardia, flushing) and altered mental state (e.g., anxiety, agitation, hypomania). In accordance with the Hunter Criteria, serotonin toxicity diagnosis is likely when, in the presence of at least one serotonergic agent, one of the following is observed:

• Spontaneous clonus
• Inducible clonus or ocular clonus with agitation or diaphoresis
• Tremor and hyperreflexia
• Hypertonia and body temperature >38°C and ocular clonus or inducible clonus.

If concomitant treatment with HYDROmorphone Hydrochloride Injection USP and other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see 9 DRUG INTERACTIONS). If serotonin toxicity is suspected, discontinuation of the serotonergic agents should be considered.

Head Injury

The respiratory depressant effects of HYDROmorphone with carbon dioxide (CO₂) retention and the secondary elevation of cerebrospinal fluid pressure may be greatly increased in the presence of head injury, other intracranial lesions, or pre-existing increase in intracranial pressure. Opioid analgesics, including HYDROmorphone may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients, HYDROmorphone Hydrochloride Injection USP should not be used (see 2 CONTRAINDICATIONS).

Peri-Operative Considerations

HYDROmorphone Hydrochloride Injection USP is not indicated for pre-emptive analgesia (administration pre-operatively for the management of post-operative pain).

In the case of planned chordotomy or other pain-relieving operations, patients should not be treated with HYDROmorphone Hydrochloride Injection USP for at least 24 hours before the operation.

Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate. Thereafter, if HYDROmorphone Hydrochloride Injection USP is to be continued after the patient recovers from the post-operative period, a new dosage should be administered in accordance with the changed need for pain relief. The risk of withdrawal in opioid-tolerant patients should be addressed as clinically indicated.

The administration of analgesics in the peri-operative period should be managed by healthcare providers with adequate training and experience (e.g., by an anesthesiologist).

HYDROmorphone and other HYDROmorphone-like opioids have been shown to decrease bowel motility. Ileus is a common post-operative complication, especially after intra-abdominal surgery with opioid analgesia. Caution should be taken to monitor for decreased bowel motility in post- operative patients receiving opioids. Standard supportive therapy should be implemented.

Respiratory

Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. HYDROmorphone should be used with extreme caution in patients with substantially decreased respiratory reserve, pre -existing respiratory depression, hypoxia or hypercapnia (see 2 CONTRAINDICATIONS).

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of HYDROmorphone Hydrochloride Injection USP, the risk is greatest during the initiation of therapy or following a dose increase. Patients should be closely monitored for respiratory depression when initiating therapy with HYDROmorphone Hydrochloride Injection USP and following dose increases.

Life-threatening respiratory depression is more likely to occur in the elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

To reduce the risk of respiratory depression, proper dosing and titration of HYDROmorphone Hydrochloride Injection USP are essential. Overestimating the HYDROmorphone Hydrochloride Injection USP dose when converting patients from another opioid product can result in a fatal overdose with the first dose. In these patients, the use of non-opioid analgesics should be considered, if feasible (see 7 WARNINGS AND PRECAUTIONS, Special Populations, Special Risk Groups, and 4 DOSAGE AND ADMINISTRATION).

Use in Patients with Chronic Pulmonary Disease

Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when initiating therapy and titrating with HYDROmorphone Hydrochloride Injection USP, as in these patients, even usual therapeutic doses of HYDROmorphone Hydrochloride Injection USP may decrease respiratory drive to the point of apnea. In these patients, use of alternative non-opioid analgesics should be considered, if possible. The use of HYDROmorphone Hydrochloride Injection USP is contraindicated in patients with acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus (see 2 CONTRAINDICATIONS).

Sleep Apnea

Opioids can cause sleep-related breathing disorders such as sleep apnea syndromes (including central sleep apnea [CSA]) and hypoxia (including sleep-related hypoxia).

Opioid use increases the risk of CSA in a dose-dependent fashion. Evaluate patients on an ongoing basis for the onset of a new sleep apnea, or a worsening of an existing sleep apnea. In these patients, consider reducing or stopping the opioid treatment if appropriate, using best practices for tapering of opioids (see 7 WARNINGS AND PRECAUTIONS, Dependence/Tolerance; 4 DOSAGE AND ADMINISTRATION, Adjustment or Reduction of Dosage).

Sexual Health Reproduction

Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility (see 8 ADVERSE REACTIONS, Post- Market Adverse Reactions).

Patient Counselling Information

A patient information sheet should be provided to patients when HYDROmorphone Hydrochloride Injection USP is dispensed to them.

Patients receiving HYDROmorphone Hydrochloride Injection USP should be given the following instructions by the physician:

1. 1. Patients should be informed that accidental ingestion or use by individuals (including children) other than the patient for whom it was originally prescribed, may lead to severe, even fatal consequences. HYDROmorphone Hydrochloride Injection USP should be kept under lock and out of sight and out of reach of children.
2. 2. Patients should be advised that HYDROmorphone Hydrochloride Injection USP contains HYDROmorphone, an opioid pain medicine.
3. 3. Patients should be advised that HYDROmorphone Hydrochloride Injection USP should only be taken as directed. The dose of HYDROmorphone Hydrochloride Injection USP should not be adjusted without consulting with a physician.
4. 4. Patients should not combine HYDROmorphone Hydrochloride Injection USP with alcohol or other central nervous system depressants (sleep aids, tranquilizers) because dangerous additive effects may occur, resulting in serious injury or death
5. 5. Patients should be advised to consult their physician or pharmacist if other medications are being used or will be used with HYDROmorphone Hydrochloride Injection USP.
6. 6. Patients should be advised that if they have been receiving treatment with HYDROmorphone Hydrochloride Injection USP and cessation of therapy is indicated, it may be appropriate to taper HYDROmorphone Hydrochloride Injection USP dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms.
7. 7.

   Patients should be advised of the most common adverse reactions that may occur while taking HYDROmorphone Hydrochloride Injection USP: constipation, dizziness, light-headedness, nausea, sedation, sweating and vomiting. If symptoms worsen,

   • seek immediate medical attention.
8. 8. Patients should be advised that HYDROmorphone Hydrochloride Injection USP may cause drowsiness, dizziness or light- headedness and may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Patients started on HYDROmorphone Hydrochloride Injection USP or patients whose dose has been adjusted should be advised not to drive a car or operate machinery unless they are tolerant to the effects of HYDROmorphone Hydrochloride Injection USP.
9. 9. Patients should be advised that HYDROmorphone Hydrochloride Injection USP is a potential drug of abuse. They should protect it from theft or misuse.
10. 10. Patients should be advised that HYDROmorphone Hydrochloride Injection USP should never be given to anyone other than the individual for whom it was prescribed.
11. 11. Women of childbearing potential who become or are planning to become pregnant should be advised to consult a physician prior to initiating or continuing therapy with HYDROmorphone Hydrochloride Injection USP. Women who are breast-feeding or pregnant should not use HYDROmorphone Hydrochloride Injection USP.

7.1 Special Populations Special Risk Groups

HYDROmorphone should be administered with caution to patients with a history of alcohol and drug abuse and in a reduced dosage to debilitated patients, and in patients with severely impaired pulmonary function, Addison’s disease, hypothyroidism, myxedema, toxic psychosis, prostatic hypertrophy or urethral stricture.

The administration of opioid analgesics, including HYDROmorphone, may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

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

7.1.1 Pregnant Women

Studies in humans have not been conducted. HYDROmorphone Hydrochloride Injection USP crosses the placental barrier and is contraindicated in pregnant women (see 2 CONTRAINDICATIONS).

Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal Opioid Withdrawal Syndrome (NOWS), unlike opioid withdrawal syndrome in adults, may be life-threatening (see 7 WARNINGS AND PRECAUTIONS, Neonatal Opioid Withdrawal Syndrome (NOWS) and 8 ADVERSE REACTIONS, Post-Market Adverse Reactions).

Pregnant women using opioids should not discontinue their medication abruptly as this can cause pregnancy complications such as miscarriage or still-birth. Tapering should be slow and under medical supervision to avoid serious adverse events to the fetus.

7.1.2 Breast-feeding

Since opioids can cross the placental barrier and are excreted in breast milk, HYDROmorphone Hydrochloride Injection USP is contraindicated in nursing women and during labour and delivery. Life-threatening respiratory depression can occur in the infant if opioids are administered to the mother. Naloxone, a drug that counters the effects of opioids, should be readily available if HYDROmorphone Hydrochloride Injection USP is used in this population. Respiratory depression may occur in the infant if opioids are administered during labour. Therefore, HYDROmorphone Hydrochloride Injection USP should not be used during or immediately prior to labour or in nursing mothers.

7.1.3 Pediatrics (<18 years of age)

The safety and efficacy of HYDROmorphone Hydrochloride Injection USP has not been studied in the pediatric population. Therefore the use of HYDROmorphone Hydrochloride Injection USP is not recommended in patients under 18 years of age.

7.1.4 Geriatrics (>65 years of age)

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and titrated slowly, reflecting the greater frequency of decreased hepatic, renal or cardiac function, concomitant disease or other drug therapy (see 4 DOSAGE AND ADMINISTRATION).

7.1.5 Patients with 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. 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.

7.1.6 Patients with 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). Patients with renal impairment should be closely monitored during dose titration.

8 ADVERSE REACTIONS

• 8.1 Adverse Reaction Overview

The adverse effects of HYDROmorphone Hydrochloride Injection USP are similar to those of other opioid analgesics and represent an extension of pharmacological effects of the drug class. The major hazards include respiratory depression, central nervous system depression and apnea. To a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest have occurred.

The most frequently observed adverse effects are constipation, light-headedness, dizziness, sedation, nausea, vomiting, and hyperhidrosis.

Pain at injection site, local tissue irritation and induration following subcutaneous injection, particularly when repeated in the same area, have occurred.

Sedation

Sedation is a common side effect of opioid analgesics, especially in opioid naïve individuals. Sedation may also occur partly because patients often recuperate from prolonged fatigue after the relief of persistent pain. Most patients develop tolerance to the sedative effects of opioids within three to five days and, if the sedation is not severe, will not require any treatment except reassurance. If excessive sedation persists beyond a few days, the dose of the opioid should be reduced and alternate causes investigated. Some of these are: concurrent CNS depressant medication, hepatic or renal dysfunction, brain metastases, hypercalcemia and respiratory failure. If it is necessary to reduce the dose, it can be carefully increased again after three or four days if it is obvious that the pain is not being well controlled. Dizziness and unsteadiness may be caused by postural hypotension particularly in elderly or debilitated patients and may be alleviated if the patient lies down.

Nausea and Vomiting

Nausea is a common side effect on initiation of therapy with opioid analgesics and is thought to occur by activation of the chemoreceptor trigger zone, stimulation of the vestibular apparatus and through delayed gastric emptying. The prevalence of nausea declines following continued treatment with opioid analgesics. When instituting prolonged therapy with an opioid for chronic pain, the routine prescription of an antiemetic should be considered. In the cancer patient, investigation of nausea should include such causes as constipation, bowel obstruction, uremia, hypercalcemia, hepatomegaly, tumor invasion of celiac plexus and concurrent use of drugs with emetogenic properties. Persistent nausea which does not respond to dosage reduction may be caused by opioid-induced gastric stasis and may be accompanied by other symptoms including anorexia, early satiety, vomiting and abdominal fullness. These symptoms respond to chronic treatment with gastrointestinal prokinetic agents.

Constipation

Practically all patients become constipated while taking opioids on a persistent basis. In some patients, particularly the elderly or bedridden, fecal impaction may result. It is essential to caution the patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged opioid analgesic therapy. Stool softeners, stimulant laxatives and other appropriate measures should be used as required. As fecal impaction may present as overflow diarrhea, the presence of constipation should be excluded in patients on opioid therapy prior to initiating treatment for diarrhea.

8.2 Adverse Reactions

The following adverse effects occur with opioid analgesics and include those reported in HYDROmorphone clinical trials, as well as post-marketing adverse events related to HYDROmorphone. The reactions are categorized by body system and frequency according to the following definitions: Very common (≥ 1/10); Common (≥ 1/100 to <1/10); Uncommon (≥ 1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (< 1/10,000), Not known (cannot be estimated from the available data).

Immune System Disorders:

Not known: anaphylactic reactions, hypersensitivity reactions (including oropharyngeal swelling).

Metabolism and Nutrition Disorders:

Common: decreased appetite

Psychiatric Disorders:

Common: anxiety, confusional state, insomnia, euphoric mood, dysphoria. Uncommon: Agitation, depression, hallucinations, nightmares, mood altered.

Not known: drug dependence, nervousness, disorientation.

Nervous System Disorders:

Very common: dizziness, somnolence, sedation.

Common: headache.

Uncommon: myoclonus, paraesthesia, tremor, presyncope.

Rare: lethargy

Not known: convulsions, dyskinesia, hyperalgesia, syncope, increased intracranial pressure, nystagmus, obstructive sleep apnea syndrome.

Eye Disorders:

Uncommon: visual impairment.

Not known: blurred vision, miosis, diplopia.

Cardiac Disorders:

Rare: bradycardia, palpitations, tachycardia.

Vascular Disorders:

Very common: flushing Uncommon: hypotension Not known: hypertension

Respiratory Thoracic and Mediastinal Disorders:

Uncommon: dyspnea.

Rare: respiratory depression.

Not known: bronchospasm, and laryngospasm.

Gastrointestinal Disorders:

Very common: constipation, nausea

Common: abdominal pain, dry mouth, vomiting.

Uncommon: diarrhea, dysgeusia.

Not known: paralytic ileus.

Hepatobiliary Disorders:

Uncommon: hepatic enzymes increased Not known: biliary colic

Skin and Subcutaneous Tissue Disorders: Common: pruritus, hyperhidrosis

Uncommon: rash

Not known: urticaria

Musculoskeletal and Connective Tissue Disorders

Common: muscle contractions involuntary

Not known: muscle rigidity.

Renal and Urinary Disorders:

Uncommon: urinary retention, urinary hesitancy.

Reproductive System and Breast Disorders:

Uncommon: erectile dysfunction

General Disorders and Administration Site Conditions:

Common: asthenia, injection site reaction, weakness.

Uncommon: drug withdrawal syndrome, fatigue, malaise, peripheral edema.

Not known: drug tolerance, chills, drug withdrawal syndrome neonatal, feeling abnormal

8.3 Post-Market Adverse Reactions

The following adverse reactions have been identified during post approval use of HYDROmorphone. Because these reactions 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.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use (see 7 WARNINGS AND PRECAUTIONS - Endocrine).

Anaphylaxis: Anaphylactic reaction has been reported with ingredients contained in HYDROmorphone hydrochloride injection.

Androgen deficiency: Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

There have also been post-marketing reports of Neonatal Opioid Withdrawal Syndrome (NOWS) in patients treated with HYDROmorphone (see 7 WARNINGS AND PRECAUTIONS, Neonatal Opioid Withdrawal Syndrome (NOWS)).

9 DRUG INTERACTIONS

• 9.1 Serious Drug Interactions Box

• 9.2 Overview

Interactions with Central Nervous System (CNS) Depressants (including benzodiazepines and alcohol)

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants (e.g. other opioids, sedatives, hypnotics, antidepressants, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, phenothiazines, neuroleptics, antihistamines, antiemetics, and alcohol) and beta-blockers, increases the risk of respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation (see 7 WARNINGS AND PRECAUTIONS, Neurologic), Interactions with CNS Depressants (including benzodiazepines and alcohol) and Driving and Operating Machinery). HYDROmorphone Hydrochloride Injection USP should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects.

9.3 Drug-Drug Interactions

Administration with Mixed Activity Agonist/Antagonist Opioids

Mixed agonist/antagonist opioid 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.

MAO Inhibitors

MAO Inhibitors intensify the effects of opioid drugs which can cause anxiety, confusion and decreased respiration. HYDROmorphone Hydrochloride Injection USP is contraindicated in patients receiving MAO inhibitors or who have used them within the previous 14 days (see 2 CONTRAINDICATIONS).

HYDROmorphone may increase the anticoagulant activity of coumarin and other anticoagulants.

Serotonergic Agents

Coadministration of HYDROmorphone with a serotonergic agent, such as a selective serotonin re- uptake inhibitor (SSRI) or a serotonin norepinephrine re-uptake inhibitor (SNRI), may increase the risk of serotonin syndrome, a potentially life-threatening condition (see 7 WARNINGS AND PRECAUTIONS, Neurologic).

9.4 Drug-Food Interactions

Interactions with food have not been established.

9.5 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.6 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

9.7 Drug-Lifestyle Interactions

The concomitant use of alcohol should be avoided (see 7 WARNINGS AND PRECAUTIONS, General).

10 ACTION AND CLINICAL PHARMACOLOGY

• 10.1 Mechanism of Action

HYDROmorphone Hydrochloride Injection USP (HYDROmorphone hydrochloride) has analgesic and antitussive activity. Small doses of HYDROmorphone produce effective and prompt relief of pain, usually with minimal nausea and vomiting.

Opioid 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. Opioid analgesics also suppress the cough reflex and cause respiratory depression, mood changes, mental clouding, euphoric mood, dysphoria, nausea, vomiting, increased cerebrospinal fluid pressure, pinpoint constriction of the pupils, increased biliary tract pressure, increased parasympathetic activity and transient hyperglycemia.

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.

10.2 Pharmacodynamics

When given parenterally, HYDROmorphone's analgesic action is generally apparent within five minutes. The onset of action of oral HYDROmorphone hydrochloride is somewhat slower, with measurable analgesia occurring within 30 minutes. When sleep follows the administration of HYDROmorphone, it is usually due to relief of pain, not to hypnosis.

Estimates of the relative analgesic potency of parenterally administered HYDROmorphone to morphine in acute pain studies in man range from approximately 7:1 to 11:1. In addition, HYDROmorphone is better absorbed orally than is morphine, the former approximately 20 to 25% as active orally as intramuscularly HYDROmorphone has greater antitussive potency than codeine on a weight basis; however, its dependence liability is also greater than that of codeine.

Cardiovascular System

HYDROmorphone may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, hyperhidrosis and/or orthostatic hypotension.

Central Nervous System

HYDROmorphone produces respiratory depression by direct action on brain stem respiratory centres. The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO₂ tension and to electrical stimulation.

HYDROmorphone depresses the cough reflex by direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia.

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

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.

Gastrointestinal Tract and Other Smooth Muscle

HYDROmorphone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum 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, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.

Hepatobiliary System

Opioids may induce biliary spasm.

Immune System

In vitro and animal studies indicate that opioids have a variety of effects on immune functions, depending on the context in which they are used. The clinical significance of these findings is unknown.

10.3 Pharmacokinetics

Absorption: When HYDROmorphone is taken orally, it is absorbed from the gastrointestinal tract.

Distribution: Following intravenous administration of HYDROmorphone to normal volunteers, the mean t _1/2 of elimination was 2.65 +/- 0.88 hours. The mean volume of distribution was 91.5 liters, suggesting extensive tissue uptake. HYDROmorphone is rapidly removed from the bloodstream and distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. It also crosses the placental membranes.

Metabolism: In normal human volunteers HYDROmorphone is metabolized primarily in the liver.

Elimination: HYDROmorphone is excreted in the urine, predominantly as the glucuronidated conjugate, with small amounts of parent drug and minor amounts of 6-hydroxy reduction metabolites. The pharmacologic activity of this and other HYDROmorphone metabolites in humans is not known.

Special Populations and Conditions

Pediatrics (<18 years of age): Individuals under 18 years of age should not take HYDROmorphone Hydrochloride Injection USP.

Geriatrics (>65 years of age): HYDROmorphone should be administered with caution, and in reduced dosages, to elderly or debilitated patients. Respiratory depression has occurred in the elderly following administration of large initial doses of opioids to patients who were not opioid- tolerant or when opioids were co-administered with other agents that can depress respiration.

HYDROmorphone should be initiated at a low dose and slowly titrated to effect (see 7 WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).

Sex: No data available.

11 STORAGE AND STABILITY

Sterile Solution for Injection: Store HYDROmorphone Hydrochloride Injection USP at room temperature at 15⁰C to 30⁰C. Protect from light. Discard unused portion.

12 SPECIAL HANDLING INSTRUCTIONS

HYDROmorphone Hydrochloride Injection USP should be kept in a safe place, such as under lock and out of the sight and reach of children before, during and after use. HYDROmorphone Hydrochloride Injection USP should not be used in front of children, since they may copy these actions.

PART II: SCIENTIFIC INFORMATION

• 13 PHARMACEUTICAL INFORMATION Drug Substance

Proper Name: HYDROmorphone hydrochloride

Chemical Name : (1) Morphinan-6-one ,4,5-epoxy-3-hydroxy-17-methyl-, hydrochloride , (5α)-(2) 4,5α-Epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride

Molecular Formula and Molecular Mass: C₁₇H₁₉NO₃·HCl / 321.8 g / mol

Structural Formula:

Physicochemical

Properties: HYDROmorphone hydrochloride is a hydrogenated ketone of morphine.

Appearance: Fine, white, or practically white, crystalline powder.

Solubility: Freely soluble in water and sparingly soluble in alcohol.

Melting Point: Decomposes at 305⁰ to 315⁰C.

pH: A 1% aqueous solution of HYDROmorphone hydrochloride has a pH of 5.3.

pKa: 8.2 (20⁰C)

14 SUPPORTING PRODUCT MONOGRAPHS

1. 1. DILAUDID (sterile solution for injection, 2 mg/mL), Submission Control No. 237679, Prescribing Information, Purdue Pharma. July 29, 2020.
2. 2. HYDROmorphone Hydrochloride Injection USP (1 mg/mL and 2 mg/mL sterile solution,), Submission Control No. 237401, Product Monograph, Sandoz Canada Inc., April 1, 2021.