DBL™ Morphine Sulfate Injection BP

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Morphine sulfate pentahydrate 15 mg/mL
Available from:
Pfizer New Zealand Limited
INN (International Name):
Morphine sulfate pentahydrate 15 mg/mL
Dosage:
15 mg/mL
Pharmaceutical form:
Solution for injection
Composition:
Active: Morphine sulfate pentahydrate 15 mg/mL Excipient: Hydrochloric acid Sodium chloride Water for injection
Units in package:
Ampoule, glass, 1mL, 5 dose units
Class:
Class B1 Controlled Drug
Prescription type:
Class B1 Controlled Drug
Manufactured by:
Macfarlan Smith Ltd
Therapeutic indications:
Latest Regulatory Activity
Product summary:
Package - Contents - Shelf Life: Ampoule, glass, 1mL - 5 dose units - 30 months from date of manufacture stored at or below 25°C - Ampoule, glass, 1mL - 50 dose units - 30 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-3546c
Authorization date:
1983-04-27

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NEW ZEALAND DATA SHEET

1. PRODUCT NAME

Morphine Sulfate Injection BP, 5 mg/mL, solution for injection

Morphine Sulfate Injection BP, 10 mg/mL, solution for injection

Morphine Sulfate Injection BP, 15 mg/mL, solution for injection

Morphine Sulfate Injection BP, 30 mg/mL, solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of DBL Morphine Sulfate Injection BP contains 5, 10, 15, or 30mg of morphine sulfate

pentahydrate. All four strengths are isotonic preparations.

For the full list of excipients, see

section 6.1

3. PHARMACEUTICAL FORM

Solution for injection: clear colourless to slightly yellow, sterile solution.

The pH of these solutions ranges from 3.2 to 4.0.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Morphine sulfate is indicated for the relief of moderate to severe pain not responsive to non-

opioid analgesics. It may also be used as a pre-operative medication and as an analgesic adjunct

in general anaesthesia.

4.2 Dose and method of administration

Dose

Note: Opioid antagonists and facilities for administration of oxygen and control of respiration

should be available during, and immediately following parenteral administration.

Subcutaneous, Intramuscular and Slow Intravenous Administration

Adults:

Morphine sulfate is usually administered by intramuscular or subcutaneous injection,

in the range of 5 to 20 mg, depending on the cause of pain and the patient response. Doses may

be repeated every 4 to 6 hours.

Morphine sulfate may also be given intravenously when a rapid onset of action is desired. The

dose is usually in the range of 2.5 to 15 mg diluted in 4 to 5 mL of Water for Injections given

slowly over 4 to 5 minutes.

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Children:

Morphine sulfate is given by intramuscular or subcutaneous injection in doses of 0.1

to 0.2 mg/kg bodyweight to a maximum of 15 mg. Injection may be repeated every 4 to 6 hours.

When a rapid onset of action is desirable, in a closely monitored environment, morphine may

be titrated intravenously with caution, in a dose of 0.05 to 0.1 mg/kg, incrementally over 5 to

15 minutes. Repeat intravenous dosing is unsubstantiated as a method of analgesia in children.

Morphine sulfate is not usually given pre-operatively in children under 1 year, and it should be

given with extreme care to neonates. It should not be given to premature infants (see

section

4.3

Continuous Intravenous Infusion

The dosage of morphine should be titrated according to the patient’s analgesic requirements

and previous opiate experience. For the management of acute pain via intravenous infusion,

most adults with no previous history of opioid intake can be continued on 0.5 to 2.0 mg/hour

after adequate analgesia has been established.

In children, an infusion dose of 0.01 to 0.05 mg/kg/hour morphine to a maximum intravenous

dose of 4 mg/hour is recommended.

It is recommended that an opioid antagonist and equipment for artificial ventilation be available.

Patient-Controlled Analgesia (PCA)

Patient-controlled analgesia allows patients to assess their own level of pain and consequently

titrate the amount of morphine they require for adequate pain control against sedation and other

side effects.

The dosages and time intervals are preset into a microprocessor-controlled infusion pump.

When the patient experiences pain, a button is depressed by the patient and a dose of morphine

is administered intravenously. If the patient should depress the button before the preset time

interval (lockout interval) has elapsed, no extra drug is administered. For adults, demand doses

of 0.5 to a maximum of 1.5 mg morphine have been given via PCA using a lockout interval of

6 to 10 minutes. Along with the self-administered dose of morphine, some syringe pumps also

deliver a background continuous infusion of morphine at a basal rate. If a background infusion

is adopted, a dose of 1 mg/hour morphine is often used in adults. Some PCA pumps allow a

maximum dosage over a defined period to be preset in order to avoid patient overdosage.

There is limited clinical experience of the use of patient-controlled analgesia in children.

However, a demand dose of 0.01 to 0.025 mg/kg morphine has been used successfully in

children and adolescents between the ages of 7 to 19 years with a lockout interval of 6 to 10

minutes. If a background infusion is employed, an infusion dose of 0.015 mg/kg/hour morphine

may be used in children.

The demand dosage and lockout interval should be determined according to the patient’s

analgesic requirements. Patients receiving a background infusion of morphine should generally

receive a smaller demand dose relative to equivalent patients utilising a demand dose only.

Techniques such as PCA with background continuous infusion are associated with a higher rate

of adverse effects and require close monitoring.

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General Information for Cancer Pain

When morphine is administered by continuous intravenous or subcutaneous infusion for relief

of severe, chronic pain associated with cancer, the dosage of morphine must be individualised

according to the response and tolerance of the patient. In some patients with exceptionally

severe, chronic pain it may be necessary to exceed the usual dosage. Reduced dosage is

indicated in poor-risk patients, in very young or very old patients, and in patients receiving other

CNS depressants.

Orally administered morphine should be used in preference to parenteral morphine whenever

adequate pain control can be achieved by this route. However, oral morphine is often

inadequate or impractical in the terminally ill patient.

Patients being converted from oral morphine to either intramuscular (IM), intravenous (IV) or

subcutaneous (SC) morphine require dosage reduction (about one-sixth), since about 60% of

oral morphine is metabolised in first-pass metabolism (i.e. 1 mg of either IM, SC or IV

morphine for every 6 mg of oral morphine). The dose should then be titrated according to the

patient’s clinical response.

For cancer pain, DBL Morphine Sulfate Injection BP should be given regularly around the

clock, in most instances every 4 hours. The basis of pain control with DBL Morphine Sulfate

Injection BP should be regular scheduling rather than on an ‘as required’ or PRN narcotic order.

Patients requiring high doses of morphine usually need to be awakened for medication during

the night to prevent morning pain.

Morphine Dosage Increase

Dosage increases for intravenous, subcutaneous or intramuscular administration of morphine

should not be made more frequently than every 24 hours, since it will take approximately 4 to

5 morphine half-lives to attain a new steady state concentration in a patient with normal liver

and kidney function.

Following all dosage increases, the patient must be monitored closely for side-effects, the most

common being sedation, nausea, vomiting, constipation and hypotension.

4.3 Contraindications

Morphine sulfate is contraindicated in the following situations:

patients with known hypersensitivity to morphine or other opioids

with acute or severe bronchial asthma or other obstructive airways disease

respiratory insufficiency or depression, especially in the presence of cyanosis and/or

excessive bronchial secretion

other conditions where respiratory reserve is depleted, such as severe emphysema, chronic

bronchitis or kyphoscoliosis

cor pulmonale

severe CNS depression

diabetic acidosis where there is a danger of coma

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severe liver disease or incipient hepatic encephalopathy

following biliary tract surgery or surgical anastomosis

biliary colic

gastrointestinal obstruction

suspected surgical abdomen

in patients who are taking or who have taken MAO inhibitors within the previous fourteen

days

cardiac arrhythmias

heart failure secondary to pulmonary disease

acute alcoholism or delirium tremens

head injuries

brain tumour

raised intracranial or cerebrospinal pressure and in convulsive states such as status

epilepticus, tetanus or strychnine poisoning (see

section 4.4

Morphine is contraindicated in premature infants or during labour for delivery of premature

infants.

The administration of morphine via patient-controlled analgesia to children less than six years

of age and adults with poor cognitive function is contraindicated.

The continuous intravenous infusion of morphine in patients with hepatic or renal disease is

contraindicated (see

section 4.4

4.4 Special warnings and precautions for use

Therapy should only be initiated by a specialist with experience in chronic pain management

and in accordance with guidelines approved by the New Zealand Medical Association.

Large doses and/or rapid administration of morphine may produce rapid onset of respiratory

depression including central sleep apnoea (CSA) and sleep-related hypoxemia, bradycardia, or

even cardiac arrest.

Morphine delays gastric emptying, which may be expected to increase the risks of aspiration,

either associated with morphine induced CNS depression or coma, or during or after general

anaesthesia.

Profound sedation, respiratory depression, coma, and death may result from the concomitant

use of morphine with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine

sedatives/hypnotics,

anxiolytics,

tranquilizers,

muscle

relaxants,

general

anaesthetics,

medicines with antihistamine-sedating actions such as antipsychotics, other opioids, alcohol).

Because of these risks, reserve concomitant prescribing of these drugs for use in patients for

whom alternative treatment options are inadequate.

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Observational studies have demonstrated that concomitant use of opioid analgesics and

benzodiazepines increases the risk of medicine-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

section 4.5

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly

with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of

concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose

of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and

titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a

benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic,

and titrate based on clinical response. Follow patients closely for signs and symptoms of

respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when

morphine 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

section 4.5

). If respiratory depression of any form occurs, consider

decreasing the opioid dosage using best practices for opioid taper.

Drug Dependence and Tolerance

Morphine can produce drug dependence and therefore has the potential for being abused.

Psychological dependence, physical dependence, and tolerance may develop upon repeated

administration of morphine. However it should be noted that clinically significant respiratory

depression, addiction, rapid tolerance and euphoria rarely develop when doses of morphine are

carefully titrated against the pain in patients with terminal disease and severe pain.

Drug dependence does not develop if morphine is administered regularly at individually

optimised doses to the cancer patient with moderate to severe pain. While a certain degree of

physical dependence occurs, a psychological dependence does not occur. If a cancer patient no

longer requires an opioid for pain control, a gradual reduction in dose will prevent any

withdrawal

symptoms,

although

these

usually

mild

absent

even

after

abrupt

discontinuance. Clinically significant tolerance to morphine is unusual in the cancer patient

being treated for severe pain. In most cases, a plateauing of dose requirements is seen, as a

need to increase morphine dose means an increase in pain and not tolerance.

Withdrawal of morphine should be undertaken gradually, as abrupt withdrawal in patients who

are physically dependent may precipitate an acute withdrawal syndrome, including convulsions.

Use with Other CNS Depressants

Morphine should be used with caution and in reduced dosage in patients who are concurrently

receiving other opioid analgesics, general anaesthetics, phenothiazines, other tranquillisers,

sedative hypnotics, tricyclic antidepressants, and other CNS depressants (including alcohol).

Respiratory depression, hypotension and profound sedation or coma may result.

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Impaired Respiration

The respiratory depressant effects of morphine and its capacity to elevate cerebrospinal fluid

pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions,

or a pre-existing increase in intracranial pressure. Furthermore, opioids produce adverse

reactions, including confusion, miosis and vomiting, which may obscure the clinical course of

patients with head injuries. Morphine should only be used in such patients with extreme

caution, and only if it is judged to be essential.

Respiratory depression is the chief hazard of all morphine preparations. Respiratory depression

occurs most frequently in elderly and debilitated patients, and in those suffering from conditions

accompanied

hypoxia

hypercapnia

when

even

moderate

therapeutic

doses

significantly decrease pulmonary ventilation. Morphine should be used with extreme caution

in patients having a substantially decreased respiratory reserve, and patients with pre-existing

respiratory depression, hypoxia or hypercapnia. In such patients, even the usual therapeutic

doses of morphine may decrease respiratory drive while simultaneously increasing airways

resistance to the point of apnoea (see

section

4.3

Nervous System

The development of serotonin syndrome (SS), which is potentially life-threatening, has been

reported with opioid use, including with morphine. These reports generally occurred when

morphine was used concomitantly with serotonergic drugs (see Section 4.5 Interactions with

Other Medicines). Signs of SS may include clonus, agitation, diaphoresis, tremor, hyperreflexia,

hypertonia and temperature elevation.

Endocrine

Cases of adrenal insufficiency have been reported with opioid use. Presentation of adrenal

insufficiency may include non-specific symptoms and signs including nausea, vomiting,

anorexia, fatigue, weakness, dizziness, and low blood pressure.

Hypotensive Effect

The administration of morphine may result in severe hypotension in the post-operative patient

or any individual whose ability to maintain blood pressure has been compromised by a depleted

blood volume, shock, or the administration of such drugs as the phenothiazines or certain

anaesthetics.

Morphine may produce orthostatic hypotension in ambulatory patients.

Supraventricular Tachycardias

Because of possible vagolytic action that may produce a significant increase in the ventricular

response rate, morphine should be used with caution in patients with atrial flutter and other

supraventricular tachycardias.

Acute Abdominal Condition

The administration of morphine or other opioids may obscure the diagnosis or clinical course

in patients with acute abdominal conditions. Morphine should be used with caution in patients

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with inflammatory or obstructive bowel disorders, or with ulcerative colitis, and should only be

used when necessary in patients with acute pancreatitis.

Convulsions

Morphine may aggravate pre-existing convulsions in patients with convulsive disorders. If

dosage is escalated substantially above recommended levels because of tolerance development,

convulsions may occur in individuals without a history of convulsive disorders.

Other Special Risk Patients

Morphine should be given with caution, and in reduced dosages, to certain patients, such as the

elderly

debilitated

those

with

severe

impairment

hepatic

renal

function,

hypothyroidism,

Addison’s

disease,

myxoedema,

prostatic

hypertrophy

urethral

stricture. Caution should also be observed if morphine is administered to patients with toxic

psychosis or myasthenia gravis. Morphine should be used with extreme caution in patients with

disorders characterised by hypoxia, since even usual therapeutic doses of opioids may decrease

respiratory drive to the point of apnoea while simultaneously increasing airway resistance.

Renal or Hepatic Disease

Morphine may have a prolonged duration and cumulative effect in patients with kidney or liver

dysfunction. In these patients, analgesia may last for 6, 8 or even up to 24 hours following a

standard dose. Continuous infusions are contraindicated in these patients (see

section

4.3

Caution should be observed when morphine is administered to patients with impaired renal

function, as the pharmacologically active metabolite, morphine-6-glucuronide, may accumulate

in these patients. This may lead to CNS and respiratory depression.

Shock Patients

In patients with shock, impaired perfusion may prevent complete absorption following

subcutaneous or intramuscular injection of morphine. Repeated administration may result in

overdosage due to an excessive amount of morphine suddenly being absorbed when circulation

is restored.

Paediatric Use

Safety and efficacy of morphine in neonates have not been established. However, neonates

have an enhanced susceptibility to the respiratory depressant effects of morphine. Morphine

should not be administered to premature infants (see

section

4.3

Elderly Patients

section

4.4 – Other Special Risk Patients

Renal or Hepatic Disease

Morphine should be administered with caution and in reduced dosages to elderly or debilitated

patients.

Respiratory

depression

occurs

more

frequently

these

patients.

pharmacodynamics of morphine are more variable in geriatric patients than in younger adults.

Therefore, initial dosage should be selected carefully based on clinical assessment of response

to test doses and consideration of the patient’s age and ability to clear the drug.

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Effect on Laboratory Tests

Morphine delays gastric emptying, thereby invalidating test results in gastric emptying studies.

Morphine

interfere

with

hepatobiliary

imaging

using

technetium

disofenin.

Morphine may constrict the sphincter of Oddi and increase biliary tract pressure, preventing

delivery of Tc

disofenin to the small bowel. These actions result in delayed visualisation,

and thus resemble obstruction of the common bile duct.

4.5 Interaction with other medicines and other forms of interaction

Acidifying agents generally increase the clearance of morphine, thus antagonising its effects,

while alkalising agents decrease clearance and so potentiate the effects of morphine.

CNS Depressants:

Morphine should be used with great caution and in reduced dosage in

patients concurrently receiving other central nervous system depressants including other

opioids, sedatives, hypnotics, general anaesthetics, phenothiazines, other tranquillisers and

alcohol because of the risk of respiratory depression, hypotension and profound sedation or

coma. When such combined therapy is contemplated, the dose of one or both agents should be

reduced.

Benzodiazepines and other Central Nervous System (CNS) Depressants

Clinical Impact

additive

pharmacologic

effect,

concomitant

benzodiazepines

other

depressants

including

alcohol,

increases the risk of respiratory depression, profound sedation, coma,

and death.

Intervention

Reserve concomitant prescribing of these drugs for use in patients for

whom alternative treatment options are inadequate. Limit dosages

and durations to the minimum required. Follow patients closely for

signs of respiratory depression and sedation (see

section

4.4

Examples

Benzodiazepines

other

sedatives/hypnotics,

anxiolytics,

tranquilizers,

muscle

relaxants,

general

anaesthetics,

drugs

with

antihistamine-sedating actions such as antipsychotics, other opioids,

alcohol.

Significant impairment of motor function has also been noted following concomitant morphine

administration and alcohol ingestion.

Concurrent administration with tricyclic antidepressants or beta-blockers may enhance the CNS

depressant effects of morphine.

Diazepam, when used following high doses of morphine, exacerbates the hypotensive effects

produced by morphine, and is associated with reduced plasma catecholamine levels.

Antihypertensive Agents:

Concurrent administration of morphine may increase the hypotensive

effects of antihypertensive agents or other drugs with hypotensive effects.

Muscle Relaxants:

Morphine may enhance the neuromuscular blocking action of skeletal

muscle relaxants and produce an increased degree of respiratory depression.

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Mixed

Agonist/Antagonist

Opioid

Analgesics:

From

theoretical

perspective,

mixed

agonist/antagonist opioid analgesics (e.g., pentazocine and buprenorphine) should NOT be

administered to a patient who has received or is receiving a course of therapy with a pure opioid

agonist analgesic. In these patients, mixed agonist/antagonist analgesics may reduce the

analgesic effect or may precipitate withdrawal symptoms.

Monoamine Oxidase Inhibitors (MAOIs):

MAOIs intensify the effects of morphine and other

opioid drugs which can cause anxiety, confusion, and significant depression of respiration,

sometimes leading to coma. Morphine should not be given to patients taking MAOIs or within

14 days of stopping such treatment. It is unknown whether there is an interaction between the

new selective MAOIs (e.g., moclobemide and selegiline) and morphine. Therefore, caution is

advised with such drug combinations.

Cimetidine and Other H2 Receptor Antagonists:

There is a report of confusion and severe

respiratory

depression

when

haemodialysis

patient

administered

morphine

cimetidine.

A potentially lethal interaction between cimetidine and morphine, in which the patient exhibited

apnoea, a significantly reduced respiratory rate and suffered a grand mal seizure, has been

reported. Administration of naloxone increased the respiratory rate; however, confusion,

disorientation, generalised twitching and periods of apnoea persisted for 80 hours. Confusion

has also been associated with concomitant use of ranitidine and morphine.

Diuretics:

Morphine reduces the efficacy of diuretics by inducing the release of antidiuretic

hormone. Morphine may also lead to acute retention of urine by causing spasm of the sphincter

of the bladder, particularly in men with prostatism.

Phenothiazines:

The analgesic effect of morphine is potentiated by chlorpromazine.

Amphetamines:

Dexamphetamine and other amphetamines may enhance the analgesic effects

and decrease the sedation and lack of alertness caused by morphine.

Anticoagulants:

Morphine may potentiate the anticoagulant activity of coumarin anticoagulant

agents.

Metoclopramide:

Morphine may antagonise the effects of metoclopramide on gastrointestinal

motility. Intravenous metoclopramide antagonises the effects of morphine on gastric emptying.

Zidovudine:

Morphine may alter the metabolism of zidovudine, by competitively inhibiting

glucuronidation or directly inhibiting hepatic

microsomal metabolism. Zidovudine and

morphine should therefore not be administered concurrently, because the toxicity of either or

both of these drugs may be increased.

Ritonavir:

Ritonavir may increase the activity of glucuronyl transferases and co-administration

with morphine may result in decreased morphine serum levels and possible loss of analgesic

efficacy.

Oral Drugs:

Morphine delays gastric emptying, so may affect the absorption of orally

administered drugs. For example, morphine delays the absorption of paracetamol and

mexiletine.

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Anticholinergic Agents:

Concurrent administration of morphine and anticholinergic agents or

other drugs with anticholinergic activity may increase the risk of severe constipation; this may

lead to paralytic ileus and/or urinary retention.

Antidiarrhoeal Agents:

Concurrent administration of morphine and antidiarrhoeal agents with

antiperistaltic actions may increase the risk of severe constipation and CNS depression.

Opioid Antagonists:

Naloxone antagonises the analgesic, CNS and respiratory depressive

effects of morphine, and may precipitate withdrawal in patients who are physically dependent

on opioids.

Naltrexone blocks the therapeutic effects of opioids, so should be discontinued several days

prior to elective surgery if administration prior to, during, or following surgery is unavoidable.

Administration of naltrexone to a patient who is physically dependent on morphine will

precipitate withdrawal symptoms.

P2Y

12

inhibitors

Clinical Impact: The co-administration of oral P2Y

inhibitors and morphine can decrease the

absorption and peak concentration of oral P2Y

inhibitors and delay the onset of the antiplatelet

effect.

Intervention: Consider the use of a parenteral antiplatelet agent in the setting of acute coronary

syndrome requiring co-administration of morphine.

Examples of P2Y

inhibitors include but are not limited to: clopidogrel, prasugrel, ticagrelor.

Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter

system has resulted in serotonin syndrome. Drugs that affect the serotonergic neurotransmitter

system include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine

reuptake

inhibitors

(SNRIs),

tricyclic

antidepressants

(TCAs),

triptans,

5-HT3

receptor

antagonists, and monoamine oxidase inhibitors (MAOIs).

4.6 Fertility, pregnancy and lactation

Effects on Fertility

Prolonged use of opioids may result in impairment of reproductive function, including fertility

and sexual dysfunction in both sexes, and irregular menses in women.

Use in Pregnancy - Category C

Morphine has been associated with foetal CNS defects in rodent studies. It is not known

whether morphine can cause foetal harm in humans when administered during pregnancy.

Pregnant patients should only be given morphine when the benefits clearly outweigh potential

risks to the foetus.

Long term use of morphine during pregnancy may result in a neonatal opioid withdrawal state.

Babies born to mothers who are physically dependent on morphine may also be physically

dependent on the drug.

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Use in Labour/Delivery

Morphine is not recommended for use in women during and immediately before labour. The

effects of opioid analgesics are unpredictable. They may prolong labour by temporarily

reducing the strength, duration and frequency of uterine contractions, or conversely they may

tend to shorten labour by increasing the rate of cervical dilatation.

Morphine crosses the placenta, and can produce respiratory depression in the neonate if it is

administered during labour. Infants born to mothers receiving opioid analgesics during labour

should be observed closely for signs of respiratory depression. In such infants, a specific opioid

antagonist,

naloxone

hydrochloride,

should

available

reversal

opioid-induced

respiratory depression.

Use in Lactation

Morphine is excreted in human milk and breast-feeding is not recommended while a patient is

receiving morphine. Withdrawal symptoms have been observed in breast-fed infants when

maternal administration of morphine sulfate is stopped.

4.7 Effects on ability to drive and use machines

Occupational hazards: Morphine may impair the mental and/or physical abilities required for

the performance of potentially hazardous tasks, such as driving a car or operating machinery.

Morphine in combination with other opioid analgesics, phenothiazines, sedative-hypnotics and

alcohol have additive depressant effects. Patients should be cautioned accordingly.

4.8 Undesirable effects

The adverse reactions caused by morphine are essentially the same as those observed with other

opioid analgesics. They include the following major hazards: respiratory depression, apnoea

and to a lesser degree circulatory depression, respiratory arrest, shock and cardiac arrest.

Most Common Adverse Effects:

Constipation, light-headedness, dizziness, sedation, nausea,

vomiting, sweating, dysphoria and euphoria.

Sedation:

Most patients receiving morphine will experience initial drowsiness. This usually

disappears in three to five days and is not a cause for concern unless it is excessive, or

accompanied with unsteadiness or confusion. Excessive or persistent sedation should be

investigated. Factors to be considered should include: concurrent sedative medications, the

presence of hepatic or renal insufficiency, exacerbated respiratory failure, tolerance to the dose

used, especially in older patients, disease severity and the patient’s general condition. If the

dose of morphine has been reduced and pain is not adequately controlled, the dose may be

carefully increased again after a few days.

Dizziness and unsteadiness may be associated with morphine-induced postural hypotension

particularly in elderly or debilitated patients. The dosage should be adjusted according to

individual needs but, because of reduced clearance, dosage may be lower in patients over 50

years of age.

Nausea and Vomiting:

Nausea and vomiting are common after single doses of morphine or as

an early undesirable effect of regular opioid therapy. The prescription of a suitable antiemetic

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should be considered. The frequency of nausea and vomiting usually decreases within a week

or so but may persist due to opioid-induced gastric stasis. Metoclopramide is often useful in

such patients.

Constipation:

Virtually all patients suffer from constipation while taking opioids on a chronic

basis. Some patients, particularly elderly, debilitated or bedridden patients, may become

impacted. Patients must be cautioned accordingly and laxatives, softeners and other appropriate

treatments should be initiated at the beginning of opioid therapy.

Other Adverse Reactions Include:

Cardiovascular:

Flushing of the face, chills, tachycardia, bradycardia, palpitations, faintness,

syncope, hypotension and hypertension.

Central Nervous System:

Euphoria, dysphoria, weakness, headache, restlessness, anxiety,

agitation, tremor, uncoordinated muscle movements, insomnia, dizziness, vertigo, delirium,

confusional symptoms, occasionally hallucinations, allodynia and hyperalgesia.

Gastrointestinal:

mouth,

anorexia,

constipation,

cramps,

laryngospasm,

colic,

taste

alterations and biliary tract cramps and biliary spasm.

Genitourinary:

Urinary retention or hesitancy, ureteric spasm, reduced libido or potency,

amenorrhoea, erectile dysfunction and hypogonadism.

Endocrine:

A syndrome of inappropriate antidiuretic hormone secretion characterised by

hyponatraemia

secondary

decreased

free-water

excretion

occur

(monitoring

electrolytes may be necessary). Morphine stimulates prolactin release, and may also cause

hyperglycaemia.

Visual Disturbances:

Blurred vision, nystagmus, diplopia and miosis.

Allergic:

Pruritis, urticaria, other skin rashes including contact dermatitis, and oedema.

Allergic reactions may be due to histamine release, and may be more frequent in asthmatic

patients. Anaphylactic reactions following intravenous injection have been reported rarely.

Local

Effects:

Pain

injection

site;

local

tissue

irritation

induration

following

subcutaneous injection, particularly when repeated.

Dependence/Tolerance:

Physical dependence and tolerance may develop with long term use

of morphine.

Withdrawal (Abstinence) Syndrome:

Chronic use of opioid analgesics may be associated with

the development of physical dependence, with or without psychological dependence. An

abstinence syndrome may be precipitated when opioid administration is suddenly discontinued

or opioid antagonists administered.

Withdrawal symptoms that may be observed after discontinuation of opioid use include; body

aches, diarrhoea, piloerection, anorexia, nervousness or restlessness, rhinorrhoea, sneezing,

tremors or shivering, abdominal colic, nausea, sleep disturbance, unusual increase in sweating

and yawning, weakness, tachycardia and unexplained fever. With appropriate dose adjustments

and gradual withdrawal these symptoms are usually mild.

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Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are

asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.

4.9 Overdose

Symptoms

Overdosage with morphine is characterised by respiratory depression (a decrease in respiratory

rate

and/or

tidal

volume,

Cheyne-Stokes

respiration,

cyanosis),

extreme

somnolence

progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes

bradycardia and hypotension. In severe overdosage, apnoea, circulatory collapse, cardiac arrest

and death may occur.

Treatment

Immediate attention should be given to the re-establishment of adequate respiratory exchange

through provision of a patient airway and institution of assisted or controlled ventilation.

In patients physically dependent on opioids, respiratory support is the first line of treatment. In

these patients, the use of naloxone is potentially dangerous.

Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed

as indicated.

The opioid antagonist, naloxone, is a specific antidote against respiratory depression which may

result from overdosage or unusual sensitivity to opioids. The recommended adult dose of

naloxone for the treatment of severe opiate induced respiratory depression is 0.4 to 2 mg

intravenously every 2 to 3 minutes as necessary, simultaneously with assisted respiration.

For children, the initial dose recommended is 0.01 mg/kg naloxone. A response should be seen

after 2 to 3 doses. Note the duration of action of naloxone is usually shorter than that of

morphine and thus the patient should be carefully observed for signs of CNS depression

returning.

If the response to naloxone is suboptimal or not sustained, additional naloxone may be

administered as needed, or given by continuous intravenous infusion to maintain alertness and

respiratory function. There is no information available about the cumulative dose of naloxone

that may be safely administered.

Naloxone should not be administered in the absence of clinically significant respiratory or

circulatory depression secondary to morphine overdosage.

Naloxone should be administered cautiously to persons who are known or suspected to be

physically dependent on morphine. In such cases, an abrupt or complete reversal of opioid

effects may precipitate an acute withdrawal syndrome. The severity of the withdrawal

syndrome produced will depend on the degree of physical dependence and the dose of the

antagonist administered. If it is necessary to treat serious respiratory depression in the

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physically dependent patient, the antagonist should be administered with extreme care and by

titration with smaller than usual doses of the antagonist.

Morphine toxicity may be a result of overdosage but because of the large inter-individual

variation in sensitivity to opioids, it is difficult to assess the exact dose of any opioid that is

toxic or lethal. The toxic effects of morphine tend to be overshadowed by the presence of pain

or tolerance. Patients having chronic morphine therapy have been known to take in excess of

3,000 mg/day with no apparent toxic effects being present.

For advice on the management of overdose please contact the National Poisons Centre on 0800

POISON (0800 764766).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Morphine is the principal alkaloid of opium. Morphine acts as an agonist, binding to receptors

in the brain, spinal cord and other tissues. These sites have been classified as

mu

receptors and

widely

distributed

throughout

central

nervous

system

being

present

highest

concentration in the limbic system.

Morphine exerts its primary effects in the central nervous system and organs containing smooth

muscle.

Morphine produces many effects, including analgesia, decreased gastrointestinal motility,

respiratory depression, drowsiness, changes in mood and alterations of the endocrine and

autonomic nervous systems.

Nausea and vomiting may occur through direct stimulation of the chemoreceptor trigger zone

(CTZ).

Urinary retention may occur due to increased bladder sphincter tone.

5.2 Pharmacokinetic properties

Absorption

Absorption of morphine sulfate after intramuscular and subcutaneous injection is fairly rapid

with peak analgesia occurring 30 to 60 minutes and 50 to 90 minutes after injection via the

respective routes. Peak analgesia occurs within 20 minutes after intravenous administration.

Distribution

Morphine is distributed throughout the body, but particularly to parenchymatous tissue such as

kidney, lung, liver and spleen. Lower concentrations are found in skeletal muscle and brain

tissue. Morphine diffuses across the placenta and trace amounts are found in sweat and breast

milk. About 35% is protein bound, mainly to albumin.

Metabolism

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Morphine is metabolised principally in the liver by conjugation with glucuronic acid. The

principal metabolites are morphine-3-glucuronide and morphine-6-glucuronide. Morphine-6-

glucuronide is pharmacologically active and has a half-life somewhat longer than morphine.

Elimination

Elimination half-life from serum is approximately 1.5 to 2 hours in healthy subjects and 90%

of the dose is recovered in urine within 24 hours. Approximately 7 to 10% of the dose is

recovered in faeces, the majority after conjugation and excretion via bile.

Chinese subjects given intravenous morphine have a higher rate of clearance when compared

to white subjects (1852 + 116 mL/min versus 1495 + 80 mL/min) because of an increase in the

partial metabolic clearance by glucuronidation.

Children

section 4.4

– Paediatric Use and

section 4.2 Dose and method of administration

Elderly

In older patients, the volume of distribution is considerably smaller and initial concentrations

of morphine are correspondingly higher. See also

section

4.4

– Other Special Risk Patients and

Elderly Patients.

Disease states

section

4.4

– Renal or Hepatic Disease.

5.3 Preclinical safety data

The carcinogenic or mutagenic potential of morphine has not been established.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Water for injections

1N hydrochloric acid (for pH adjustment)

The solution does not contain any antioxidant or preservative.

6.2 Incompatibilities

A solution of thiopentone and morphine forms an inactive preparation.

6.3 Shelf life

The shelf life of unopened DBL Morphine Sulfate Injection BP ampoules is 24 months for the

5 mg/mL and 30 mg/mL presentations, and 30 months for the 10 mg/mL and 15 mg/mL

presentations.

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6.4 Special precautions for storage

Store at or below 25°C. Protect from light.

DBL Morphine Sulfate Injection BP should be used within 24 hours of opening, in order to

avoid the risk of microbial contamination.

Warning:

As with all parenteral drug products, intravenous admixtures should be visually

inspected for clarity, particulate matter, precipitate and leakage prior to administration,

whenever solution and container permit. Solutions showing haziness, particulate matter,

precipitate or leakage should not be used. Development of a yellow colour in morphine

solutions does not indicate toxicity or loss of potency or efficacy.

6.5 Nature and contents of container

Package Quantities

DBL Morphine Sulfate Injection BP ampoules are available as follows:

Strength

Pack Size(s)

5 mg/mL

10 mg/mL

5 and 50

15 mg/mL

5 and 50

30 mg/mL

5 and 50

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Contains no antimicrobial agent. Product is for single use in one patient only. Discard any

residue.

No special requirements for disposal. Any unused medicinal product or waste material should

be disposed of in accordance with local requirements.

7. MEDICINE SCHEDULE

Class B1 Controlled Drug

8. SPONSOR

Pfizer New Zealand Limited

PO Box 3998

Auckland, New Zealand

Toll Free Number: 0800 736 363

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9. DATE OF FIRST APPROVAL

28 April 1983

10. DATE OF REVISION OF THE TEXT

15 November 2019

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Inclusion of central sleep apnoea (CSA) and sleep-related hypoxemia.

Inclusion of endocrine effects and serotonin syndrome including signs

and symptoms.

Addition of interaction with P2Y12 inhibitors and serotonergic drugs.

™ = Trademark

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