PRODUCT
MONOGRAPH
N
TEVA-MORPHINE SR
Morphine Su
lfate
Sustained Release
Tablets
15 mg, 30 mg, 60 mg, 100 mg and 200
m
g
Teva
Standard
Opioid
Analgesic
Teva Canada Limited
30 Novopharm Court
Toronto, Ontario
Canada M1B 2K9
www.tevacanada.com
Date of Revision:
June 12, 2018
Submission Control No: 215463
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TABLE OF CONTENTS
PART I: HEALTH PROFESSIONAL INFORMATION .............................................................. 3
SUMMARY PRODUCT INFORMATION
..................................................................................... 3
INDICATIONS AND CLINICAL USE
........................................................................................... 3
CONTRAINDICATIONS
................................................................................................................ 4
WARNINGS AND PRECAUTIONS
.............................................................................................. 5
ADVERSE REACTIONS
.............................................................................................................. 13
DRUG INTERACTIONS
............................................................................................................... 16
DOSAGE AND ADMINISTRATION
........................................................................................... 17
OVERDOSAGE
............................................................................................................................. 21
ACTION AND CLINICAL PHARMACOLOGY
......................................................................... 21
STORAGE AND STABILITY
...................................................................................................... 24
SPECIAL HANDLING INSTRUCTIONS
.................................................................................... 24
DOSAGE FORMS, COMPOSITION AND PACKAGING
.......................................................... 24
PART II: SCIENTIFIC INFORMATION .................................................................................... 26
PHARMACEUTICAL INFORMATION
...................................................................................... 26
CLINICAL STUDIES
.................................................................................................................... 27
DETAILED PHARMACOLOGY
.................................................................................................. 32
TOXICOLOGY
.............................................................................................................................. 33
REFERENCES
............................................................................................................................... 34
PATIENT MEDICATION INFORMATION ............................................................................... 38
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N
TEVA-MORPHINE
SR
(morphine sulfate sustained release
tablets)
15 mg, 30 mg, 60 mg, 100 mg and 200
m
g
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Route of
Administration
Dosage For
m
/ Strength
Nonmedicinal Ingredients
Oral
Sustained Release Tablets /
15 mg, 30 mg, 60 mg, 100
mg and 200 mg
Tablet core (all strengths): Colloidal Silicon
Dioxide, Hydroxypropyl Methylcellulose, Lactose
Monohydrate, Magnesium Stearate and Stearic
Acid.
Tablet Coating: Polyvinyl Alcohol
(Partially Hydrolyzed), Polyethylene
Glycol 3350, Talc, Titanium Dioxide
Additional coating ingredients specific to each
strength:
15 mg: D&C Yellow #10/Aluminum Lake
FD&C Blue #1/Aluminum Lake
FD&C Red #40/ Aluminum Lake
30 mg: FD&C Blue #2/ Aluminum Lake
D&C Red #27/Aluminum Lake
FD&C Yellow #6/Aluminum Lake
60 mg: FD&C Yellow #6/Aluminum Lake
FD&C Red #40/Aluminum Lake
100 mg: FD&C Blue #2/Aluminum Lake
FD&C Yellow #6/Aluminum Lake
FD&C Red #40/Aluminum Lake
200 mg: D&C Red #30/Aluminum Lake
FD&C Red #40/Aluminum Lake
INDICATIONS AND CLINICAL USE
Adults
TEVA-MORPHINE SR
(morphine sulfate sustained release tablets) is indicated for
the management of pain severe enough to require daily, continuous, long-term opioid
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treatment, and:
that is opioid-responsive; and,
for which alternative treatment options are inadequate
TEVA-MORPHINE SR is not indicated as an as-needed (prn) analgesic.
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, reflecting the greater frequency of decreased hepatic, renal or cardiac
function, concomitant disease or other drug therapy (see ACTION AND CLINICAL
PHARMACOLOGY, Special Populations and Conditions, Geriatrics).
Pediatrics (< 18 years of age)
Individual dosing requirements vary considerably based on each patient’s age, weight,
severity
of pain, medical and analgesic history (see ACTION AND CLINICAL PHARMACOLOGY,
Special Populations and Conditions, Pediatrics).
CONTRAINDICATIONS
TEVA-MORPHINE SR
(morphine sulfate sustained release tablets) is contraindicated in:
• Patients who are hypersensitive to the active substance (morphine) 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 Product
Monograph.
• 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, intermittent or short duration pain that can be managed with other pain
medications.
• The management of acute pain, including use in outpatient or day surgeries.
• Patients with acute or severe bronchial asthma, chronicobstructive airway, and status
asthmaticus.
• 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, brain
tumour and/or head injury.
• Patients with cardiac arrhythmias.
• 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 SERIOUS
WARNINGS AND PRECAUTIONS and WARNINGS AND PRECAUTIONS).
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WARNINGS AND PRECAUTIONS
Serious Warnings and Precautions
Limitations of Use
Because the risks of addiction, abuse, and misuse with opioids, even at recommended doses,
and because of the greater risks of overdose and death with sustained release opioid
formulations, TEVA-MORPHINE SR
®
(morphine sulfate sustained release tablets) 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
TEVA-MORPHINE SR 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 TEVA-
MORPHINE SR, and all patients should be monitored regularly for the development of these
behaviours or conditions (see WARNINGS AND PRECAUTIONS). TEVA-MORPHINE SR
should be stored securely to avoid theft or misuse.
Life-threatening Respiratory Depression: OVERDOSE
Serious, life-threatening, or fatal respiratory depression may occur with use of TEVA-
MORPHINE SR. Infants exposed in-utero or through breast milk are at risk of life-
threatening respiratory depression upon delivery or when nursed. Patients should be
monitored for respiratory depression, especially during initiation of TEVA-MORPHINE SR
or following a dose increase.
TEVA-MORPHINE SR 15, 30, 60 and 100 mg tablets must be swallowed whole. Cutting,
breaking, crushing, chewing, or dissolving TEVA-MORPHINE SR can lead to rapid release
and absorption of a potentially fatal dose of morphine (see WARNINGS AND
PRECAUTIONS). Further, instruct patients of the hazards related to taking opioids
including fatal overdose. Only the 200 mg tablet is scored and may be broken in half. The half
tablet must also be swallowed intact.
Accidental Exposure
Accidental ingestion of even one dose of TEVA-MORPHINE SR, especially by children, can
result in a fatal overdose of morphine (see DOSAGE AND ADMINISTRATION, Disposal, for
instructions on proper disposal).
Neonatal Opioid Withdrawal Syndrome
Prolonged maternal use of TEVA-MORPHINE SR 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 TEVA-MORPHINE SR 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
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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 TEVA-MORPHINE SR 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
TEVA-MORPHINE SR
(morphine sulfate sustained release tablets) 15, 30, 60 and 100 mg
tablets must be swallowed whole, and must not be cut, chewed, dissolved or crushed. Taking
cut, broken, chewed, dissolved or crushed tablets could lead to the rapid release and
absorption of a potentially fatal dose of morphine. Only the 200 mg tablet is scored and may
be broken in half. The half tablet must also be swallowed intact.
TEVA-MORPHINE SR 100 mg and 200 mg tablets are for use in opioid tolerant patients
only (see also DOSAGE AND ADMINISTRATION). These tablet strengths may cause fatal
respiratory depression if administered to patients not previously exposed to daily morphine
equivalent dosages of 200 mg or more. Care should be taken in the prescribing of these
tablet strengths.
Patients should be instructed not to give TEVA-MORPHINE SR to anyone other than for
whom it was prescribed, as such, inappropriate use may have severe medical consequences,
including death.
Patients should be cautioned not to consume alcohol while taking TEVA-MORPHINE SR, as it
may increase the chance of experiencing dangerous side effects.
Hyperalgesia that will not respond to a further dose increase of morphine may occur in particular in
high doses. A morphine dose reduction or change in opioid may be required.
Addiction, Abuse and Misuse
Like all opioids, TEVA-MORPHINE SR is a potential drug of abuse and misuse, which can lead
to overdose and death. Therefore, TEVA-MORPHINE SR should be prescribed and handled with
caution.
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 TEVA-MORPHINE SR, 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.
With parenteral abuse, the tablet excipients, especially talc, can be expected to result in local
tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular
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heart injury, which may also be fatal.
Carcinogenesis and Mutagenesis
See TOXICOLOGY section.
Cardiovascular
Morphine 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
such drugs as phenothiazines or certain anaesthetics.
Dependence/Tolerance
As with other opioids, tolerance and physical dependence may develop upon repeated
administration of TEVA-MORPHINE SR and there is a potential for development of
psychological dependence.
Physical dependence and tolerance reflect the neuroadaptaion 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 tapered 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.
Physical dependence with or without psychological dependence tends to occur with chronic
administration. An abstinence syndrome may be precipitated when opioid administration is
discontinued or opioid antagonists administered. With appropriate medical use of opioids and
gradual withdrawal from the drug, these symptoms are usually mild.
Use in Drug and Alcohol Addiction
TEVA-MORPHINE SR
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 TEVA-
MORPHINE SR 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
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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
Morphine (and other morphine-like opioids) has been shown to decrease bowel motility.
Morphine may obscure the diagnosis or clinical course of patients with acute abdominal
conditions (see CONTRAINDICATIONS and ADVERSE REACTIONS, Nausea and
Vomiting and Constipation).
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 TEVA-MORPHINE SR is contraindicated in pregnant women (see
CONTRAINDICATIONS).
Neurologic
Interactions with Central Nervous System Depressants (including benzodiazepines and
alcohol):
Morphine should be used with caution and in a reduced dosage during concomitant
administration of other opioid analgesics, general anaesthetics, phenothiazines and other
tranquilizers, sedative-hypnotics, tricyclic antidepressants, antipsychotics, antihistamines,
benzodiazepines, centrally-active anti-emetics and other CNS depressants. Respiratory
depression, hypotension and profound sedation or coma may result.
When such combination therapy is contemplated, a substantial reduction in the dose of one or
both agents should be considered and patients should be carefully monitored. TEVA-
MORPHINE SR should not be consumed with alcohol as it may increase the chance of
experiencing dangerous side effects (see DRUG INTERACTIONS).
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
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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
TEVA-MORPHINE SR 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).
TEVA-MORPHINE SR 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.
Use in Patients with Convulsive or Seizure Disorders: The morphine sulfate in TEVA-
MORPHINE SR may aggravate convulsions in patients with convulsive disorders, and may
induce or aggravate seizures in some clinical settings. Therefore, TEVA-MORPHINE SR
should not be used in these patients (see CONTRAINDICATIONS).
Serotonin syndrome: TEVA-MORPHINE SR 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. TEVA-
MORPHINE SR 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 morphine, and the capacity to elevate
cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated
intracranial pressure produced by trauma. Also, morphine may produce confusion, miosis,
vomiting and other side effects which obscure the clinical course of patients with head
injury.
In
such patients, morphine must be used with extreme caution and only if it is judged essential.
Seizures: Morphine may lower the seizure threshold in patients with a history of epilepsy.
Peri-Operative Considerations
TEVA-MORPHINE SR
is not recommended for preoperative use or postoperatively within the
first 24 hours.
In the case of planned chordotomy or other pain-relieving operations, patients should not be
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treated with TEVA-MORPHINE SR
for at least 24 hours before the operation and TEVA-
MORPHINE SR
should not be used in the immediate post-operative period.
Physicians should individualize treatment, moving from parenteral to oral analgesics as
appropriate. Thereafter, if TEVA-MORPHINE SR
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).
Morphine (and other morphine-like opioids) has 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
TEVA-MORPHINE SR
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 morphine
with other
CNS depressants, including other opioids, phenothiazines, sedative/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. Carbon dioxide (CO
2
)
retention from opioid-induced respiratory depression can exacerbate the sedating effects of
opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the
use of TEVA-MORPHINE SR, 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 TEVA-MORPHINE SR and following dose increases.
To reduce the risk of respiratory depression, proper dosing and titration of TEVA-MORPHINE
SR are essential (see DOSAGE AND ADMINISTRATION). Overestimating the TEVA-
MORPHINE SR dose when converting patients from another opioid product can result in a fatal
overdose with the first dose.
TEVA-MORPHINE SR
100 mg and 200 mg tablets are for use in opioid tolerant patients only
(see DOSAGE AND ADMINISTRATION). These tablet strengths may cause fatal respiratory
depression if administered to patients not previously exposed to daily morphine equivalent
dosages of 200 mg or more. Care should be taken in the prescribing of these tablet strengths.
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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 pre-existing respiratory depression for respiratory
depression, particularly when initiating therapy and titrating with
TEVA-MORPHINE SR, as in these
patients, even usual therapeutic doses of
TEVA-MORPHINE SR 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
TEVA-MORPHINE SR is contraindicated in patients with acute or severe
bronchial asthma, chronic obstructive airway, or status asthmaticus (see CONTRAINDICATIONS).
Patient Counselling Information
A patient information sheet should be provided when TEVA-MORPHINE SR
is dispensed to
the patient.
Patients receiving TEVA-MORPHINE SR
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.
2. Patients should be advised that TEVA-MORPHINE SR
contains morphine, an opioid pain
medicine.
3. Patients should be advised that TEVA-MORPHINE SR
should only be taken as directed.
The dose of TEVA-MORPHINE SR should not be adjusted without consulting with a
physician.
4. TEVA-MORPHINE SR
must be swallowed whole (not cut, broken, chewed, dissolved or
crushed)
due to
the risk of fatal morphine overdose. Only the 200 mg tablet is scored and
may be broken in half. The half tablet must also be swallowed intact.
5. Patients should be advised to report episodes of pain and adverse experiences occurring
during therapy. Individualization of dosage is essential to make optimal use of this
medication.
6. Patients should not combine TEVA-MORPHINE SR
with alcohol or other central
nervous system depressants (sleep aids, tranquilizers) because dangerous additive
effects may occur resulting in serious injury or death.
7. Patients should be advised to consult their physician or pharmacist if other medications are
being used or will be used with TEVA-MORPHINE SR.
8. Patients should be advised that if they have been receiving treatment with TEVA-
MORPHINE SR
and cessation of therapy is indicated, it may be appropriate to taper the
TEVA-MORPHINE SR
dose, rather than abruptly discontinue it, due to the risk of
precipitating withdrawal symptoms.
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9. Patients should be advised of the most common adverse reactions that may occur while
taking TEVA-MORPHINE SR: constipation, dizziness, hyperhidrosis, nausea, sedation
and vomiting.
10. Patients should be advised that TEVA-MORPHINE SR 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 onTEVA-MORPHINE SR 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
TEVA-MORPHINE SR.
11. Patients should be advised not to take TEVA-MORPHINE SR
if they have seizure
disorders.
12. Patients should be advised that TEVA-MORPHINE SR
is a potential drug of abuse. They
should protect it from theft or misuse.
13. Patients should be advised that TEVA-MORPHINE SR
should never be given to anyone
other than the individual for whom it was prescribed.
14. 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 TEVA-
MORPHINE SR. Women who are breast-feeding or pregnant should not use TEVA-
MORPHINE SR.
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-
Market Adverse Drug Reactions).
Special Populations
Special Risk Groups: Morphine should be administered with caution to patients with a history
of alcohol, seizures, and drug abuse and in a reduced dosage to elderly or debilitated patients,
patients with reduced hepatic function or severe renal dysfunction, and to patients with
adrenocortical insufficiency (e.g., Addison's disease), biliary tract disorders, hypotension with
hypovolaemia, hypothyroidism, prostatic hypertrophy or urethral stricture.
Pregnant Women: Animal studies with morphine and other opioids have indicated the
possibility of teratogenic effects. In humans, it is not known whether morphine can cause fetal
harm when administered during pregnancy or can affect reproductive capacity. Since morphine
crosses the placental barrier, TEVA-MORPHINE SR
is contraindicated in patients who are
pregnant (see CONTRAINDICATIONS).
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 (see WARNINGS AND PRECAUTIONS, Neonatal Opioid Withdrawal
Syndrome).
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Labour, Delivery and Nursing Mothers:
TEVA-MORPHINE SR is contraindicated during labour, delivery, pregnancy and in nursing
mothers. Morphine sulfate can cross the placental barrier and is also excreted in breast milk.
Life-threatening respiratory depression may 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
TEVA-MORPHINE SR is used in this population.
Pediatrics (< 18 years of age): Individual dosing requirements vary considerably based on each
patient’s age, weight, severity of pain, medical and analgesic history.
An appropriate initial dose for children inadequately controlled on non-opioids or weak opioids is
0.5 - 1 mg/kg
TEVA-MORPHINE SR
orally every 12 hours.
Geriatrics (> 65 years of age): 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, and of concomitant disease or other drug therapy.
Patients over 50 years of age tend to require much lower doses of morphine than in the younger
age group. Morphine should be administered with caution and in a reduced dosage to elderly or
debilitated patients. The initial dose usually starts at the low end of the dosing range.
In Vitro Dissolution Studies of Interaction with Alcohol
Increasing concentrations of alcohol in the dissolution medium resulted in a decrease in the rate
of release of morphine from morphine sulfate sustained release tablets. The clinical significance
of these findings is unknown.
ADVERSE REACTIONS
Adverse Drug Reaction Overview
Adverse effects of morphine sulfate sustained release tablets are similar to those of other opioid
analgesics, and represent an extension of pharmacological effects of the drug class. The major
hazards of opioids include respiratory and central nervous system depression and, to a lesser
degree, circulatory depression respiratory arrest, shock and cardiac arrest.
The most frequently observed side effects of morphine sulfate sustained release
tablets are constipation, dizziness, hyperhidrosis, nausea, sedation and vomiting.
Sedation: Some degree of sedation is experienced by most patients upon initiation of therapy.
This may be at least partly because patients often recuperate from prolonged fatigue after the
relief of persistent pain. Drowsiness usually clears in three to five days and is usually not a
reason for concern providing that it is not excessive, or associated with unsteadiness or
confusion. If excessive sedation persists, the reason for it must be sought. Some of these are:
concomitant sedative medications, hepatic or renal failure, exacerbated respiratory failure, higher
doses than tolerated in an older patient, or the patient is actually more severely ill than realized.
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
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caused by postural hypotension particularly in elderly or debilitated patients. It can be
alleviated
if
the patient lies down. Because of the slower clearance in patients over 50 years of age, an
appropriate dose in this age group may be as low as half or less the usual dose in the younger age
group.
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 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 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 TEVA-MORPHINE SR and opioid analgesics. 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).
General Disorders and Administration Site Conditions:
Common: asthenia, fatigue, malaise, pruritus, weakness, sedation
Uncommon: peripheral edema
Not known: drug tolerance, drug withdrawal syndrome, drug withdrawal syndrome neonatal
Cardiac Disorders:
Uncommon: palpitations
Rare: faintness
Unknown: supraventricular tachycardia, bradycardia
Ear and Labyrinth Disorders:
Uncommon: vertigo
Endocrine Disorders: a syndrome of inappropriate antidiuretic hormone secretion characterized by
hyponatremia secondary to decreased free-water excretion may be prominent (monitoring of
electrolytes may be necessary)
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Eye Disorders:
Uncommon: visual disturbance
Not known: miosis
Gastrointestinal Disorders:
Very common: constipation, nausea
Common: abdominal pain, anorexia, dry mouth, vomiting
Uncommon: dyspepsia, ileus, taste perversion
Hepato-biliary Disorders:
Uncommon: increased hepatic enzyme
Not known: biliary pain, exacerbation of pancreatitis
Immune System Disorders:
Uncommon: hypersensitivity
Not known: anaphylactic reaction, anaphylactoid reaction
Nervous System Disorders:
Common: dizziness, headache, involuntary muscle contractions, somnolence
Uncommon: convulsions, hypertonia, paraesthesia, syncope, myoclonus
Not known: hyperalgesia
Psychiatric Disorders:
Common: confusion, insomnia
Uncommon: agitation, euphoria, hallucinations, mood altered
Not known: drug dependence, dysphoria, thinking disturbances
Renal and Urinary Disorders:
Uncommon: urinary retention
Unknown: ureteric spasm
Respiratory, Thoracic and Mediastinal Disorders:
Uncommon: bronchospasm, pulmonary edema, respiratory depression
Not known: cough decreased
Reproductive System and Breast Disorders:
Not known: amenorrhoea, decreased libido, erectile dysfunction
Skin and Subcutaneous Tissue Disorders:
Common: hyperhidrosis, rash
Uncommon: urticaria
Vascular Disorders:
Uncommon: facial flushing, hypotension
Unknown: hypertension
Post-Marketing Experience
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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.
DRUG INTERACTIONS
Overview
Interactions with Central Nervous System (CNS) Depressants (including benzodiazepines
and alcohol): TEVA-MORPHINE SR
(morphine sulfate sustained release tablets) should be
dosed with caution and started in a reduced dosage in patients who are currently talking other
central nervous system depressants (e.g., other opioids, anaesthetics, sedatives, hypnotics,
antidepressants, phenothiazines, neuroleptics, antihistamines and antiemetics) glutethimide or
gabapentin, and beta-blockers, as they may enhance the CNS-depressant effect (e.g., respiratory
depression) of TEVA-MORPHINE SR. TEVA-MORPHINE SR should not be consumed with
alcohol as it may increase the chance of experiencing dangerous side effects.
Drug-Drug Interactions
Generally, the effects of morphine may be antagonized by acidifying agents and potentiated by
alkalizing agents. The analgesic effect of morphine is potentiated by amphetamines,
chlorpromazine and methocarbamol.
Warfarin and Other Coumarin Anticoagulants: Morphine may increase the anticoagulant
activity of coumarin and other anticoagulants.
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 morphine. In this situation, mixed agonist/antagonist
analgesics may reduce the analgesic effect of morphine and/or may precipitate withdrawal
symptoms in these patients.
MAO Inhibitors: Monoamine oxidase inhibitors intensify the effects of opioid drugs which can
cause anxiety, confusion and decreased respiration. TEVA-MORPHINE SR
is contraindicated in
patients receiving MAO inhibitors or who have taken them within the previous 14 days (see
CONTRAINDICATIONS).
Serotonergic Agents: Coadministration of morphine sulfate 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-Food Interactions
Food has no significant effect on the extent of absorption of morphine from morphine sulfate
sustained release tablet.
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Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.
Drug-Lifestyle Interaction
The concomitant use of alcohol should be avoided (see WARNINGS AND PRECAUTIONS,
General).
DOSAGE AND ADMINISTRATION
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 90 mg of TEVA-MORPHINE SR (morphine sulfate sustained release
tablets) not be exceeded. Each patient should be assessed for their risk prior to prescribing
TEVA-MORPHINE SR, 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 TEVA-MORPHINE SR (see DOSAGE AND
ADMINISTRATION - Adjustment or Reduction of Dosage).
Dosing Considerations
TEVA-MORPHINE SR (morphine sulfate sustained release tablets) 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.
TEVA-MORPHINE SR
15 mg, 30 mg, 60 mg and 100 mg tablets must be swallowed whole.
Cutting, breaking, crushing, chewing, or dissolving TEVA-MORPHINE SR can lead to the
rapid release and absorption of a potentially fatal dose of morphine. Only the 200 mg tablet
is scored and may be broken in half. The half tablet must also be swallowed intact (see
WARNINGS AND PRECAUTIONS).
Administration and dosing of morphine should be individualized bearing in mind the properties of
the drug. In addition, the nature and severity of the pain or pains experienced, and the total
condition of the patient must be taken into account. Of special importance is other medication
given previously or concurrently.
As with other opioid analgesics, use of morphine for the management of persistent pain should
be preceded by a thorough assessment of the patient and diagnosis of the specific pain or pains
and their causes. Use of opioids for the relief of chronic pain, including cancer pain, all
important as it may be, should be only one part of a comprehensive approach to pain control
including other treatment modalities or drug therapy, non-drug measures and psychosocial
support.
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TEVA-MORPHINE SR
should be used with caution within 24 hours pre-operatively and within
the first 24 hours post-operatively (see WARNINGS AND PRECAUTIONS, Peri-operative
Considerations).
TEVA-MORPHINE SR
tablets are not indicated for rectal administration.
The sustained release tablets may be taken with or without food, with a glass of water.
Recommended Dose and Dosage Adjustment
Adults: Individual dosing requirements vary considerably based on each patient's age, weight,
severity of pain, and medical and analgesic history.
The most frequent initial dose is 30 mg orally every 12 hours.
Patients over the Age of 50: Patients over 50 years of age tend to require much lower doses of
morphine than in the younger age group.
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, reflecting the greater frequency of decreased
hepatic, renal or cardiac function, concomitant disease or other drug therapy.
Pediatrics (< 18 years of age): Individual dosing requirements vary considerably based on each
patient’s age, weight, severity of pain, medical and analgesic history.
An appropriate initial dose for children inadequately controlled on non-opioids or weak opioids is
0.5 - 1 mg/kg TEVA-MORPHINE SR
orally every 12 hours.
Patients Not Receiving Opioids at the Time of Initiation of Morphine Treatment: The usual
initial adult dose of TEVA-MORPHINE SR for patients who have not previously received
opioid analgesics is 30 mg orally, every 12 hours.
Patients Currently Receiving Opioids: Patients currently receiving other oral morphine
formulations may be transferred to TEVA-MORPHINE SR
at the same total daily morphine
dosage, equally divided into two 12 hourly TEVA-MORPHINE SR
doses.
For patients who are receiving an alternate opioid, the “oral morphine sulfate 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 morphine
sulfate dosage that should provide equivalent analgesia. This total daily oral morphine dosage
should then be equally divided into two 12 hourly TEVA-MORPHINE SR
doses. Further dose
reductions should be considered due to incomplete cross-tolerance between opioids.
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. TEVA-MORPHINE SR
can be
safely used concomitantly with usual doses of other non-opioid analgesics.
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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 conversion Table
a
Opiods To convert to
oral morphine
equivalent
To convert from
oral morphine
multiply by
Daily 90 mg
MED
b
Morphine 1 1 90 mg
Codeine 0.15 6.67 600 mg
Hydromorphone 5 0.2 18 mg
Oxycodone 1.5 0.667 60 mg
Tapentadol 0.3 – 0.4 2.5 – 3.33 300 mg
Tramadol 0.1 – 0.2 6 ***
Methadone Morphine dose equivalence is not reliably established
*** The maximum recommended daily dose of tramadol is 300 mg – 400 mg depending on the formulation.
a. Adapted from the 2017 Canadian guideline for opioids for chronic non-cancer pain. McMaster University; 2017
b. MED. Morphine Equivalent Dose
Dose Titration: Dose titration is the key to success with morphine therapy. Proper
optimization of doses scaled to the relief of the individual's pain should aim at regular
administration of the lowest dose of sustained release morphine (TEVA-MORPHINE SR)
which will achieve the overall treatment goal of satisfactory pain relief with acceptable
side effects.
Dose adjustments should be based on the patient's clinical response. Higher doses, at certain
times, may be justified in some patients to cover periods of physical activity.
Because of the sustained release properties of TEVA-MORPHINE SR, dosage adjustments
should generally be separated by 48 hours. If dose increments turn out to be required, they should
be proportionately greater at the lower dose level (in terms of percentage of previous dose), than
when adjusting a higher dose. The usual recommended dose (q12h) increments for TEVA-
MORPHINE SR
tablets are 15, 30, 45, 60, 90, 120, 150, 180 and 200 mg. Above the 200
mg/dose (400 mg/day) increments should be by 30-60 mg/dose.
TEVA-MORPHINE SR
is designed to allow 12 hourly dosing. If pain repeatedly occurs at the
end of a dose interval, it is generally an indication for a dosage increase, rather than more frequent
administration of sustained release TEVA-MORPHINE SR. However, where judged necessary
for optimization of drug effects, TEVA-MORPHINE SR
tablets may be administered q8h. More
frequent (than q8h) administration is not recommended.
Adjustment or Reduction of Dosage: Physical dependence with or without psychological
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dependence tends to occur with chronic administration of opioids, including TEVA-
MORPHINE SR 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 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 improved 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.
Management of Patients Requiring Rescue Medication
Some patients taking TEVA-MORPHINE SR according to a fixed time schedule may require
immediate-release analgesics as "rescue" medication for pain. Selection of rescue medication should
be based on individual patient conditions. TEVA-MORPHINE SR is a sustained release
formulation and therefore is not intended for use as rescue medication.
Missed Dose
If the patient forgets to take one or more doses, they should take their next dose at the next
scheduled time and in the normal amount.
Disposal
TEVA-MORPHINE SR 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. TEVA-MORPHINE SR should not be used in front
of children, since they may copy these actions.
Unused or expired TEVA-MORPHINE SR should be properly disposed of as soon as it is no
longer needed to prevent accidental exposure to others, including children or pets. TEVA-
MORPHINE SR should not be shared with others and steps should be taken to protect it from
theft or misuse. The patient should speak to their pharmacist about temporary storage options, if
required, until the medication can be returned to the pharmacy for safe disposal.
TEVA-MORPHINE SR should never be disposed of in household trash. Disposal via a pharmacy
take back program is recommended.
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OVERDOSAGE
For management of a suspected drug overdose, contact your regional Poison Control Centre.
Symptoms: Serious overdosage with morphine may be characterized by respiratory depression
(respiratory rate and/or tidal volume; Cheyne-Stokes respiration; cyanosis), dizziness, confusion,
extreme somnolence progressing to stupor or coma, pneumonia aspiration, miosis, rhabdomyolysis
progressing to renal failure, hypotonia, cold and clammy skin, and sometimes bradycardia and
hypotension. Pinpoint pupils are a sign of narcotic 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 morphine overdose. Severe
overdosage may result in apnea, circulatory collapse, cardiac arrest and death.
Treatment: Primary attention should be given to the establishment of adequate respiratory
exchange through the provision of a patent airway and controlled or assisted ventilation. The
opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression due
to overdosage or as a result of unusual sensitivity to morphine. An appropriate dose of one of
the
antagonists should therefore be administered, preferably by the intravenous route. The usual
initial intravenous adult dose of naloxone is 0.4 mg or higher. Concomitant efforts at respiratory
resuscitation should be carried out. Since the duration of action of morphine, particularly
sustained release formulations, may exceed that of the antagonist, the patient should be under
continued surveillance and doses of the antagonist should be repeated as needed to maintain
adequate respiration.
An antagonist should not be administered in the absence of clinically significant respiratory or
cardiovascular depression. Oxygen, intravenous fluids, vasopressors and other supportive
measures should be used as indicated.
In an individual physically dependent on opioids, the administration of the usual dose of opioid
antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will
depend on the degree of physical dependence and the dose of antagonist administered. The use of
opioid antagonists in such individuals should be avoided if possible. If an opioid antagonist must
be used to treat serious respiratory depression in the physically dependent patient, the antagonist
should be administered with extreme care by using dosage titration, commencing with 10% to
20% of the usual recommended initial dose.
Evacuation of gastric contents may be useful in removing unabsorbed drug, particularly when a
sustained release oral formulation has been taken.
ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
Morphine is an opioid analgesic which exerts an agonist effect at specific, saturable opioid
receptors in the CNS and other tissues. In man, morphine produces a variety of effects including
analgesia, constipation from decreased gastrointestinal motility, suppression of the cough reflex,
respiratory depression from reduced responsiveness of the respiratory center to CO
2
, nausea and
vomiting via stimulation of the CTZ, changes in mood including euphoria and dysphoria, sedation,
mental clouding, and alterations of the endocrine and autonomic nervous systems.
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Pharmacodynamics
Morphine is an opioid agonist. Adequate doses will relieve even the most severe pain. Clinically
however, dosage limitations are imposed by the adverse effects, primarily respiratory depression,
nausea and vomiting, which can result from high doses.
Cardiovascular System: Morphine may produce release of histamine with or without
associated peripheral vasodilation. Manifestations of histamine release and/or peripheral
vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Central Nervous System: In man, the principal pharmacological actions of morphine are in the
CNS; analgesia, drowsiness, mood changes, mental clouding, respiratory depression, nausea or
emesis and miosis.
Morphine produces respiratory depression by direct action on brain stem respiratory centres. It
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.
Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of narcotic 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
morphine 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: Morphine 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 is increased to the point of
spasm resulting in constipation.
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.
Concentration – Efficacy Relationships
Morphine induced analgesia is a result of increases in both the pain threshold and pain tolerance.
Morphine alters the affective response to pain in that patients remain aware of its existence
but are
less distressed. Morphine relieves most types of pain but is more effective against dull constant
pains than sharp intermittent ones.
Concentration – Adverse Reaction Relationship
There is a significant relationship between increasing morphine plasma concentrations and
increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS
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effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by
the development of tolerance to opioid-related side effects.
The dose of morphine sulfate sustained release tablet must be individualized (see DOSAGE
AND ADMINISTRATION) because the effective analgesic dose for some patients will be too
high to be tolerated by other patients.
Pharmacokinetics
With repeated regular dosing, oral morphine is about 1/3 as potent as when given by intramuscular
injection. The relationship between mean plasma concentration and dose has been shown to be
linear over a dosage range of 60 - 600 mg/day in the case of the morphine sulfate sustained release
tablets.
Absorption: Morphine is readily absorbed when given orally, rectally or by subcutaneous or
intramuscular injection. Due to "first-pass" metabolism in the liver, the effect of an oral dose is
less than after parenteral administration.
When administered every 12 hours, the sustained-release tablets provide equivalent analgesia to
morphine oral solution given 4 hourly. In most cases, administration on a twelve
hourly schedule
produces equivalent pain control to eight hourly administration.
Distribution: Following absorption, approximately 30% to 35% of morphine is reversibly bound
to plasma proteins. Free morphine readily leaves the circulation and is concentrated in the liver,
kidney, lung, spleen and, to a lesser extent, skeletal muscle. In adults, only small quantities of
morphine pass the blood brain barrier.
Metabolism: Conjugated morphine excreted in the bile may be hydrolyzed and reabsorbed from
the large bowel. Conjugation with glucuronic acid is the major metabolic pathway for morphine.
The major metabolites are morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).
Minor metabolites include normorphine, morphine-3-6 diglucuronide and morphine-3-ethereal
sulfate.
The mean elimination half-life of morphine is 2 to 3 hours with great inter-patient variability.
Excretion: The major route of elimination is via the kidney. Morphine is primarily excreted in
the urine as morphine-3-glucuronide. About 7% to 10% of a dose of morphine is excreted in the
feces via the bile.
Special Populations and Conditions
Pediatrics: Individual dosing requirements vary considerably based on each patient’s age,
weight, severity of pain, medical and analgesic history.
Geriatrics: Dose selection for an elderly patient should be cautious, usually starting at one half
the recommended adult dose, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy.
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STORAGE AND STABILITY
TEVA-MORPHINE SR 15 mg tablets: store tablets at room temperature (15°C - 25°C).
Protect from light.
TEVA-MORPHINE SR 30 mg, 60 mg, 100 mg and 200 mg tablets: Store tablets at room
temperature (15°C - 30°C). Protect from light.
SPECIAL HANDLING INSTRUCTIONS
Not applicable.
DOSAGE FORMS, COMPOSITION AND PACKAGING
Dosage Forms
TEVA-MORPHINE SR (morphine sulfate sustained release tablets) are available as:
15 mg: Green, round, sustained release, film-coated, biconvex tablets, engraved N on one side and
15 on the other side.
30 mg: Violet, round, sustained release, film-coated, biconvex tablets, engraved N on one side and
30 on the other side.
60 mg: Orange, round, sustained release, film-coated, biconvex tablets, engraved N on one side
and 60 on the other side.
100 mg: Grey, round, sustained release, film-coated, biconvex tablets, engraved N on one side and
100 on the other side.
200 mg: Red, scored, caplet-shaped, sustained release, film-coated, biconvex tablets,
engraved N scoreline N on one side and 200 on the other side.
Composition
Tablet core (all strengths): Colloidal Silicon Dioxide, Hydroxypropyl Methylcellulose, Lactose
Monohydrate, Magnesium Stearate and Stearic Acid.
Tablet Coating: Polyvinyl Alcohol (Partially Hydrolyzed), Polyethylene Glycol 3350,
Talc, Titanium Dioxide
Additional coating ingredients specific to each strength:
15 mg: D&C Yellow #10/Aluminum Lake
FD&C Blue #1/Aluminum Lake
FD&C Red #40/ Aluminum Lake
30 mg: FD&C Blue #2/ Aluminum Lake
D&C Red #27/Aluminum Lake
FD&C Yellow #6/Aluminum Lake
60 mg: FD&C Yellow #6/Aluminum Lake
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FD&C Red #40/Aluminum Lake
100 mg: FD&C Blue #2/Aluminum Lake
FD&C Yellow #6/Aluminum Lake
FD&C Red #40/Aluminum Lake
200 mg: D&C Red #30/Aluminum Lake
FD&C Red #40/Aluminum Lake
Packaging
TEVA-MORPHINE SR 15 mg tablets are supplied in bottles of 50.
TEVA-MORPHINE SR 30 mg, 60 mg, 100 mg and 200 mg tablets are supplied in bottles of
50 and 100 tablets.
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PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Proper name: morphine sulfate
Chemical name: (5α,6α) 7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol sulphate (2:1
salt) pentahydrate
di[(5R,6S)-4,5-epoxy-N-methylmorphin-7-ene-3,6-diol]sulphate
pentahydrate
Molecular formula: (C17H19NO3)2 H2SO4•5H2O
Molecular mass: 758.8 (pentahydrate) g/mol
668.8 (anhydrous) g/mol
Structural Formula:
Description: Morphine sulfate is a white or almost white crystalline powder. Morphine sulfate is
soluble 1:21 in water and 1:1000 in ethanol. It is practically insoluble in ether or chloroform.
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CLINICAL STUDIES
SUMMARY TABLES:
A randomized, two period, two treatment crossover comparative bioavailability study of Teva-
Morphine SR (sustained-release) 15 mg tablets (Teva Canada Limited, Canada) and MS Contin
®
15
mg sustained-release tablets (Purdue Pharma, Canada) administered as a single 1 x 15 mg dose, was
conducted in 34 healthy adult male and female subjects under fed conditions. A summary of the
bioavailability data is presented below.
Morphine
(1x 15 mg)
From measured data
uncorrected for potency
Geometric Mean
Arithmetic Mean (CV %)
Parameter Test* Reference
†
% Ratio of
Geometric Means
Confidence Interval, 90%
AUC
T
(ng
*
h/mL)
53.284
55.066 (27)
52.958
54.638 (25)
100.62 96.81 - 104.57
AUC
(0-12)
(ng
*
h/mL)
40.504
41.696 (25)
39.793
40.966 (24)
101.79 97.95 - 105.78
AUC
I
(ng
*
h/mL)
60.319
61.347 (26)
58.688
60.122 (22)
102.78 99.37 - 106.31
C
max
(ng/mL)
8.109
8.401 (25)
8.784
9.222 (33)
92.32 85.04 - 100.21
T
max
§
(h)
2.79 (48) 2.72 (46)
T
½
§
(h)
12.17 (35) 13.05 (32)
* Teva-Morphine SR Tablets 15 mg (Teva Canada Limited, Canada)
† MS Contin
®
15 mg Sustained Release Tablets (Purdue Pharma, Canada). Purchased in Canada.
§
Expressed as the arithmetic mean (CV %) only
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A randomized, two period, two treatment crossover comparative bioavailability study of Teva-
Morphine SR (sustained-release) 15 mg tablets (Teva Canada Limited, Canada) and MS Contin
®
15
mg sustained-release tablets (Purdue Pharma, Canada) administered as a single 1 x 15 mg dose, was
conducted in 22 healthy adult male and female subjects under fasting conditions. A summary of the
bioavailability data is presented below.
Morphine
(1 x 15 mg)
From measured data
uncorrected for potency
Geometric Mean
Arithmetic Mean (CV %)
Parameter Test* Reference
†
% Ratio of
Geometric Means
90% Confidence Interval
AUC
t
(ng*h/mL)
52.667
54.631 (27)
53.373
55.504 (27)
98.68 95.05 – 102.44
AUC
0-12
(ng
*
h/mL)
36.189
37.405 (25)
37.755
39.086 (26)
95.85 92.76 – 99.05
AUC
inf
(ng
*
h/mL)
58.850
62.263 (22)
59.879
61.014 (25)
98.28 94.51 – 102.21
C
max
(ng/mL)
6.298
6.519 (27)
6.800
7.048 (26)
92.61 87.62 – 97.90
T
max
§
(h)
1.75 (55) 1.74 (72)
T
½
§
(h)
10.78 (68) 11.19 (42)
* Teva-Morphine SR Tablets 15 mg (Teva Canada Limited, Canada)
† MS Contin® 15 mg Sustained Release Tablets (Purdue Pharma, Canada). Purchased in Canada.
§
Expressed as the arithmetic mean (CV %) only
Teva-Morphine S
R
Tablets
Page 29
A randomized, two period, two treatment crossover comparative bioavailability study of Teva-
Morphine SR (sustained-release) 15 mg tablets (Teva Canada Limited, Canada) and MS Contin
®
15
mg sustained-release tablets (Purdue Pharma, Canada) administered as a a multiple-dose 1 x 15 mg
(q12h), was conducted in 20 healthy adult male and female subjects under fasting conditions. A
summary of the bioavailability data is presented below.
Morphine
(1 x 15 mg, q12h)
From measured data
uncorrected for potency
Geometric Mean
Arithmetic Mean (CV %)
Parameter Test* Reference
†
% Ratio of
Geometric Means
Confidence Interval, 90%
AUC
tau
(ng
*
h/mL)
61.637
63.162 (23)
62.059
63.687 (24)
99.32 94.61 - 104.26
C
max
(ng/mL)
8.634
8.804 (20)
9.347
9.601 (24)
92.37
87.57 – 97.42
C
min
(ng/mL)
2.481
2.604 (35)
2.322
2.490 (38)
106.85
93.01 – 122.74
T
max
§
(h)
2.30 (57) 1.98 (58)
FL
§
(%) 119.88 (19) 135.45 (22)
* Teva-Morphine SR Tablets 15 mg (Teva Canada Limited, Canada)
† MS Contin
®
15 mg Sustained Release Tablets (Purdue Pharma, Canada). Purchased in Canada.
§
Expressed as the arithmetic mean (CV %) only
Teva-Morphine S
R
Tablets
Page 30
A randomized, two period, two treatment crossover comparative bioavailability study of Teva-
Morphine SR (sustained-release) 200 mg tablets (Teva Canada Limited, Canada) and MS Contin
®
200 mg sustained-release tablets (Purdue Pharma, Canada) administered as a single 1 x 200 mg
dose, was conducted in 28 healthy adult male and female subjects under fed conditions. A summary
of the bioavailability data is presented below.
Morphine
(1x 200 mg)
From measured data
uncorrected for potency
Geometric Mean
Arithmetic Mean (CV %)
Parameter Test* Reference
†
% Ratio of
Geometric Means
Confidence Interval, 90%
AUC
T
(ng
*
h/mL)
957.661
1023.926 (44)
962.002
1017.232 (43)
99.55 96.51 - 102.68
AUC
(0-12)
(ng
*
h/mL)
647.855
677.971 (33)
632.479
656.155 (32)
102.43 98.66 - 106.35
AUC
I
(ng
*
h/mL)
1012.937
1082.006 (45)
1024.003
1083.680 (45)
98.92 95.79 - 102.15
C
max
(ng/mL)
106.752
113.304 (37)
108.112
115.107 (38)
98.74 89.53 - 108.90
T
max
§
(h)
4.07 (37) 3.82 (65)
T
½
§
(h)
10.15 (28) 11.46 (28)
* Teva-Morphine SR Tablets 200 mg (Teva Canada Limited, Canada)
† MS Contin
®
200 mg Sustained Release Tablets (Purdue Pharma, Canada). Purchased in Canada.
§
Expressed as the arithmetic mean (CV %) only
Teva-Morphine S
R
Tablets
Page 31
A randomized, two period, two treatment crossover comparative bioavailability study of Teva-
Morphine SR (sustained-release) 200 mg tablets (Teva Canada Limited, Canada) and MS Contin
®
200 mg sustained-release tablets (Purdue Pharma, Canada) administered as a single 1 x 200 mg
dose, was conducted in 19 healthy adult male and female subjects under fasting conditions. A
summary of the bioavailability data is presented below.
Morphine
(1 x 200 mg)
From measured data
uncorrected for potency
Geometric Mean
Arithmetic Mean (CV %)
Parameter Test* Reference
†
% Ratio of
Geometric Means
Confidence Interval, 90%
AUC
T
(ng
*
h/mL)
878.020
901.993 (23)
813.662
843.039 (25)
107.91 99.88 – 116.59
AUC
I
(ng
*
h/mL)
910.635
936.033 (23)
845.628
878.553 (26)
107.69 99.17 – 116.94
C
max
(ng/mL)
84.958
90.453 (34)
69.899
75.132 (36)
121.54 112.58 – 131.22
T
max
§
(h)
2.91 (33) 2.64 (44)
T
½
§
(h)
9.70 (22) 9.97 (24)
* Teva-Morphine SR Tablets 200 mg (Teva Canada Limited, Canada)
† MS Contin
®
200 mg Sustained Release Tablets (Purdue Pharma, Canada). Purchased in Canada.
§
Expressed as the arithmetic mean (CV %) only
Teva-Morphine S
R
Tablets
Page 32
A randomized, two period, two treatment crossover comparative bioavailability study of Teva-
Morphine SR (sustained-release) 200 mg tablets (Teva Canada Limited, Canada) and MS Contin
®
200 mg sustained-release tablets (Purdue Pharma, Canada) administered as a multiple-dose 1 x 200
mg (q12h), was conducted in 23 healthy adult male and female subjects under fasting conditions. A
summary of the bioavailability data is presented below.
Morphine
(1 x 200 mg, q12h)
From measured data
uncorrected for potency
Geometric Mean
Arithmetic Mean (CV %)
Parameter Test* Reference
†
% Ratio of
Geometric Means
Confidence Interval, 90%
AUC
tau
(ng
*
h/mL)
1232.468
1290.281 (30)
1086.101
1148.681 (34)
113.48 105.59 - 121.96
C
max
(ng/mL)
160.345
169.748 (34)
137.237
144.065 (34)
116.84 110.05 - 124.05
C
min
(ng/mL)
57.085
60.330 (33)
47.985
54.161 (45)
118.97 105.34 - 134.36
T
max
§
(h)
3.70 (24) 3.39 (44)
FL
§
(%)
101.02 (25) 98.63 (37)
* Teva-Morphine SR Tablets 200 mg (Teva Canada Limited, Canada)
† MS Contin
®
200 mg Sustained Release Tablets (Purdue Pharma, Canada). Purchased in Canada.
§
Expressed as the arithmetic mean (CV %) only
DETAILED PHARMACOLOGY
Morphine is readily absorbed from the gastrointestinal tract, nasal mucosa, lung, and after
subcutaneous or intramuscular injection. Due to first-pass metabolism the effect of an oral dose is
less than that of the same dose given parenterally. The parenteral to oral morphine potency ratio
has been reported to range from 1:6 to 1:2. In general, the greatest difference between parenteral
and oral potency is seen in acute studies. With chronic dosing, oral morphine is about 1/3 as
potent as when given by injection.
Absorption of the sustained-release tablets is equivalent to that of immediate-release tablet or liquid
formulations and is not significantly affected by administration with food. At steady-state, the
sustained-release tablets produce peak morphine levels approximately 4 to 5 hours post-dose and
therapeutic levels persist for a 12 hour period.
In a steady-state crossover study utilizing morphine sulfated sustained release tablets every 12
hours versus morphine sulfate solution every 4 hours in cancer patients, there was no significant
difference between formulations in respect to the extent of absorption of morphine. The mean
maximum concentration following morphine sulfate sustained release was approximately 15%
higher than with morphine oral solution and was achieved at a mean of 3.4 hours post-dose
compared with 1.2 hours for the solution. There was a linear relationship between mean plasma
morphine concentration and dose over the range of 60-600 mg/day.
Teva-Morphine S
R
Tablets
Page 33
TOXICOLOGY
Animal
Acut e : Or a l LD
50
Mice 650 mg/kg
Rats 460 mg/kg
Guinea Pigs 1000 mg/kg
Morphine toxicity varies considerably from species to species. In some species, relatively low
doses of morphine cause hypothermia and gross excitation. In the rat, for example, doses
suitable for analgesia also affect a continually restless and seemingly frightened state. These
effects are antagonized by naloxone and are prevented by phenytoin.
Human
Morphine toxicity may result from overdosage but because of the great interindividual variation in
sensitivity to opioids it is difficult to determine an exact dose of any opioid that is toxic or lethal.
The presence of pain or tolerance tends to diminish the toxic effects of morphine. Published data
suggests that in a morphine naive, pain-free individual, the lethal oral dose would be in excess of
120 mg. Patients on chronic oral morphine therapy have been known to take in excess of
3000 mg/day with no apparent toxicity.
Teva-Morphine S
R
Tablets
Page 34
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rectal administration: evidence of route specificity. Clin Pharmacol Ther 1993;54:286-92.
2. Bianchi G, Ferretti P, Recchia M, Rocchetti M, Tavani A, Manara L. Morphine tissue levels
and reduction of gastrointestinal transit in rats. Correlation supports primary action site in the
gut. Gastroenterology 1983;85:852-8.
3. Brunk SF, Delle M. Morphine metabolism in man. Clin Pharmacol Ther 1974;16:51-7.
4. Bullingham RE, Moore RA, Symonds HW, Allen MC, Baldwin D, McQuay HJ. A novel
form of dependency of hepatic extraction ratio of opioids in vivo upon the portal vein
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buprenorphine in the chronically cannulated cow. Life Sci 1984;34:2047-56.
5. Cronin CM, Kaiko RF, Healy N, Grandy RP, Thomas G, Goldenheim PD. Controlled-
release oral morphine insensitivity to a high fat meal. J Clin Pharmacol 1988;28:944.
6. Dickson PH, Lind A, Studts P, Nipper HC, Makoid M, Makoid M, et al. The routine analysis
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9. Goughnour BR, Arkinstall WW, Stewart JH. Analgesic response to single and multiple doses
of controlled-release morphine tablets and morphine oral solution in cancer patients. Cancer
1989;63:2294-7.
10. Goughnour BR, Arkinstall WW. Potential cost-avoidance with oral extended-release
morphine sulfate tablets versus morphine sulfate solution. Am J Hosp Pharm 1991;48:
101-4.
11. Hanks GW, Trueman T. Controlled-release morphine tablets are effective in twice-daily
dosage in chronic cancer pain. In: Wilkes E, Levy J, editors. Advances in morphine therapy/the
1983 International Symposium on Pain Control. New York: Oxford University Press;1984.
p.103-5.
12. Health and Public Policy Committee, American College of Physicians: Drug therapy of
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In: Wilkes E, Levy J, editors. Advances in morphine therapy/the 1983 International
Symposium on Pain Control. New York: Oxford University Press;1984. p.123-6.
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Gilman AG, editors. The Pharmacological Basis of Therapeutics. 6th ed. New York:
Macmillan Press; 1980. p. 494-534.
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15. Kaiko RF, Grandy RP, Oshlack B, Pav J, Horodniak J, Thomas G, et al. The United States
experience with oral controlled-release morphine (MS Contin
®
tablets). Parts I and II. Review
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tablet strengths in normal subjects. Cancer 1989;63:2348-54.
16. Knodell RG, Farleigh RM, Steele NM, Bond JH. Effects of liver congestion on hepatic drug
metabolism in the rat. J Pharmacol Exp Ther 1982;221:52-7.
17. Lamerton RC. Evaluation of MST Continus tablets 60 mg and 100 mg in the treatment of pain
in terminal illness - a hospice overview. In: Wilkes E, Levy J, editors. Advances in morphine
therapy/the 1983 International Symposium on Pain Control. New York: Oxford University
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18. McQuay HJ, Moore RA, Bullingham RES, Carroll D, Baldwin D, Allen MS, et al. High
systemic relative bioavailability of oral morphine in both solution and sustained-release
formulation. In: Wilkes E, Levy J, editors. Advances in morphine therapy/the 1983
International Symposium on Pain Control. New York: Oxford University Press;1984.
p.149-54.
19. Mignault GG, Latreille J, Viguié F, Richer P, Lemire F, Harsanyi Z, et al. Control of
cancer-related pain with MS Contin: a comparison between 12-hourly and 8-hourly
administration. J Pain Symptom Manage 1995;10(6):416-22.
20. Misra AL. Metabolism of opiates. [Factors affecting the action of narcotics.] In: Adler ML,
Manara L, Samanin R, editors. New York: Raven Press; 1978. p. 197-343.
21. Moore A, Sear J, Baldwin D, Allen M, Hunnise A, Bullingham R, McQuay H. Morphine
kinetics during and after renal transplantation. Clin Pharmacol Ther 1984;35:641-5.
22. Patwardhan RV, Johnson RF, Hoyumpa A Jr., Sheehan JJ, Desmond PV, Wilkinson GR,
Branch RA, Schenker S. Normal metabolism of morphine in cirrhosis. Gastroenterology
1981;81:1006-11.
23. Portenoy RK, Maldonado M, Fitzmartin R, Kaiko RF, Kanner R. Oral controlled-release
morphine sulfate. Analgesic efficacy and side effects of a 100-mg tablet in cancer pain
patients: Cancer 1989;63:2284-8.
24. Portenoy RK. Chronic opioid therapy in non-malignant pain. J Pain Symptom Manage
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25. Portenoy RK, Foley KM, Intrussisi CE. The nature of opioid responsiveness and its
implications for neuropathic pain: new hypotheses derived from studies of opioid
infusions. Pain 1990;43:273-86.
26. Principles of analgesic use in the treatment of acute pain and cancer pain. 3rd ed. Illinois:
American Pain Society; 1992.
27. Regnard CB, Randell F. Controlled-release morphine in advanced cancer pain. In: Wilkes E,
Levy J, editors. Advances in morphine therapy/the 1983 International Symposium on Pain
Control. New York: Oxford University Press;1984. p.142-4.
28. Thirlwell MP, Sloan PA, Maroun JA, Boos GJ, Besner JG, Stewart JH, et al. Pharmacokinetics
and clinical efficacy of oral morphine solution and controlled-release morphine tablets in cancer
patients: Cancer 1989;63:2275-83.
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29. Stewart JJ, Weisbrodt NW, Burks TF. Central and peripheral actions of morphine on
intestinal transit. J Pharmacol Exp Ther 1978;205:547-55.
30. Stimmel B. Pain, analgesia and addiction: the pharmacologic treatment of pain. New York:
Raven Press, 1983.
31. Twycross RG, Lack SA. Symptom control in far advanced cancer: pain relief. London:
Pitman; 1983.
32. United States. Management of Cancer Pain Guideline Panel. Management of cancer pain.
Rockville (MD): U.S. Department of Health and Human Services, Public Health Service,
Agency for Health Care Policy and Research, 1994. Publication No. AHCPR94-0592.
33. Vandenberghe HM, Soldin SJ, MacLeod SM. Pharmacokinetics of morphine: a review. Ther
Drug Monit 1982;11:1-5.
34. Wall PD, Melzack R, editors. Textbook of pain. 3rd ed. New York: Churchill Livingstone;1994.
35. Walsh TD. Opiates and respiratory function in advanced cancer. Recent Results Cancer Res
1984;89:115-7.
36. Walsh TD. A controlled study of MST Continus tablets for chronic pain in advanced
cancer. In: Wilkes E, editor. Advances in morphine therapy. The 1983 International
Symposium on Pain Control. Royal Soc Med International Congress Series 1984;64:99-
102.
37. Welsh J, Stuart JF, Habeshaw T, Blackie R, Whitehill D, Setanoians A, et al. A comparative
pharmacokinetic study of morphine sulphate solution and MST Continus 30 mg tablets in
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of morphine estimation in biological fluids and the concept of free morphine. New York:
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38. MS Contin
®
SR Tablets Product Monograph, Purdue Pharma, Canada, Control No. 210003,
Revision Date: March 29, 2018.
39. A Single-Dose, Comparative Bioavailability Study of Two Formulations of Morphine
Sulfate 15 mg Sustained Release Tablets Under Fed Conditions. Data on file at Teva Canada
Limited.
40. A Single-Dose, Comparative Bioavailability Study of Two Formulations of Morphine
Sulfate 15 mg Sustained Release Tablets Under Fasting Conditions. Data on file at Teva
Canada Limited.
41. A Multiple-Dose, Comparative Bioavailability Study of Two Formulations of Morphine
Sulfate Sustained Release Tablets 15 mg q12h Under Fasting Conditions. Data on file at
Teva Canada Limited.
42. A Single-Dose, Comparative Bioavailability Study of Two Formulations of Morphine
Sulfate 200 mg Sustained Release Tablets Under Fed Conditions. Data on file at Teva
Canada Limited.
43. A Single-Dose, Comparative Bioavailability Study of Two Formulations of Morphine
Sulfate 200 mg Sustained Release Tablets Under Fasting Conditions. Data on file at Teva
Canada Limited.
Teva-Morphine S
R
Tablets
Page 37
44. A Multiple-Dose, Comparative Bioavailability Study of Two Formulations of Morphine
Sulfate Sustained Release Tablets 200 mg q12h Under Fasting Conditions. Data on file at
Teva Canada Limited.
_____________________________________________________________________________________________________
Teva-Morphine SR Tablets Page 38
READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE
PATIENT MEDICATION INFORMATION
N
TEVA-MORPHINE SR
Morphine Sulfate Sustained Release Tablets
15 mg, 30 mg, 60 mg, 100 mg and 200
m
g
Read this carefully before you start taking TEVA-MORPHINE SR 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
TEVA-MORPHINE SR.
Serious Warnings and Precautions
Even if you take
TEVA-MORPHINE SR as prescribed you are at risk for opioid
addiction, abuse, and misuse that can lead to overdose and death. To understand your risk
of opioid addiction, abuse, and misuse you should speak to your prescriber (e.g., doctor).
Life-threatening breathing problems can happen while taking
TEVA-MORPHINE SR,
especially if not taken as directed. Babies are at risk of life-threatening breathing problems
if their mothers take opioids while pregnant or nursing.
Never give anyone your
TEVA-MORPHINE SR. They could die from taking it. If a
person has not been prescribed
TEVA-MORPHINE SR, taking even one dose can cause a fatal
overdose. This is especially true for children.
If you took
TEVA-MORPHINE SR 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
TEVA-MORPHINE SR 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 TEVA-MORPHINE SR used for?
TEVA-MORPHINE SR is used for the long-term management of pain, when:
the pain is severe enough to require daily, around-the-clock pain medication
the doctor determines that other treatment options are not able to effectively manage your pain
TEVA-MORPHINE SR is NOT used (“as needed”) to treat pain that you only have once in a while.
How does TEVA-MORPHINE SR work?
TEVA-MORPHINE SR is an oral sustained release tablet that slowly releases morphine over a 12 hour
period. TEVA-MORPHINE SR contains morphine which is a pain medication belonging to the class of
_____________________________________________________________________________________________________
Teva-Morphine SR Tablets Page 39
medicines known as opioids which includes codeine, fentanyl and oxycodone. It relieves pain by acting on
specific nerve cells of the spinal cord and brain.
What are the ingredients in TEVA-MORPHINE SR?
Medicinal ingredient: Morphine sulfate
Non-medicinal ingredients: Tablet core (all strengths): Colloidal Silicon Dioxide, Hydroxypropyl
Methylcellulose, Lactose Monohydrate, Magnesium Stearate and Stearic Acid.
Tablet Coating:
Polyvinyl Alcohol (Partially Hydrolyzed), Polyethylene Glycol 3350, Talc, Titanium Dioxide
Additional coating ingredients specific to each strength:
15 mg: D&C Yellow #10/Aluminum Lake
FD&C Blue #1/Aluminum Lake
FD&C Red #40/ Aluminum Lake
30 mg: FD&C Blue #2/ Aluminum Lake
D&C Red #27/Aluminum Lake
FD&C Yellow #6/Aluminum Lake
60 mg: FD&C Yellow #6/Aluminum Lake
FD&C Red #40/Aluminum Lake
100 mg: FD&C Blue #2/Aluminum Lake
FD&C Yellow #6/Aluminum Lake
FD&C Red #40/Aluminum Lake
200 mg: D&C Red #30/Aluminum Lake
FD&C Red #40/Aluminum Lake
TEVA-MORPHINE SR comes in the following dosage forms:
Sustained Release Tablets: 15 mg, 30 mg, 60 mg, 100 mg and 200 mg.
Do not use TEVA-MORPHINE SR if:
your doctor did not prescribe it for you
you are allergic to morphine, other opioids, or any of the other ingredients of TEVA-MORPHINE SR
you have mild or short term pain that can be controlled by the occasional use of pain medications,
including those available without a prescription
you have severe asthma, trouble breathing, or lung problems
you have a condition where the small bowel does not work properly (paralytic ileus) or you have severe pain
in your abdomen
you have a head injury
if you are at risk for seizures
you suffer from alcoholism
you are taking, or have taken within the past 2 weeks, a monoamine oxidase inhibitor medication (e.g.
phenelzine sulphate, tranylcypromine sulphate, moclobemide or selegiline)
you are pregnant or plan to become pregnant, breast-feeding, or in labour
_____________________________________________________________________________________________________
Teva-Morphine SR Tablets Page 40
are going to have, or recently had a planned surgery
To help avoid side effects and ensure proper use, talk to your healthcare professional before you take
TEVA-MORPHINE SR. Talk about any health conditions or problems you may have, including if you:
have a history of illicit or prescription drug or alcohol abuse
have severe kidney, liver or lung disease
have heart disease
have low blood pressure
have problems with your thyroid, adrenal or prostate gland
have past or current depression
suffer from chronic or severe constipation
have, or had in the past, hallucinations or other severe mental problems
suffer from migraines
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 TEVA-MORPHINE SR while pregnant, nursing,
during labour or delivery. Opioids can be transferred to your baby through breast milk, or while still in the
womb. TEVA-MORPHINE SR can then cause life-threatening breathing problems in your unborn baby or
nursing infant.
Driving and using machines: Before you do tasks which may require special attention, you should wait until
you know how you react to TEVA-MORPHINE SR. TEVA-MORPHINE SR can cause:
drowsiness
dizziness or
lightheadedness
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 TEVA-
MORPHINE SR.
Serotonin syndrome: TEVA-MORPHINE SR can cause serotonin syndrome, a rare but potentially
lifethreatening condition. It can cause serious changes in how your brain, muscles and digestive system work.
You may develop serotonin syndrome if you take TEVA-MORPHINE SR with certain antidepressants 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;
_____________________________________________________________________________________________________
Teva-Morphine SR Tablets Page 41
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 TEVA-MORPHINE SR:
alcohol, including prescription and non-prescription medications containing alcohol.
Do not drink alcohol while taking TEVA-MORPHINE SR. This can lead to drowsiness,
depressed breathing, unusually slow or weak breathing, serious side effects or a fatal
overdose
other sedative drugs which may enhance the drowsiness caused by TEVA-MORPHINE SR
other opioid analgesics (for pain)
general anesthetics (used during surgery)
drugs used to help you sleep or to reduce anxiety
antidepressants (for depression and mood disorders). Do not take TEVA-MORPHINE SR with
monoamine oxidase (MAO) inhibitors or if you have taken MAO inhibitors in the last 14 days
before treatment with TEVA-MORPHINE SR
drugs used to treat serious mental or emotional disorders, such as schizophrenia
antihistamines (for allergies)
anti-emetics (for prevention of vomiting)
drugs used to treat muscle spasms and back pain
some heart medication (beta blockers)
warfarin and other coumarin anticoagulants (for prevention/treatment of blood clots)
St. John’s Wort
How to take TEVA-MORPHINE SR:
TEVA-MORPHINE SR tablets are designed to work properly over 12 hours when swallowed whole.
TEVA-MORPHINE SR 100 mg and 200 mg tablets are for use in “opioid tolerant” patients only. Your
doctor will tell you when you are “opioid tolerant” to a certain dose of TEVA-MORPHINE SR.
Swallow whole. Do not cut, break, chew, dissolve or crush since this can cause the release of the entire 12-
hour dose of morphine, which can seriously harm you. Only the 200 mg tablet is scored and may be
broken in half. The half tablet must also be swallowed intact.
TEVA-MORPHINE SR tablets must be taken regularly, every 12 hours (with or without food and with
sufficient fluid, e.g., 4 to 6 oz. of water), to treat pain.
Usual Adult Starting Dose:
Dosage is individualized. Be sure to follow your doctor’s dosing instructions exactly. Do not increase or
decrease your dose without consulting your doctor. 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 TEVA-MORPHINE SR. Be sure to
use TEVA-MORPHINE SR only for the condition for which it was prescribed.
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Teva-Morphine SR Tablets Page 42
Should your pain increase or any other complaint as a result of taking TEVA-MORPHINE SR, tell your doctor
immediately.
Stopping your Medication:
You should not stop taking TEVA-MORPHINE SR 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 TEVA-MORPHINE SR. 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 with 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 TEVA-MORPHINE SR.
Refilling Prescriptions for TEVA-MORPHINE SR:
A new written prescription is required from your doctor each time you need more TEVA-MORPHINE SR.
Therefore, it is important that you contact your doctor before your current supply runs out.
Only obtain prescriptions for this medicine from the doctor in charge of your treatment. Do not seek
prescriptions from other doctors unless you switch to another doctor for your pain management.
Overdose:
If you think you have taken too much TEVA-MORPHINE SR, contact your healthcare professional,
hospital emergency department or regional Poison Control Centre immediately, even if there are no
symptoms.
Signs of overdose may include:
abnormally slow or weak breathing
dizziness
confusion
extreme drowsiness
Missed Dose:
It is important that you do not miss any doses. If you miss a dose, take your next dose at your usual time. You
should always try to get back on track with your regular dosing schedule (e.g., 8 o’clock in the morning and 8
o’clock in the evening). If you miss several doses in a row, talk to your doctor before restarting your medication.
What are possible side effects from using TEVA-MORPHINE SR?
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Teva-Morphine SR Tablets Page 43
These are not all the possible side effects you may feel when taking TEVA-MORPHINE SR. If you experience
any side effects not listed here, contact your healthcare professional.
Side effects may include:
Constipation
Dizziness
Drowsiness
Dry mouth
Headache
Itching
Lack of muscle strength
Nausea and/or vomiting
Sweating
Low sex drive, impotence (erectile dysfunction), infertility
Talk with your doctor or pharmacist about ways to prevent constipation when you start using TEVA-
MORPHINE SR.
If nausea and vomiting become troublesome during prolonged therapy with TEVA-MORPHINE SR, talk to
your doctor or pharmacist
Serious side effects and what to do about them
Symptom/ effect Talk to your healthcare
p
rofessional
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 clamm
y
skin.
√
Respiratory Depression:
Slow, shallow or weak
b
reathin
g
.
√
Allergic Reaction: rash,
hives, swelling of the face,
lips, tongue or throat,
difficulty swallowing or
breathing
√
Bowel Blockage
(impaction):
abdominal pain, severe
consti
p
ation, nausea
√
Withdrawal: nausea,
vomiting, diarrhea, anxiety,
√
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Teva-Morphine SR Tablets Page 44
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, less
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 (http://www.hc-sc.gc.ca/dhp-
mps/medeff/report-declaration/index-eng.php) for information on how to report online, by mail or by
fax; or
Calling toll-free at 1-866-234-2345.
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 TEVA-MORPHINE SR in a secure place to prevent theft, misuse or accidental
exposure.
TEVA-MORPHINE SR 15 mg tablets: store tablets at room temperature (15°C - 25°C). Protect from light.
TEVA-MORPHINE SR 30, 60, 100 and 200 mg tablets: Store tablets at room temperature (15°C - 30°C).
Protect from light.
Keep TEVA-MORPHINE SR 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 TEVA-MORPHINE SR, get
emergency help right away.
Disposal:
TEVA-MORPHINE SR should never be thrown into household trash, where children and pets may find
it. It should be returned to a pharmacy for proper disposal.
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Teva-Morphine SR Tablets Page 45
If you want more information about TEVA-MORPHINE SR:
Talk to your healthcare professional
Find the full product monograph 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.tevacanada.com; or by calling 1-800-268-4127 ext. 3; or email
This leaflet was prepared by Teva Canada Limited, Toronto, Ontario M1B 2K9
Last revised: June 12, 2018
