HYDROMORPHONE HYDROCHLORIDE INJECTION, USP SOLUTION

Canada - English - Health Canada

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Active ingredient:
HYDROMORPHONE HYDROCHLORIDE
Available from:
FRESENIUS KABI CANADA LTD
ATC code:
N02AA03
INN (International Name):
HYDROMORPHONE
Dosage:
10MG
Pharmaceutical form:
SOLUTION
Composition:
HYDROMORPHONE HYDROCHLORIDE 10MG
Administration route:
INTRAMUSCULAR
Units in package:
100
Prescription type:
Narcotic (CDSA I)
Therapeutic area:
OPIATE AGONISTS
Product summary:
Active ingredient group (AIG) number: 0108698001; AHFS: 28:08.08
Authorization status:
APPROVED
Authorization number:
02491680
Authorization date:
2019-08-21

Documents in other languages

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 1 of 34

PRESCRIBING INFORMATION

INCLUDING PATIENT MEDICATION INFORMATION

N

HYDROmorphone Hydrochloride Injection, USP

(Hydromorphone Hydrochloride Injection, USP)

2 mg/mL Sterile Solution for Injection

Intramuscular, Intravenous, Subcutaneous

Opioid Analgesic

NOT A PRODUCT MONOGRAPH

Fresenius Kabi Canada Ltd.

Date of revision:

165 Galaxy Blvd. Suite 100

August 20, 2019

Toronto, Ontario

M9W 0C8

Submission Control No.: 212894

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 2 of 34

TABLE OF CONTENTS

PART I: HEALTH PROFESSIONAL INFORMATION ................................................................. 3

SUMMARY PRODUCT INFORMATION ........................................................................................ 3

INDICATIONS AND CLINICAL USE ............................................................................................. 3

CONTRAINDICATIONS ................................................................................................................... 3

WARNINGS AND PRECAUTIONS ................................................................................................. 4

ADVERSE REACTIONS ................................................................................................................. 12

DRUG INTERACTIONS .................................................................................................................. 15

DOSAGE AND ADMINISTRATION .............................................................................................. 16

OVERDOSAGE ................................................................................................................................ 20

ACTION AND CLINICAL PHARMACOLOGY ............................................................................ 20

STORAGE AND STABILITY ......................................................................................................... 22

SPECIAL HANDLING INSTRUCTIONS ....................................................................................... 22

DOSAGE FORMS, COMPOSITION AND PACKAGING ............................................................. 23

PART II: SCIENTIFIC INFORMATION ....................................................................................... 24

PHARMACEUTICAL INFORMATION ......................................................................................... 24

REFERENCES .................................................................................................................................. 25

PATIENT MEDICATION INFORMATION .................................................................................. 27

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 3 of 34

N

HYDROmorphone Hydrochloride Injection, USP

(Hydromorphone Hydrochloride Injection, USP)

2 mg/mL Sterile Solution for Injection

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form / Strength

Non-medicinal Ingredients

Intramuscular,

Intravenous,

Subcutaneous

Sterile Solution for Injection /

2 mg/mL

Citric acid, sodium

citrate, and water for injection

INDICATIONS AND CLINICAL USE

Adults:

HYDROmorphone Hydrochloride Injection, USP (Hydromorphone Hydrochloride Injection,

USP) is indicated for the relief of moderate to severe pain.

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 WARNINGS AND

PRECAUTIONS, Special Populations, Geriatrics).

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.

CONTRAINDICATIONS

Patients who are hypersensitive to the active substances (Hydromorphone) or other opioid

analgesics or to any ingredient in the formulation. For a complete listing, see the DOSAGE

FORMS, COMPOSITION AND PACKAGING section of the Prescribing Information.

In patients with known or suspected mechanical gastrointestinal obstruction (e.g., bowel

obstruction, 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.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 4 of 34

Patients with acute respiratory depression, elevated carbon dioxide 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 concomitant monoamine oxidase (MAO) inhibitors (or within 14 days

of such therapy).

Women who are breast-feeding, pregnant, or during labour and delivery (see Serious

Warnings and Precautions, and WARNINGS AND PRECAUTIONS).

WARNINGS AND PRECAUTIONS

SERIOUS WARNINGS AND PRECAUTIONS

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, even at

recommended doses, and because of the risks of overdose and death with immediate

release opioid formulations, HYDROmorphone Hydrochloride Injection, USP

(Hydromorphone Hydrochloride, USP) should only be used in patients for whom

alternative treatment options (e.g., non-opioid analgesics) are ineffective, not

tolerated, or would be otherwise inadequate to provide appropriate management of

pain (see DOSAGE AND ADMINISTRATION).

Addiction, Abuse, and Misuse

HYDROmorphone Hydrochloride Injection, USP poses risks of opioid addiction,

abuse, and misuse, which can lead to overdose and death. Each patient’s risk

should be assessed prior to prescribing HYDROmorphone Hydrochloride

Injection, USP, and all patients should be monitored regularly for the development

of these behaviours or conditions (see WARNINGS AND PRECAUTIONS).

HYDROmorphone Hydrochloride Injection, USP should be stored securely to

avoid theft or misuse.

Accidental Exposure

Accidental ingestion of even one dose of HYDROmorphone Hydrochloride

Injection, USP, especially by children, can result in a fatal overdose of

hydromorphone.

Life-threatening Respiratory Depression: OVERDOSE

Serious, life-threatening, or fatal respiratory depression may occur with use of

HYDROmorphone Hydrochloride Injection, USP. Infants exposed in –utero or

through breast milk at risk of life-threatening respiratory depression upon delivery or

when nursed. Patients should be monitored for respiratory depression, especially

during initiation of HYDROmorphone Hydrochloride Injection, USP or following a

dose increase. Further, instruct patients of the hazards related to taking opioids

including fatal overdose.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 5 of 34

Neonatal Opioid Withdrawal Syndrome

Prolonged maternal use of HYDROmorphone Hydrochloride Injection, USP during

pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-

threatening (see WARNINGS AND PRECAUTIONS).

Interaction with Alcohol

The co-ingestion of alcohol with HYDROmorphone Hydrochloride Injection, USP

should be avoided as it may result in dangerous additive effects, causing serious

injury or death (see WARNINGS AND PRECAUTIONS and DRUG

INTERACTIONS).

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other CNS depressants,

including alcohol, may result in profound sedation, respiratory depression, coma,

and death (see WARNINGS AND PRECAUTIONS, Neurologic and DRUG

INTERACTIONS).

Reserve concomitant prescribing of HYDROmorphone Hydrochloride Injection,

USP and benzodiazepines or other CNS depressants for use in patients for

whom alternative treatment options are inadequate.

Limit dosages and durations to the minimum required.

Follow patients for signs and symptoms of respiratory depression and sedation.

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.

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.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 6 of 34

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

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. 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 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,

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 7 of 34

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 ADVERSE

REACTIONS, 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; unless used under

extreme caution and awareness.

Endocrine

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 Effects

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 (see CONTRAINDICATIONS).

Neonatal Opioid Withdrawal Syndrome (NOWS)

Prolonged maternal use of opioid 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 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

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 8 of 34

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 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 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

CONTRAINDICATIONS and ADVERSE REACTIONS, Sedation, and DRUG

INTERACTIONS).

Severe pain antagonizes the subjective and respiratory depressant actions of opioid

analgesics. Should pain suddenly subside, these effects may rapidly become manifest.

Serotonin Syndrome: HYDROmorphone Hydrochloride Injection, USP could cause a rare but

potentially life-threatening condition resulting from concomitant administration of serotonergic

drugs (e.g. anti-depressants, migraine medications). Treatment with the serotonergic drug should

be discontinued if such events (characterized by clusters of symptoms such as hyperthermia,

rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental

status changes including confusion, irritability, extreme agitation progressing to delirium and

coma) occur and supportive symptomatic treatment should be initiated. HYDROmorphone

Hydrochloride Injection, USP should not be used in combination with MAO inhibitors or

serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in

combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium,

tramadol, St. John’s Wort) due to the risk of serotonergic syndrome (see DRUG

INTERACTIONS).

Head Injury: The respiratory depressant effects of hydromorphone, and the capacity to elevate

cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 9 of 34

intracranial pressure produced by trauma. Also, hydromorphone may produce confusion, miosis,

vomiting and other side effects which obscure the clinical course of patients with head injury. In

such patients, hydromorphone must be used with extreme caution and only if it is judged

essential (see 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.

Psychomotor Impairment

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.

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. Hydromorphone should be used with

extreme caution in patients with substantially decreased respiratory reserve, pre-existing

respiratory depression, hypoxia or hypercapnia (see 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.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 10 of 34

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 WARNINGS AND PRECAUTIONS, Special Populations, Special

Risk Groups, and 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

titrating

with

HYDROmorphone

Hydrochloride

Injection,

USP,

these

patients,

even

usual

therapeutic

doses

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

severe

bronchial

asthma,

chronic

obstructive

airway,

status

asthmaticus (see CONTRAINDICATIONS).

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. 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. Patients should be advised that HYDROmorphone Hydrochloride Injection, USP contains

hydromorphone, an opioid pain medicine.

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. 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. 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. 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.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 11 of 34

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. 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. Patients should be advised that HYDROmorphone Hydrochloride Injection, USP is a

potential drug of abuse. They should protect it from theft or misuse.

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. 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.

Sexual Function / 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 ADVERSE REACTIONS, Post-

Marketing Experience).

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.

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.

Pregnant Women:

Studies in humans have not been conducted. HYDROmorphone Hydrochloride Injection, USP

crosses the placental barrier and is contraindicated in pregnant women.

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 WARNINGS AND PRECAUTIONS, Neonatal Opioid

Withdrawal Syndrome (NOWS), ADVERSE REACTIONS, Post-Marketing Experience).

Pregnant women using opioids should not discontinue their medication abruptly as this can

cause pregnancy complication such as miscarriage or still-birth. Tapering should be slow and

under medical supervision to avoid serious adverse events to the fetus.

Labour, Delivery and Nursing Women:

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 12 of 34

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.

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.

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 DOSAGE AND ADMINISTRATION).

Patients with Hepatic Impairment: Mean exposure to hydromorphone (Cmax and AUC∞) is

increased 4-fold in patients with moderate (Child-Pugh Group B) hepatic impairment compared

with subjects with normal hepatic function. The pharmacokinetics of HYDROmorphone in

patients with severe hepatic impairment has not been studied. A further increase in Cmax and

AUC of hydromorphone in this group is expected and should be taken into consideration when

selecting a starting dose.

Patients with Renal Impairment: Mean exposure to hydromorphone (Cmax 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.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The adverse effects of HYDROmorphone Hydrochloride Injection, USP (Hydromorphone

Hydrochloride, 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

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 13 of 34

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.

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

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 14 of 34

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.

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: flushing, 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.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 15 of 34

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

Post-Marketing Experience

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 WARNINGS AND

PRECAUTIONS - Endocrine).

Anaphylaxis: Anaphylactic reaction has been reported with ingredients contained in

HYDROmorphone Hydrochloride Injection, USP.

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 WARNINGS AND PRECAUTIONS, Neonatal

Opioid Withdrawal Syndrome (NOWS)).

DRUG INTERACTIONS

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,

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 16 of 34

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 WARNINGS AND PRECAUTIONS, Neurologic, Interactions with CNS

Depressants (including benzodiazepines and alcohol) and Psychomotor Impairment).

HYDROmorphone Hydrochloride Injection, USP should not be consumed with alcohol as it may

increase the chance of experiencing dangerous side effects.

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 CONTRAINDICATIONS).

Serotonergic Agents: Coadministration of hydromorphone with a serotonergic agent, such as a

Selective Serotonin Re-uptake Inhibitor or a Serotonin Norepinephrine Re-uptake Inhibitor, may

increase the risk of serotonin syndrome, a potentially life-threatening condition (see

WARNINGS AND PRECAUTIONS, Neurologic).

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

The concomitant use of alcohol should be avoided (see WARNINGS AND

PRECAUTIONS, General).

DOSAGE AND ADMINISTRATION

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

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 17 of 34

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 DOSAGE AND ADMINISTRATION -

Adjustment or reduction of Dosage).

HYDROmorphone Hydrochloride Injection, USP should only be used in patients for whom

alternative treatment options are ineffective or not tolerated (e.g., non-opioid analgesics).

Rapid intravenous injection of opioid analgesics increases the possibility of hypotension

and respiratory depression.

Dosing Considerations

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.

Recommended Dose and Dosage Adjustment

Adults: 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, USP 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

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 18 of 34

Drug

Equivalent Dose

(mg)

2

(compared to morphine 10 mg IM)

Duration of

Action

(hours)

Parenteral

Oral

Strong Opioid Agonists:

Morphine

3 - 4

Oxycodone

2 - 4

Hydromorphone

2 - 4

Anileridine

2 - 3

Levorphanol

4 - 8

Meperidine

1 - 3

Oxymorphone

5 (rectal)

3 - 4

Methadone

Heroin

5 - 8

10 - 15

3 - 4

Weak Opioid Agonists:

Codeine

3 - 4

Propoxyphene

2 - 4

Mixed Agonist-Antagonist

Pentazocine

3 - 4

Nalbuphine

3 - 6

Butorphanol

3 - 4

Footnotes:

References:

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).

Based on single entity oral oxycodone in acute pain.

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

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

morphine dose.

Not recommended for the management of chronic pain.

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

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 which will achieve the overall treatment goal of satisfactory

pain relief with acceptable side effects.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 19 of 34

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 WARNINGS AND PRECAUTIONS). Tapering should be

individualized and carried out under medical supervision.

Patient 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.

Patients with Hepatic Impairment: One-fourth to one-half the usual HYDROmorphone

Hydrochloride Injection, USP injection starting dose depending on the extent of impairment.

Patients with Renal Impairment: One-fourth to one-half the usual HYDROmorphone

Hydrochloride Injection, USP injection starting dose depending on the degree of 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 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.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 20 of 34

OVERDOSAGE

For management of a suspected drug overdose, contact your Regional Poison Control Centre.

Symptoms

Serious overdosage with HYDROmorphone Hydrochloride Injection, USP (Hydromorphone

hydrochloride, 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, coma, pneumonia aspiration, skeletal muscle

flaccidity, cold and clammy skin, constricted pupils 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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

HYDROmorphone Hydrochloride Injection, USP (Hydromorphone hydrochloride, USP) has

analgesic and antitussive activity. Small doses of hydromorphone produce effective and prompt

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 21 of 34

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.

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 CO

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.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 22 of 34

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.

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

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.

Special Population and Conditions

Pediatrics:

Individuals under 18 years of age should not take HYDROmorphone Hydrochloride Injection,

USP.

STORAGE AND STABILITY

Sterile Solution for Injection: Store HYDROmorphone Hydrochloride Injection, USP

sterile solution for injection at 15°C to 30°C. Protect from light. Discard unused portion.

SPECIAL HANDLING INSTRUCTIONS

Not applicable.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 23 of 34

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms and Composition

Sterile solution for injection: Each mL of sterile solution contains: 2 mg hydromorphone

hydrochloride. Non-medicinal ingredients: citric acid 2 mg, sodium citrate 2 mg, and water for

injection.

Packaging

Sterile solution for injection: HYDROmorphone Hydrochloride Injection, USP

sterile solution for

injection, containing 2 mg hydromorphone hydrochloride per mL is available in 2 mL single use

vials (1 mL fill) in boxes of 25.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 24 of 34

PART II: SCIENTIFIC INFORMATION

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: C

·HCl

Molecular Mass: 321.80 g/mol

Structural Formula:

Physicochemical

Properties

Appearance:

White to off-white odorless powder.

Solubility:

Soluble in 3 parts water and sparingly soluble in alcohol.

Melting Point:

Decomposes at 305°C to 315°C.

pKa:

8.095 ± 0.013 (basic)

9.190 ± 0.013 (acidic)

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 25 of 34

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Bruera E, Brenneis C, Michaud M, Bacovsky R, Chadwick S, Emeno A, MacDonald N.

Use of the subcutaneous route for the administration of narcotics in patients with cancer

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Cone EJ, Phelps BA, Gorodetzky CW. Urinary excretion of hydromorphone and

metabolites in humans, rats, dogs, guinea pigs and rabbits. J Pharm Sci 1977;66(12):1709-

Cone EJ, Darwin WD. Simultaneous determination of hydromorphone, hydrocodone and

their 6 and 6β hydroxy metabolites in urine using selected ion recording with methane

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Dickson PH, Lind A, Studts P, Nipper HC, Makoid M, Makoid M, et al. The routine analysis

of breast milk for drugs of abuse in a clinical toxicology laboratory. J Forensic Sci

1994;39(1):207-14.

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.

Goldberg RI and Shuman FI. Oral hydromorphone in trauma. Curr Ther Res Clin Exp

1965;7(5):284-8.

Hagen N, Thirlwell MP, Dhaliwal HS, Babul N, Harsanyi Z, Darke AC. Steady-state

pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide in cancer patients

after immediate and controlled-release hydromorphone. J Clin Pharmacol 1995;35:37-44.

Hanks GW, Justins DM. Cancer pain: management. Lancet 1992;339(8800):1031-6.

Hays H, Hagen N, Thirlwell M, Dhaliwal H, Babul N, Harsanyi Z, Darke AC.

Comparative clinical efficacy and safety of immediate release and controlled release

hydromorphone for chronic severe cancer pain. Cancer 1994;74(6):1808-16.

Hill HF, Coda BA, Tanaka A, Schaffer R. Multiple-dose evaluation of intravenous

hydromorphone pharmacokinetics in normal human subjects. Anesth Analg 1991;72(3):

330-6.

Houde RW. Clinical analgesic studies of hydromorphone. In: Foley KM, Inturrisi CE,

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Hydromorphone levels and pain control in patients with severe chronic pain. Clin

Pharmacol Ther 1988;49(4):376-82.

Steinberg SK, Kornijenko M. The role of hydromorphone in the treatment of cancer pain.

Can Pharm J 1988;121(3):182-6.

Vallner JJ, Stewart JT, Kotzan JA, Kirsten EB, Honigberg IL. Pharmacokinetics and

bioavailability of hydromorphone following intravenous and oral administration to human

subjects. J Clin Pharmacol 1981;21(4):152-6.

Sandoz Canada Inc., Prescribing Information:

HYDROmorphone Hydrochloride Injection

USP. Control No.: 216086. Date of Revision: June 11, 2018.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 27 of 34

READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE

PATIENT MEDICATION INFORMATION

N

HYDROmorphone Hydrochloride Injection, USP

(Hydromorphone Hydrochloride Injection, USP)

2 mg/mL Sterile Solution for Injection

Read this carefully before you start taking HYDROmorphone Hydrochloride Injection, USP and each

time you get a refill. This leaflet is a summary and will not tell you everything about this drug. Talk

to your healthcare professional about your medical condition and treatment and ask if there is any new

information about HYDROmorphone Hydrochloride Injection, USP.

Serious Warnings and Precautions

Even if you take HYDROmorphone Hydrochloride Injection, USP as prescribed you

are at a risk for opioid addiction, abuse and misuse. This can lead to overdose and

death.

You may get life-threatening breathing problems while taking HYDROmorphone

Hydrochloride Injection, USP. This is less likely to happen if you take it as prescribed

by your doctor. Babies are at risk of life-threatening breathing problems if their

mothers take opioids while pregnant or nursing.

You should never give anyone your HYDROmorphone Hydrochloride Injection,

USP.

They

could

die

from

taking

it.

If

a

person

has

not

been

prescribed

HYDROmorphone Hydrochloride Injection, USP, taking even one dose can cause a

fatal overdose. This is especially true for children.

If

you

took

HYDROmorphone

Hydrochloride

Injection,

USP

while

you

were

pregnant, whether for short or long periods of time or in small or large doses, your

baby can suffer life-threatening withdrawal symptoms after birth. This can occur in

the days after birth and for up to 4 weeks after delivery. If your baby has any of the

following symptoms:

has changes in their breathing (such as weak, difficult or fast breathing)

is unusually difficult to comfort

has tremors (shakiness)

has increased stools, sneezing, yawning, vomiting, or fever

Seek immediate medical help for your baby.

Taking HYDROmorphone Hydrochloride Injection, USP with other opioid medicines,

benzodiazepines, alcohol, or other central nervous system depressants (including

street drugs) can cause severe drowsiness, decreased awareness, breathing problems,

coma, and death.

What is HYDROmorphone Hydrochloride Injection, USP used for?

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 28 of 34

HYDROmorphone Hydrochloride Injection, USP is a pain medication used to control pain.

How does HYDROmorphone Hydrochloride Injection, USP work?

HYDROmorphone Hydrochloride Injection, USP contains hydromorphone which is a pain

medication belonging to the class of drugs known as opioids which includes codeine, fentanyl,

morphine and oxycodone. It relieves pain by acting on specific nerve cells of the spinal cord and

brain.

HYDROmorphone Hydrochloride Injection, USP is used to treat severe pain in patients who need an

opioid administered by injection. This is given under the skin, into the muscle or vein in doses or

concentrations that are higher than those usually needed.

What are the ingredients in HYDROmorphone Hydrochloride Injection, USP?

Medicinal ingredient: hydromorphone hydrochloride

Non-medicinal ingredients: citric acid, sodium citrate, and water for injection.

HYDROmorphone Hydrochloride Injection, USP comes in the following dosage forms:

Sterile solution for injection: 2 mg/mL.

Do not use HYDROmorphone Hydrochloride Injection, USP if:

your doctor did not prescribe it for you

you are allergic to hydromorphone, or any of the other ingredients in HYDROmorphone

Hydrochloride Injection, USP (see What are the ingredients in HYDROmorphone

Hydrochloride Injection, USP?)

you can control your pain by the occasional use of other pain medications. This includes those

available without a prescription

you have severe asthma, trouble breathing, or other breathing problems

you have any heart problems

you have bowel blockage or narrowing of the stomach or intestines

you have severe pain in your abdomen

you have a head injury

you are at risk for seizures

you have a brain tumor

you suffer from alcoholism

you are taking or have taken within the past 2 weeks a Monoamine Oxidase inhibitor (MAOI)

(such as phenelzine sulfate, tranylcypromine sulfate, moclobemide or selegiline)

you are going to have, or recently had, a planned surgery

you are pregnant or planning to become pregnant or you are in labour

you are breastfeeding

To help avoid side effects and ensure proper use, talk to your healthcare professional before

you take HYDROmorphone Hydrochloride Injection, USP. Talk about any health conditions

or problems you may have, including if you:

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 29 of 34

have a history of illicit or prescription drug or alcohol abuse

have severe kidney disease, liver or lung disease

have heart disease

have low blood pressure

have past or current depression

suffer from chronic or severe constipation

have problems with your adrenal or prostate gland

have, or had in the past hallucinations or other severe mental problems

suffer from migraines

are planning to become pregnant

Other warnings you should know about:

Opioid dependence and addiction: There are important differences between physical dependence and

addiction. It is important that you talk to your doctor if you have questions or concerns about abuse,

addiction or physical dependence.

Pregnancy, nursing, labour and delivery:

Do not use HYDROmorphone Hydrochloride Injection, USP while pregnant, nursing, during labour or

delivery. Opioids can be transferred to your baby through breast milk, or while still in the womb.

HYDROmorphone Hydrochloride Injection, USP can then cause life-threatening breathing problems in

your unborn baby or nursing infant.

If you are pregnant and are taking

HYDROmorphone Hydrochloride Injection, USP

, it is important

that you don’t stop taking your medication all of a sudden. If you do, it can cause a miscarriage or a

still-birth. Your doctor will monitor and guide you on how to slowly stop taking

HYDROmorphone

Hydrochloride Injection, USP

. This may help avoid serious harm to your unborn baby.

Driving and using machines: Before you do tasks which may require special attention, you should

wait until you know how you react to HYDROmorphone Hydrochloride Injection, USP.

HYDROmorphone Hydrochloride Injection, USP can cause:

drowsiness

dizziness or

light headedness

This can usually occur after you take your first dose and when your dose is increased.

Disorder of the adrenal gland: You may develop a disorder of the adrenal gland called adrenal

insufficiency. This means that your adrenal gland is not making enough of certain hormones. You

may experience symptoms such as:

nausea, vomiting

feeling tired, weak or dizzy

decreased appetite

You may be more likely to have problems with your adrenal gland if you have been taking opioids

for longer than one month. Your doctor may do tests, give you another medication, and slowly take

you off HYDROmorphone Hydrochloride Injection, USP.

Serotonin Syndrome: HYDROmorphone Hydrochloride Injection, USP can cause Serotonin

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 30 of 34

Syndrome, a rare but potentially life-threatening condition. It can cause serious changes in how

your brain, muscles and digestive system work. You may develop Serotonin Syndrome if you take

HYDROmorphone Hydrochloride Injection, USP with certain anti-depressants or migraine

medications.

Serotonin Syndrome symptoms include:

fever, sweating, shivering, diarrhea, nausea, vomiting;

muscle shakes, jerks, twitches or stiffness, overactive reflexes, loss of coordination;

fast heartbeat, changes in blood pressure;

confusion, agitation, restlessness, hallucinations, mood changes, unconsciousness, and

coma.

Sexual Function/Reproduction: Long term use of opioids may lead to a decrease in sex hormone

levels. It may also lead to low libido (desire to have sex), erectile dysfunction or being infertile.

Tell your healthcare professional about all the medicines you take, including any drugs,

vitamins, minerals, natural supplements or alternative medicines.

The following may interact with HYDROmorphone Hydrochloride Injection, USP:

Alcohol. This includes prescription and non-prescription medications that contain alcohol.

Do not drink alcohol while you are taking HYDROmorphone Hydrochloride Injection, USP.

It can lead to:

drowsiness

unusually slow or weak breathing

serious side effects or

a fatal overdose

other sedative drugs which may enhance the drowsiness caused by HYDROmorphone

Hydrochloride Injection, USP

other opioid analgesics (drugs used to treat pain)

general anesthetics (drugs used during surgery)

benzodiazepines (drugs used to help you sleep or that help reduce anxiety)

antidepressants (for depression and mood disorders). Do not take HYDROmorphone

Hydrochloride Injection, USP with MAO inhibitors (MAOI) or if you have taken MAOI’s in

the last 14 days.

drugs used to treat serious mental or emotional disorders (such as schizophrenia)

antihistamines (drugs used to treat allergies)

anti-emetics (drugs used for the prevention of vomiting)

drugs used to treat muscle spasms and back pain

some heart medications (such as beta blockers)

drugs used to treat migraines (e.g. triptans)

St. John’s Wort

How to take HYDROmorphone Hydrochloride Injection, USP:

Take HYDROmorphone Hydrochloride Injection, USP:

usually every 4 to 6 hours, or as directed by your doctor.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 31 of 34

HYDROmorphone Hydrochloride Injection, USP should be visually inspected prior to use. Only

clear solutions free from particles should be used. The injection should be given immediately after

opening the ampoule. Once opened, any unused portion should be discarded.

Usual Adult Starting Dose:

Your dose is tailored/personalized just for you. Be sure to follow your doctor’s dosing instructions

exactly. Do not increase or decrease your dose without consulting your doctor.

Your doctor will prescribe the lowest dose that works to control your pain. It is recommended that

you only take HYDROmorphone Hydrochloride Injection, USP for up to 7 days. If you need to take

HYDROmorphone Hydrochloride Injection, USP for longer, your doctor will determine the best

dose for you to lower the risk of side effects and overdose. Taking higher doses can lead to more

side effects and a greater chance of overdose.

Review your pain regularly with your doctor to determine if you still need HYDROmorphone

Hydrochloride Injection, USP. Be sure to use HYDROmorphone Hydrochloride Injection, USP

only for the condition for which it was prescribed.

If your pain increases or you develop any side effect as a result of taking HYDROmorphone

Hydrochloride Injection, USP, tell your doctor immediately.

Stopping your Medication

You should not stop taking HYDROmorphone Hydrochloride Injection, USP all at once if you have

been taking it for more than a few days. Your doctor will monitor and guide you on how to

slowly stop taking HYDROmorphone Hydrochloride Injection, USP. You should do it slowly to

avoid uncomfortable symptoms such as having:

body aches

diarrhea

goosebumps

loss of appetite

nausea

feeling nervous or restless

runny nose

sneezing

tremors or shivering

stomach cramps

rapid heart rate (tachycardia)

having trouble sleeping

an unusual increase in sweating

heart palpitations

an unexplained fever

weakness

yawning

By reducing or stopping your opioid treatment, your body will become less used to opioids. If you

start treatment again, you will need to start at the lowest dose. You may overdose if you restart at

the last dose you took before you slowly stopped taking HYDROmorphone Hydrochloride Injection,

USP.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 32 of 34

Overdose:

If you think you have taken too much HYDROmorphone Hydrochloride Injection, USP,

contact your healthcare professional, hospital emergency department or regional Poison

Control Centre immediately, even if there are no symptoms.

Signs of overdose may include:

unusually slow or weak breathing

dizziness

confusion

extreme drowsiness

What are possible side effects from using HYDROmorphone Hydrochloride Injection, USP?

These are not all the possible side effects you may feel when taking HYDROmorphone

Hydrochloride Injection, USP. If you experience any side effects not listed here, contact your

healthcare professional.

Side effects may include:

Drowsiness

Insomnia

Dizziness

Fainting

Nausea, vomiting, or a poor appetite

Dry mouth

Headache

Problems with vision

Weakness, uncoordinated muscle movement

Lack of muscle strength

Itching

Light headedness

Sweating

Constipation

Confusion

Anxiety

Abdominal pain

Injection site reaction

Low sex drive, impotence (erectile dysfunction), infertility

Talk with your doctor or pharmacist about ways to prevent constipation when you start using

HYDROmorphone Hydrochloride Injection, USP.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 33 of 34

Serious side effects and what to do about them

Symptom /

effect

Talk to your

healthcare

professional

Stop taking

drug and get

immediate

medical help

Only if

severe

In all

cases

RARE

Overdose: hallucinations, confusion, inability to

walk normally, slow or weak breathing, extreme

sleepiness, sedation, or dizziness, floppy

muscles/low muscle tone, cold and clammy skin.

Respiratory Depression: slow, shallow or weak

breathing.

Allergic Reaction: rash, hives, swelling of the

face, lips, tongue or throat, difficulty

swallowing or breathing

Bowel Blockage (impaction):

abdominal pain, severe constipation, nausea

Withdrawal: nausea, vomiting, diarrhea, anxiety,

shivering, cold and clammy skin, body aches, loss

of appetite, sweating.

Fast, Slow or Irregular Heartbeat: heart

palpitations.

Low Blood Pressure: dizziness, fainting, light-

headedness.

Serotonin Syndrome: agitation or

restlessness, loss of muscle control or muscle

twitching, tremor, diarrhea

If you have a troublesome symptom or side effect that is not listed here or becomes bad

enough to interfere with your daily activities, talk to your healthcare professional.

Reporting Side Effects

You can report any suspected side effects associated with the use of health products to Health

Canada by:

Visiting the Web page on Adverse Reaction Reporting (https://www.canada.ca/en/health-

canada/services/drugs-health-products/medeffect-canada/adverse-reaction-reporting.html)

for information on how to report online, by mail or by fax; or

Calling toll-free at 1-866-234-2345.

HYDROmorphone Hydrochloride Injection, USP - 2 mg/mL

Page 34 of 34

NOTE: Contact your health professional if you need information about how to manage your side

effects. The Canada Vigilance Program does not provide medical advice.

Storage:

Keep unused or expired HYDROmorphone Hydrochloride Injection, USP in a secure

place to prevent theft, misuse or accidental exposure.

Store at 15˚ to 30˚C. Protect from light.

Keep HYDROmorphone Hydrochloride Injection, USP under lock, out of sight and

reach of children and pets.

Never take medicine in front of small children as they will want to copy you. Accidental

ingestion by a child is dangerous and may result in death. If a child accidentally takes

HYDROmorphone Hydrochloride Injection, USP, get emergency help right away.

If you want more information about HYDROmorphone Hydrochloride Injection, USP:

Talk to your healthcare professional

Find the full prescribing information that is prepared for healthcare professionals and

includes this Patient Medication Information by visiting the Health Canada website

(https://health-products.canada.ca/dpd-bdpp/index-eng.jsp); the manufacturer’s

website (http://www.fresenius-kabi.ca), or by calling 1-877-821-7724 (toll-free-

telephone).

This information is current up to the time of the date of preparation shown below, but more current

information may be available from Fresenius Kabi.

Date of Preparation: August 20, 2019.

Fresenius Kabi Canada Ltd.

165 Galaxy Blvd, Suite 100

Toronto, ON M9W 0C8

Questions or concerns? 1-877-821-7724

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