Consumer medicine information

Morphine Sulfate Medsurge

Morphine sulfate pentahydrate

BRAND INFORMATION

Brand name

Morphine Sulfate Medsurge

Active ingredient

Morphine sulfate pentahydrate

Schedule

What is in this leaflet

This leaflet answers some common questions about Morphine Sulfate injection.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up-to-date information on the medicine. Those updates may contain important information about the medicine and its use of which you should be aware. All medicines have risks and benefits.

Your doctor has weighed the risks of you having Morphine Sulfate injection against the benefits they expect it will give you.

If you have any concerns about this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What Morphine Sulfate injection is used for

Morphine is a pain reliever that belongs to a group of medicines called opioid analgesics.

Morphine acts in the brain and spinal cord.

It is used most commonly for short-term relief of severe pain. It may also be used just before or during an operation to help the anaesthetic work better.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another purpose.

Morphine may produce physical dependency if used for a long time (i.e. more than two weeks). Physical dependency means you may experience unpleasant feelings if you stop morphine suddenly.

However, it is also important to keep your pain under control. Your doctor can advise you on how to manage this.

This medicine is only available with a doctor's prescription.

Before you use Morphine Sulfate injection

When you must not use Morphine Sulfate injection

Do not have Morphine Sulfate injection if you have ever had an allergic reaction after taking:

morphine sulfate pentahydrate (the active ingredient in Morphine Sulfate injection)
any of the other ingredients listed at the end of this leaflet
any other similar medicines (such as medicines of the same class or with similar structure, as per PI).

Symptoms of an allergic reaction to morphine may include:

shortness of breath, wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

You should not be given Morphine Sulfate injection if:

you have severe bronchial asthma or any other lung or breathing problems
you have shallow or difficulty breathing
you are suffering from acute alcoholism
you are undergoing treatment with monoamine oxidase (MAO) inhibitors (e.g. phenelzine, tranylcypromine, moclobemide or selegeline), or have stopped MAO inhibitor treatment during the last fourteen days
you have an irregular heart beat (arrhythmia)
you have severe liver problems
severe central nervous system depression
diabetic acidosis where there is danger of coma
following biliary tract surgery or biliary colic
obstruction of the gastrointestinal tract
heart failure after lung disease
you have a head injury, brain tumour or increased pressure in the head.

Morphine Sulfate injection must not be given to premature infants or during labour for delivery of premature infants.

Do not have Morphine Sulfate injection after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. In that case, return it to your Pharmacist.

If you are not sure whether you should start having this medicine, talk to your doctor.

Before you start to use it

Tell your doctor or pharmacist if you have allergies to:

any other medicines
any other substances, such as foods, preservatives or dyes.

Tell your doctor if you are pregnant or intend to become pregnant. Ask your doctor about the risks and benefits involved.

Tell your doctor or pharmacist if you are breast-feeding or plan to breast-feed. As morphine passes into breast milk, breast-feeding is not recommended while you are being given morphine.

Tell your doctor if you have or have had any of the following medical conditions:

epilepsy, convulsions, fits or seizures
under-active thyroid gland (hypothyroidism) and/or adrenal gland (Addison’s disease)
enlarged prostate or problems with urination
tachycardia, fast heart beat
liver problems
kidney problems
any bowel disorders or ulcerative colitis,
biliary tract disease or inflammation of the pancreas
myasthenia gravis
snoring or sleep apnoea (you temporarily stop breathing or have difficulty breathing while asleep
long-standing pain not related to cancer
unexplained increase in pain, increased levels of pain with increasing opioid medication or sensitivity not associated with the original pain.

Tell your doctor or pharmacist if you are pregnant or plan to become pregnant or are breast-feeding or plan to breast-feed. Your doctor or pharmacist can discuss with you the risks and benefits involved.

As morphine passes into breast milk, breast-feeding is not recommended while you are being given morphine.

Your doctor may not want to give you this medicine or may want to take special precautions if you have any of the above conditions.

If you have not told your doctor about any of these things, tell him/her before you take Morphine Sulfate injection.

Addiction
You can become addicted to morphine sulfate even if you use it exactly as prescribed. Morphine sulfate may become habit forming causing mental and physical dependence. If abused it may become less able to reduce pain.

Dependence
As with all other opioid containing products, your body may become used to you taking morphine sulfate. Using it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking morphine sulfate suddenly, so it is important to take it exactly as directed by your doctor.

Tolerance
Tolerance to morphine sulfate may develop, which means that the effect of the medicine may decrease. If this happens, more may be needed to maintain the same effect.

Withdrawal
Continue using your medicine for as long as your doctor tells you. If you stop having this medicine suddenly, your pain may worsen and you may experience some or all of the following withdrawal symptoms:

nervousness, restlessness, agitation, trouble sleeping or anxiety
body aches, weakness or stomach cramps
loss of appetite, nausea, vomiting or diarrhoea
increased heart rate, breathing rate or pupil size
watery eyes, runny nose, chills or yawning
increased sweating.

Morphine Sulfate injection given to the mother during labour can cause breathing problems and signs of withdrawal in the newborn.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines and Morphine Sulfate injection may interfere with each other. These include:

antidepressants or medicines for anxiety disorders, such as:
- selective serotonin reuptake inhibitors (SSRIs) or
- serotonin and norepinephrine reuptake inhibitors (SNRIs)
- tricyclic antidepressants (TCAs)
- monoamine oxidase inhibitors (MAOIs) i.e. moclobemide, phenelzine, tranylcypromine
medicines used for migraine (triptans)
medicines used to prevent or treat nausea and vomiting (5-HT3 receptor antagonists)
selegeline, a monoamine oxidase inhibitor used to treat Parkinson’s disease
alcohol
cimetidine (Magicul), a medicine used to treat stomach or duodenal ulcers, or reflux
diuretics (fluid tablets)
other medicines which may make you drowsy such as sleeping tablets, tablets to calm your nerves, sedatives, tranquilisers, hypnotics and muscle relaxants
anti-diarrhoeal medications
medicines to treat mental disorders (antipsychotics), other opioid analgesics or strong painkillers
some antihistamines and some heart medications (e.g. beta blocker)
benzodiazepines (and other medicines) to treat anxiety, acute stress reactions, agitation, tremor, such as diazepam (Valium), alprazolam or lorazepam
medicines that lower your blood pressure (antihypertensives)
warfarin (Marevan, Coumadin), a medicine used to thin the blood
zidovudine (Retrovir, Combivir, Trizivir) a medicine used to treat HIV infection, ritonavir (Kaletra, Norvir), a medicine used to treat HIV infection
medications used to reduce risk of blood clots or stroke (e.g. clopidogrel, prasugrel and ticagrelor)
medications used for seizures such as gabapentinoids (e.g. gabapentin and pregabalin)
cannibis.

Your doctor will minimise the dose and duration of use; and monitor you for signs and symptoms of breathing difficulties and sedation. You must not drink alcohol while using morphine sulfate.

These medicines may be affected by morphine or may affect how well it works.

You may need to take different amounts of your medicines or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while you are receiving Morphine Sulfate injection.

Taking Morphine Sulfate injection

How much is given

Your doctor will decide what dose of morphine you will receive. This depends on your condition and other factors, such as your weight.

How is it given

Your doctor or nurse will usually give morphine to you.

Morphine can be given as:

an injection into a muscle
a slow injection into a vein
an injection under the skin or
by a method called patient-controlled analgesia; this method allows you, the patient, to control the amount of morphine you wish to receive. On experiencing pain, you can press a button, which allows a dose of morphine to be administered to you. To prevent you receiving too much morphine, there is a “lockout” period built into the pump which prevents continuous injection of morphine.

Your doctor will decide the most appropriate way for you to be given morphine.

If you have too much (Overdose)

If you have received too much morphine, you may have symptoms which include severe drowsiness, slow or troubled breathing, severe weakness, slow heart-beat, pale and cold skin.

If you or someone else receive too much (overdose), and experience one or more of the symptoms below, call triple zero (000) for an ambulance. Keep the person awake by talking to them or gently shaking them every now and then. You should follow the above steps even if someone other than you have accidentally used morphine sulfate that was prescribed for you. If someone has an overdose they may experience one or more of the following symptoms:

Slow, unusual or difficult breathing
Drowsiness, dizziness or unconsciousness
Slow or weak heartbeat
Nausea or vomiting
Convulsions or fits.

If you think you or someone else may have used too much morphine, you should immediately:

phone the Poisons Information Centre (by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

When seeking medical attention, take this leaflet and remaining medicine with you to show the doctor. Also tell them about any other medicines or alcohol which have been taken.

While you are being given Morphine Sulfate injection

Things you must do

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being given morphine. Tell any other doctors, dentists, and pharmacists who treats you that you are being given morphine.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are being given morphine.

If you become pregnant while you are having this medicine, tell your doctor or pharmacist immediately. Your doctor can discuss with you the risks of being given this medicine while you are pregnant.

Things you must not do

Do not give this medicine to anyone else, even if their symptoms seem to be the same as yours.

Do not use Morphine Sulfate injection to treat any other complaints unless your doctor tells you to.

Do not stop using morphine or lower the dosage without checking with your doctor or pharmacist. If you have been using morphine for more than two weeks, you may experience unpleasant feelings if you stop morphine suddenly.

Your doctor will probably want you to gradually reduce the amount of morphine you are using, before stopping it completely.

Do not take any other medicines, whether they are prescription or over-the- counter medicines, unless they have been approved or recommended by a doctor or pharmacist who knows you are being given morphine.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert while you are having Morphine Sulfate injection until you know how it affects you. Morphine may cause drowsiness, and impairment of co-ordination, in some people. Make sure you know how you react to morphine. Do not drive a car, operate machinery, or do anything else that could be dangerous if you are drowsy or feeling uncoordinated.

Do not drink alcohol, while you are undergoing treatment with morphine, unless otherwise advised by your doctor or pharmacist, as drowsiness and coordination impairment may be worse.

As morphine may cause nausea and vomiting, your doctor is likely to prescribe medicine for you to take/receive before the morphine, to stop you feeling sick.

Morphine may also cause constipation, so your doctor is likely to prescribe laxatives to prevent this happening.

Tell your doctor, pharmacist or nurse if you have any concerns about being given morphine.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are having Morphine Sulfate injection.

Morphine helps most people with severe pain, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects. If you are over 65 years of age you may have an increased chance of getting side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

If you get any side effects, do not stop using morphine without first talking to your doctor or pharmacist.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

drowsiness, dizziness or unsteadiness
light-headedness
confusion
sweating or flushing
nausea and/or vomiting
constipation
pain and irritation at the injection site
blurred vision
dry mouth
mood changes
red, itchy skin.

These are the more common side effects of Morphine Sulfate injection. Mostly they are mild and short- lived.

Tell your doctor or pharmacist immediately or go to the Accident and Emergency department at your nearest hospital if you notice any of the following:

any signs of an allergic reaction to morphine (which are listed at the start of this leaflet)
severe drowsiness
slow or troubled breathing
severe weakness
agitation
hallucinations
seizures (fits)
unconsciousness
slow or rapid heart beat
difficulty in urinating.

The above side effects could be very serious. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list. Some people may get other side effects of Morphine Sulfate injection.

After being given Morphine Sulfate injection

Storage

Morphine Sulfate injection will be stored in the pharmacy or on the ward.

Product is for single use in one patient only. Discard any residue.

Keep your ampoules in the cardboard carton until it is time to use them.

Store the ampoules in a cool dry place below 25 degrees celcius (room temperature). Protect from light. Store in original container.

Do not store this medicine or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep the ampoules where young children cannot reach them. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If you no longer need this medicine or it has passed its expiry date, return any unused ampoules to your pharmacist.

Product description

What it looks like

Morphine Sulfate injection comes in amber glass 1mL ampoule containing a clear colourless to slightly yellow solution.

There are different strengths available:

Not all presentations and/or packs are marketed.

Ingredients

As well as morphine sulfate pentahydrate, the active ingredient, the ampoules also contain sodium chloride, hydrochloric acid (to adjust pH) and water for injection.

Sponsor

Australian Sponsor

Medicianz Healthcare Pty Limited
Unit 2, 6-7 Gilda Court
MULGRAVE
VICTORIA 3170

Marketed and distributed by

Medsurge Healthcare Pty Ltd
Tel: 1300 788 261
www.medsurge.com.au

Registration Numbers

AUST R 308716 (2 mg/1 mL)

AUST R 308714 (5 mg/1 mL)

AUST R 308718 (10 mg/1 mL)

AUST R 308715 (15 mg/1 mL)

AUST R 308721 (30 mg/1 mL)

This leaflet was prepared in December 2020.

Published by MIMS February 2021

BRAND INFORMATION

Brand name

Morphine Sulfate Medsurge

Active ingredient

Morphine sulfate pentahydrate

Schedule

Notes

Distributed by Medsurge Healthcare Pty Ltd.

1 Name of Medicine

Morphine sulfate pentahydrate.

2 Qualitative and Quantitative Composition

Morphine sulfate pentahydrate 2 mg/1 mL.
Morphine sulfate pentahydrate 5 mg/1 mL.
Morphine sulfate pentahydrate 10 mg/1 mL.
Morphine sulfate pentahydrate 15 mg/1 mL.
Morphine sulfate pentahydrate 30 mg/1 mL.
Isotonic preparations of Morphine Sulfate injection 2 milligram/1 mL, 5 milligram/1 mL, 10 milligram/1 mL, 15 milligram/1 mL and 30 milligram/1 mL are available. These are sterile solutions of morphine sulfate pentahydrate and sodium chloride in water for injections. 1 M hydrochloric acid is used to adjust the pH. The pH of these solutions ranges from 3.2 to 4.5.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Morphine Sulfate injection is a clear colourless to slightly yellow solution. The solution does not contain any antioxidant or preservative.

4 Clinical Particulars

4.1 Therapeutic Indications

Morphine Sulfate injection is indicated for the short-term management of severe pain for which other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain.
Morphine Sulfate injection may also be used as a pre-operative medication and as an analgesic adjunct in general anaesthesia.

4.2 Dose and Method of Administration

Note.

Opioid antagonists and facilities for administration of oxygen and control of respiration should be available during, and immediately following parenteral administration.

One point cut opening instructions.

1) Turn the ampoule with coloured point up. If there is any solution in the upper part of the ampoule, gently tap with your finger to get all the solution to the lower part of the ampoule.
2) Use both hands to open; while holding the lower part of the ampoule in one hand, use the other hand to break off the upper part of the ampoule in the direction away from the coloured point (see manufacturer's product information for diagram).

Subcutaneous, intramuscular and slow intravenous administration.

Morphine sulfate injection may be given by the subcutaneous, intramuscular or intravenous route. The subcutaneous route is not suitable for oedematous patients.

Adults.

Morphine sulfate pentahydrate is usually administered by intramuscular or subcutaneous injection, in the range of 5 to 20 milligrams, depending on the cause of pain and the patient response. Doses may be repeated every 4 to 6 hours.
Morphine sulfate pentahydrate 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 milligram diluted in 4 to 5 mL of water for injections given slowly over 4 to 5 minutes.

Children.

Morphine sulfate pentahydrate is given by intramuscular or subcutaneous injection in doses of 0.1 to 0.2 milligram/kg bodyweight to a maximum of 15 milligram. 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 milligram/kg, incrementally over 5 to 15 minutes. Repeat intravenous dosing is unsubstantiated as a method of analgesia in children.
Morphine sulfate pentahydrate 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 Contraindications).

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 milligram/hr after adequate analgesia has been established.
In children, an infusion dose of 0.01 to 0.05 milligram/kg/hour morphine to a maximum intravenous dose of 4 milligram/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 milligram 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 milligram/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 milligram/kg morphine has been used successfully in children and adolescents between the ages of 7 and 19 years with a lockout interval of 6 to 10 minutes. If a background infusion is employed, an infusion dose of 0.015 milligram/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.

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, intravenous or subcutaneous morphine require dosage reduction (about one-sixth), since about 60% of oral morphine is metabolised in first-pass metabolism (i.e. 1 milligram of either intramuscular, subcutaneous or intravenous morphine for every 6 milligrams of oral morphine). The dose should then be titrated according to the patient's clinical response.
For cancer pain, Morphine Sulfate injection should be given regularly around the clock, in most instances every 4 hours. The basis of pain control with Morphine Sulfate injection 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 increases.

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.

Treatment goals and discontinuation.

Before initiating treatment with morphine, a treatment strategy including treatment duration and treatment goals, and a plan for end of the treatment, should be agreed together with the patient, in accordance with pain management guidelines. During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed.
When a patient no longer requires therapy with morphine, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. In absence of adequate pain control, the possibility of hyperaesthesia, drug tolerance and progression of underlying disease should be considered (see Section 4.4 Special Warnings and Precautions for Use).

Duration of treatment.

Morphine should not be used longer than necessary.

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.
Product is for single use in one patient only. Discard any residue.

4.3 Contraindications

Morphine sulfate pentahydrate is contraindicated in the following situations:
patients with known hypersensitivity to morphine or other opioids;
patients with severe respiratory disease, acute respiratory disease and respiratory depression or failure, especially in the presence of cyanosis and/or increased bronchial secretion;
patients with asthma or other obstructive airways disease;
other conditions where respiratory reserve is depleted, such as emphysema, chronic bronchitis or kyphoscoliosis;
cor pulmonale;
severe depressed level of consciousness;
diabetic ketoacidosis where there is a danger of coma;
severe liver disease or incipient hepatic encephalopathy;
following biliary tract surgery or surgical anastomosis;
biliary colic;
gastrointestinal obstruction; paralytic ileus;
suspected surgical abdomen;
acute diarrhoeal conditions associated with antibiotic-induced pseudomembranous colitis;
diarrhoea caused by poisoning (until the toxic material has been eliminated);
in patients who are taking or who have taken MAO inhibitors within the previous fourteen days;
phaeochromocytoma (due to risk of pressor response to histamine release);
arrhythmias;
cardiac failure secondary to pulmonary disease;
acute alcoholism or delirium tremens;
comatose patients;
head injuries; brain tumour;
increased intracranial or cerebrospinal pressure and in convulsive states such as status epilepticus, tetanus or strychnine poisoning (see Section 4.4 Special Warnings and Precautions for Use).
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 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Hazardous and harmful use.

Morphine sulfate injection contains morphine sulfate pentahydrate which is an opioid and a potential drug of abuse, misuse and dependence. Dependence can occur in patients appropriately prescribed Morphine Sulfate injection at recommended doses.
The risk of dependence is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) in current tobacco users or in patients with a personal history of mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for drug abuse or dependence prior to being prescribed Morphine Sulfate injection.
All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see Section 6.6 Special Precautions for Disposal). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Patients should be advised not to share Morphine Sulfate injection with anyone else.

Accidental ingestion/exposure.

Accidental ingestion or exposure of Morphine Sulfate injection, especially by children, can result in a fatal overdose of morphine sulfate pentahydrate. Patients and their caregivers should be given information on safe storage and disposal of unused Morphine Sulfate injection (see Section 6.6 Special Precautions for Disposal).

Respiratory depression.

Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of Morphine Sulfate injection but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times.
The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients, in patients with existing impairment of respiratory function, in those suffering from conditions accompanied by hypoxia or hypercapnia (e.g. chronic obstructive pulmonary disease; asthma), when even moderate therapeutic doses may significantly decrease pulmonary ventilation and in patients with abnormal hepatic function and renal impairment. Morphine should therefore be only used in such patients for whom its use is judged to be essential, with extreme caution, and close monitoring (see Section 4.2 Dose and Method of Administration). The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
The respiratory depressant effects of morphine and its capacity to increase 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 effects, including confusion, miosis and vomiting, which may obscure the clinical course of patients with head injuries.
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.
The risk of respiratory depression is greater with the use of high doses of opioids, especially high potency and modified release formulations and in opioid naïve patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations, together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response (see Section 4.2 Dose and Method of Administration).
Resuscitative equipment and opioid antagonist must be readily available.

Seizures.

Morphine may aggravate pre-existing seizure conditions. If dosage is escalated substantially above recommended levels because of drug tolerance development, seizures may occur in individuals without a history of seizures.

Serotonin syndrome (SS).

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 and Other Forms of Interactions). Signs of SS may include clonus, agitation, diaphoresis, tremor, hyperreflexia, hypertonia and increased body temperature.

Cardiovascular instability.

While low doses of intravenously administered morphine have little effect on cardiovascular stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in circulatory catecholamines. Have naloxone injection and resuscitative equipment immediately available for use in case of life-threatening or intolerable side effects and whenever morphine therapy is being initiated.

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.

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 phenothiazines or certain anaesthetics.
Morphine may produce orthostatic hypotension in ambulatory patients.

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.

Drug tolerance, opioid use disorder (abuse and dependence) and withdrawal.

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce drug tolerance and physical dependence. Drug tolerance is the need for increasing doses to maintain analgesic therapy. Drug tolerance may occur to both the desired and undesired effects of the opioid. Psychological dependence, physical dependence, and drug tolerance may develop upon repeated administration of morphine. However, it should be noted that clinically significant respiratory depression, dependence, rapid drug tolerance and euphoric mood rarely develop when doses of morphine are carefully titrated against the pain in patients with terminal disease and severe pain.
Repeated use of morphine can lead to opioid use disorder (OUD). A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of morphine may result in overdose and/or death.
The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).
Before initiating treatment with morphine and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see Section 4.2 Dose and Method of Administration). Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician.
Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.
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 syndrome, although these are usually mild or absent even after abrupt discontinuance. Clinically significant drug 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 drug tolerance.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal syndrome if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal syndrome can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine). Withdrawal syndrome can result in some or all of the following symptoms: dysphoria, restlessness/agitation, increased lacrimation, rhinorrhoea, yawning, hyperhidrosis, chills, myalgia, mydriasis, palpitations, irritability, anxiety, hyperkinesia, tremor, pain, back pain, arthralgia, asthenia, abdominal pain, insomnia, nausea, anorexia, vomiting, diarrhoea, hypertension, increased respiratory rate, tachycardia, piloerection, sneezing, seizures, and unexplained fever.
When discontinuing Morphine Sulfate injection in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids; see Section 4.2 Dose and Method of Administration).

Ceasing opioids.

Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Drug tolerance, opioid use disorder (abuse and dependence) and withdrawal). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to pain management should be in place before initiating an opioid analgesic therapy taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal syndrome.
There are no standard tapering schedules suitable for all patients and an individualised plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks (see Section 4.2 Dose and Method of Administration). If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.

Neonatal opioid withdrawal syndrome.

See Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy.

Use of opioids in chronic (long-term) non-cancer pain (CNCP).

Opioid analgesics have an established role in the treatment of acute pain, cancer pain and palliative and end-of-life care. Current evidence does not generally support opioid analgesics in improving pain and function for most patients with chronic non-cancer pain. The development of drug tolerance and physical dependence and risks of adverse effects, including hazardous and harmful use, increase with the length of time a patient takes an opioid. The use of opioids for long-term treatment of CNCP is not recommended.
The use of an opioid to treat CNCP should only be considered after maximised nonpharmacological and non-opioid treatments have been tried and found ineffective, not tolerated or otherwise inadequate to provide sufficient management of pain. Opioids should only be prescribed as a component of comprehensive multidisciplinary and multimodal pain management.
Opioid therapy for CNCP should be initiated as a trial in accordance with clinical guidelines and after a comprehensive biopsychosocial assessment has established a cause for the pain and the appropriateness of opioid therapy for the patient (see Hazardous and harmful use, above). The expected outcome of therapy (pain reduction rather than complete abolition of pain, improved function and quality of life) should be discussed with the patient before commencing opioid treatment, with agreement to discontinue treatment if these objectives are not met.
Owing to the varied response to opioids between individuals, it is recommended that all patients be started at the lowest appropriate dose and titrated to achieve an adequate level of analgesic therapy and functional improvement with minimum adverse reactions. Immediate-release products should not be used to treat chronic pain, but may be used for a short period in opioid naïve patients to develop a level of tolerance before switching to a modified-release formulation. Careful and regular assessment and monitoring is required to establish the clinical need for ongoing treatment. Discontinue opioid therapy if there is no improvement of pain and/or function during the trial period or if there is any evidence of misuse or abuse. Treatment should only continue if the trial has demonstrated that the pain is opioid responsive and there has been functional improvement. The patient's condition should be reviewed regularly and the dose tapered off slowly if opioid treatment is no longer appropriate (see Ceasing opioids).

Hyperalgesia.

Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with drug tolerance (see Drug tolerance, opioid use disorder (abuse and dependence) and withdrawal). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.

Adrenal insufficiency.

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, asthenia, dizziness, and hypotension.

Impaired gastric emptying.

Morphine impairs 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.

Acute abdominal conditions.

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 with inflammatory or obstructive bowel disorders, or with ulcerative colitis, and should only be used when necessary in patients with acute pancreatitis.

Hepatobiliary disorders.

Morphine should be avoided in patients with biliary tract disorders (see Section 4.3 Contraindications). Morphine may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract disorders and pancreatitis. . Therefore, in patients with biliary tract disorders morphine may exacerbate pain. The use of morphine in biliary colic or following biliary tract surgery or surgical anastomosis is contraindicated (see Section 4.3 Contraindications). In patients given morphine after cholecystectomy, biliary pain has been induced.

Sickle cell sisease (SCD) and acute chest syndrome (ACS).

Due to a possible association between ACS and morphine use in SCD patients treated with morphine during sickle cell anaemia with crisis, close monitoring for ACS symptoms is warranted.

Decreased sex hormones and increased blood prolactin.

Long-term use of opioid analgesic therapy may be associated with decreased sex hormone levels and increased blood prolactin. Symptoms include decreased libido, erectile dysfunction or amenorrhoea.

Other special risk patients.

Morphine should be given with caution, and in reduced dosages, to certain patients, such as the elderly or debilitated and those with severe abnormal hepatic function or renal impairment, hypothyroidism, Addison's disease, myxoedema, and benign prostatic hyperplasia or urethral stenosis. Caution should also be observed if morphine is administered to patients with psychotic disorder 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.

Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.

Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of Morphine Sulfate injection with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics, general anaesthetics, tranquilisers, beta blockers, or other CNS depressants, should be reserved for patients for whom other treatment options are not possible.
If a decision is made to prescribe Morphine Sulfate injection concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
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.
Patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers should be made aware of these symptoms. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while taking Morphine Sulfate injection.
Morphine may cause somnolence, and may impair the mental and/or physical abilities needed to perform potentially hazardous tasks, such as driving a car or operating machinery. 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 concomitant CNS depressants including alcohol and illicit drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If respiratory depression of any form occurs, consider decreasing the opioid dosage using best practices for opioid taper.
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 Interactions with Other Medicines and Other Forms of Interactions).

Oral P2Y₁₂ inhibitor antiplatelet therapy.

Within the first day of concomitant P2Y₁₂ inhibitor and morphine treatment, reduced efficacy of P2Y₁₂ inhibitor treatment has been observed (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Severe cutaneous adverse reactions (SCARs).

Acute generalised exanthematous pustulosis (AGEP), which can be life-threatening or fatal, has been reported in association with morphine treatment. Most of these reactions occurred within the first 10 days of treatment. Patients should be informed about the signs and symptoms of AGEP and advised to seek medical care if they experience such symptoms.
If signs and symptoms suggestive of these skin reactions appear, morphine should be withdrawn and an alternative treatment considered.

Use in hepatic impairment.

Morphine may have a prolonged duration and cumulative effect in patients with abnormal hepatic function. In these patients, analgesic therapy 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 Contraindications).

Use in renal impairment.

Morphine may have a prolonged duration and cumulative effect in patients with renal impairment. In these patients, analgesic therapy 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 Contraindications).
Caution should be observed when morphine is administered to patients with renal impairment, as the pharmacologically active metabolite, morphine-6-glucuronide, may accumulate in these patients. This may lead to CNS and respiratory depression.

Use in the elderly.

Morphine should be administered with caution and in reduced dosages to elderly or debilitated patients. Respiratory depression occurs more frequently in these patients. The 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.
In older patients, the volume of distribution is considerably smaller and initial concentrations of morphine are correspondingly higher (see Section 4.4 Special Warnings and Precautions for Use, Other special risk patients).

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 Contraindications).
Morphine should not be administered via patient-controlled analgesia to children less than six years of age with poor cognitive function.

Effects on laboratory tests.

Morphine impairs gastric emptying, thereby invalidating test results in gastric emptying studies.
Morphine may interfere with hepatobiliary imaging using technetium Tc^99m disofenin. Morphine may constrict the sphincter of Oddi and increase biliary tract pressure, preventing delivery of Tc^99m disofenin to the small bowel. These actions result in delayed visualisation, and thus resemble obstruction of the common bile duct.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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, analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics, general anaesthetics, tranquilisers, beta blockers, or other CNS depressants, including 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. Patients should be cautioned accordingly. See Table 1.

Significant impairment of motor function has also been noted following concomitant morphine administration and alcohol ingestion.
Diazepam, when used following high doses of morphine, exacerbates the hypotensive effects produced by morphine, and is associated with decreased blood 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.

Mixed agonist/antagonist opioid analgesics.

From a 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 syndrome.

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 (see Section 4.3 Contraindications). It is unknown whether there is an interaction between the new selective MAOIs (e.g. moclobemide and selegeline) 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 a haemodialysis patient was administered morphine and 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 and domperidone.

Morphine may antagonise the effects of metoclopramide and domperidone 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, mexiletine (anti-arrhythmic) and P2Y₁₂ inhibitors.

Anticholinergic agents.

Concurrent administration of morphine and anticholinergic agents (such as atropine) or other drugs with anticholinergic activity may increase the risk of severe constipation; this may lead to paralytic ileus and/or urinary retention.

Antidiarrhoeal and antiperistaltic agents (such as loperamide and kaolin).

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 syndrome 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.

P2Y₁₂ inhibitors.

Clinical impact: The co-administration of oral P2Y₁₂ inhibitors with morphine can decrease the absorption and peak concentration of oral P2Y₁₂ inhibitors and delay the onset of the antiplatelet effect, due to morphine's effect on gastric emptying (see Section 4.4 Special Warnings and Precautions for Use).
Intervention: Consider the use of a parenteral antiplatelet agent in the setting of acute coronary syndrome requiring co-administration of morphine.
Examples of P2Y₁₂ 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).

Rifampicin.

Plasma concentrations of morphine may be reduced by rifampicin. The analgesic effect of morphine should be monitored and doses of morphine adjusted during and after treatment with rifampicin.

Antibacterials.

The opioid analgesic papaveretum has been shown to reduce plasma ciprofloxacin concentration. The ciprofloxacin manufacturer advises that premedication with opioid analgesics be avoided.

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 menstruation in women.
(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.
Prolonged use of morphine during pregnancy can result in a neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. Babies born to mothers who are physically dependent on morphine may also be physically dependent on the drug. If prolonged use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
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 be available for reversal of opioid induced respiratory depression.
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.
⁺ Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible.
Morphine is excreted in human milk and breast-feeding is not recommended while a patient is receiving morphine. Withdrawal syndrome has been observed in breast-fed infants when maternal administration of morphine sulfate pentahydrate is stopped.

4.7 Effects on Ability to Drive and Use Machines

Morphine may cause somnolence and general impairment of co-ordination and may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. Ambulatory patients should be cautioned against driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

The adverse effects 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 cardiovascular insufficiency, respiratory arrest, shock and cardiac arrest.

Most common adverse effects.

Constipation, dizziness, sedation, nausea, vomiting, hyperhidrosis, dysphoria and euphoric mood.

Sedation.

Most patients receiving morphine will experience initial somnolence. This usually disappears in three to five days and is not a cause for concern unless it is excessive or accompanied with balance disorder or confusion. Excessive or persistent sedation should be investigated. Factors to be considered should include: concurrent sedative medications, the presence of hepatic or renal failure, 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 balance disorder may be associated with morphine induced orthostatic 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 should be considered. The frequency of nausea and vomiting usually decreases within a week or so but may persist due to opioid induced impaired gastric emptying. 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 effects.

Vascular disorders.

Flushing, hypotension, hypertension.

Cardiac disorders.

Tachycardia, bradycardia, palpitations.

Nervous system disorders.

Headache, tremor, myoclonus, dizziness, syncope, nystagmus, allodynia, hyperalgesia, taste disorder.

Gastrointestinal disorders.

Dry mouth, constipation, gastrointestinal pain, abdominal pain, biliary tract pain, biliary colic, pancreatitis.

Hepatobiliary disorders.

Spasm of sphincter of Oddi.

Respiratory, thoracic and mediastinal disorders.

Laryngospasm.

Renal and urinary disorders.

Urinary retention or hesitation, ureteric spasm.

Reproductive system and breast disorders.

Erectile dysfunction, amenorrhoea.

Endocrine disorders.

A syndrome of inappropriate antidiuretic hormone secretion characterised by hyponatraemia secondary to decreased free-water excretion may occur (monitoring of electrolytes may be necessary). Morphine stimulates prolactin release and may also cause hyperglycaemia. Hypogonadism.

Ear and labyrinth disorders.

Vertigo.

Eye disorders.

Blurred vision, diplopia and miosis.

Nutritional and metabolic disorders.

Decreased appetite.

Skin and subcutaneous tissue disorders.

Acute generalised exanthematous pustulosis (AGEP), pruritus, urticaria, other rashes including contact dermatitis.

Immune system disorders.

Hypersensitivity may be due to histamine release and may be more frequent in asthmatic patients. Anaphylactic reactions following intravenous injection have been reported rarely.

Psychiatric disorders.

Restlessness, anxiety, agitation, irritability, decreased libido, insomnia, delirium, confusional state and occasionally hallucination, altered mood including euphoric moods and dysphoria. The euphoric activity of morphine has led to its abuse.

General disorders and administration site conditions.

Chills, asthenia, oedema. Injection site pain, local tissue irritation and induration following subcutaneous injection, particularly when repeated.

Dependence/drug tolerance.

Physical and/or psychological dependence and drug tolerance may develop with long term use of morphine. In drug dependence, "drug craving" is often involved. Repeated use of morphine can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see Section 4.4 Special Warnings and Precautions for Use).

Drug withdrawal syndrome.

Chronic use of opioid analgesics may be associated with the development of physical dependence, with or without psychological dependence. Drug withdrawal syndrome may be precipitated when opioid administration is suddenly discontinued, or opioid antagonists administered.
Withdrawal syndrome symptoms that may be observed after discontinuation of opioid use include: pain, diarrhoea, piloerection, decreased appetite, nervousness or restlessness, rhinorrhoea, sneezing, tremors or chills, restless legs syndrome, abdominal pain, nausea, influenza like illness, sleep disorder, unusual hyperhidrosis and yawning, asthenia, tachycardia, mydriasis and pyrexia. With appropriate dose adjustments and gradual withdrawal these symptoms are usually mild.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

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), pneumonia aspiration, pulmonary oedema, extreme somnolence progressing to stupor or coma, confusional state, dizziness, severe drowsiness, severe nervousness or restlessness, hallucinations, seizures (especially in infants and children), skeletal muscle hypotonia, hypothermia, cold sweat, and sometimes bradycardia and hypotension. Rhabdomyolysis, progressing to renal failure, has been reported in overdosage. In severe overdosage, apnoea, circulatory collapse, cardiac arrest and death may occur.
The triad of respiratory depression, coma and miosis is considered indicative of opioid overdosage with mydriasis occurring as hypoxia develops. Death may occur from respiratory failure.

Treatment.

Immediate attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation.
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 milligrams intravenously every 2 to 3 minutes as necessary, simultaneously with assisted respiration.
For children, the initial dose recommended is 0.01 milligram/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 depressed level of consciousness 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 cardiovascular insufficiency 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 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 drug tolerance. Patients having chronic morphine therapy have been known to take in excess of 3,000 milligram/day with no apparent toxic effects being present.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 are widely distributed throughout the central nervous system being present in 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, somnolence, altered 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.

Clinical trials.

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.

5.2 Pharmacokinetic Properties

Absorption.

Absorption of morphine sulfate pentahydrate after intramuscular and subcutaneous injection is fairly rapid with peak analgesic therapy 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.

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.

Excretion.

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.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, water for injections, hydrochloric acid.

6.2 Incompatibilities

Morphine salts are sensitive to changes in pH and morphine is liable to be precipitated out of solution in an alkaline environment. Compounds incompatible with morphine salts include aminophylline and sodium salts of barbiturates and phenytoin. Other incompatibilities (sometimes attributed to particular formulations) have included aciclovir sodium, doxorubicin, fluorouracil, furosemide, heparin sodium, pethidine hydrochloride, promethazine hydrochloride and tetracyclines. Specialised references should be consulted for specific compatibility information. Physiochemical incompatibility (formation of precipitates) has been demonstrated between solutions of morphine sulfate and 5-fluorouracil.
A solution of thiopentone and morphine forms an inactive preparation.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
To reduce microbiological hazard, use as soon as practicable after preparation and/or dilution of the product. If storage is necessary, hold at 2-8°C for not more than 24 hours.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light. Store in original container.

6.5 Nature and Contents of Container

Morphine Sulfate injection is a clear colourless to slightly yellow solution, available in Type 1 amber glass ampoules in the following presentations and pack sizes (see Table 2):
Not all presentations and pack sizes are marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

The structural formula of morphine sulfate pentahydrate is shown below:

CAS number.

6211-15-0.

7 Medicine Schedule (Poisons Standard)

Schedule 8 - Controlled Drug.

Service Unavailable

Consumer medicine information

Morphine Sulfate Medsurge

Morphine sulfate pentahydrate

Keep track of your medicines

BRAND INFORMATION