Consumer medicine information

Morphine Juno

Morphine hydrochloride trihydrate

BRAND INFORMATION

Brand name

Morphine Juno

Active ingredient

Morphine hydrochloride trihydrate

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Morphine Juno.

What is in this leaflet

This leaflet answers some common questions about Morphine Juno morphine hydrochloride trihydrate injection (Morphine). It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given Morphine Juno against the benefits they expect it will have for you.

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

Keep this leaflet in a safe place You may need to read it again.

What Morphine Juno 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 relief of severe pain. It may also be used just before or during an operation to help the anaesthetic work better.

Your doctor may have prescribed morphine for another reason.

Ask your doctor if you have any questions about why morphine has been prescribed for you.

Morphine may produce physical dependency if used for a long time (ie 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 available only with a doctor’s prescription.

Before you are given Morphine Juno

When you must not be given it

You should not be given morphine if you have an allergy to morphine, or any of the ingredients listed at the end of this leaflet or any similar medicines.

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 if:

  • you have severe bronchial asthma or any other lung or breathing problems
  • you are suffering from acute alcoholism
  • you are undergoing treatment with monoamine oxidase (MAO) inhibitors (eg 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
  • a condition where the small bowel does not work properly (paralytic ileus)
  • heart failure after lung disease
  • diarrhoea caused by antibiotic-induced large bowel inflammation or by poisoning.
  • a rare adrenal gland tumour near the kidney (phaeochromocytoma)heart failure after lung disease.

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

Do not use Morphine Juno after the expiry date (EXP) printed on the pack. If you are given this medicine after the expiry date has passed, it may not work as well.

Do not use Morphine Juno if the packaging is torn or shows signs of tampering.

If you are not sure whether you should be given morphine, talk to your doctor or pharmacist.

Before you are given 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 or pharmacist if you have or have had any medical conditions, especially the following:

  • 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 heartbeat
  • 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 intend to become pregnant. Your doctor or pharmacist will discuss the possible risks and benefits of you being given morphine during pregnancy.

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.

If you have not told your doctor or pharmacist about any of the above, tell them before you are given morphine.

Addiction
You can become addicted to morphine sulfate even if you use it exactly as prescribed. Morphine 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 suddenly, so it is important to take it exactly as directed by your doctor.

Tolerance
Tolerance to morphine 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 Injection given to the mother during labour can cause breathing problems and signs of withdrawal in the newborn.

If you have not told your doctor or pharmacist about any of the above, tell them before you are given Morphine Juno.

Taking other medicines

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

Some medicines and morphine 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) ie. 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, general anaesthetics, hypnotics and muscle relaxants
  • anti-diarrhoeal medications (e.g. loperamide and kaolin)
  • medicines to treat mental disorders (antipsychotics), other opioid analgesics and strong painkillers,
  • some antihistamines and some heart medication (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.
  • medication 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)
  • cannabis
  • atropine
  • some medicines used to treat infections (e.g. rifampicin andciprofloxacin).

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.

These medicines may be affected by morphine, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor or pharmacist will advise you.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while receiving Morphine Injection.

How Morphine Juno is given

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

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 it is 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 take 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 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.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are being given Morphine Juno

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 are treating 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. It may affect other medicines used during surgery.

If you become pregnant while you are being treated with morphine, tell your doctor or pharmacist immediately.

Things you must not do

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

Do not give Morphine Juno to anyone else, even if they have the same condition as you.

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 or operating machinery until you know how morphine 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 being given morphine.

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 the following lists of 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
  • reduced libido, erectile dysfunction or no menstrual periods
  • loss of appetite or taste changes
  • 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 Injection. Mostly they are mild and short- lived.

If any of the following happen, tell your doctor or pharmacist immediately or go to the Accident and Emergency department at your nearest hospital:

  • 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.

These are serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some patients.

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

After being given Morphine Juno

Storage

If you are being given Morphine Juno while in hospital, it will be stored in the pharmacy or on the ward.

Morphine Juno should be stored in a cool, dry place, protected from light, where the temperature stays below 25°C.

Do not store Morphine Juno or any other medicine in the bathroom or near a sink. Do not leave it in the car on hot days or on window sills. Heat and dampness can destroy some medicines.

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

Disposal

If your doctor or pharmacist tells you to stop using Morphine Juno or the injections have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

Morphine Juno comes in clear (10 mg/1 ml only) or yellow ampoules (all presentations) containing a clear colourless to slightly yellow solution.

Ingredients

Morphine Juno

Active ingredient:

  • Morphine hydrochloride trihydrate

Other ingredients:

  • 0.1N Hydrochloride acid
  • Water for injections

Morphine Juno does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Australian Sponsor:

Juno Pharmaceuticals Pty Ltd
42, Kelso Street,
Cremorne,
VIC 3121
Australia

Morphine Juno is available in the following strengths:

This leaflet was prepared in:
July 2021.

Published by MIMS August 2021

BRAND INFORMATION

Brand name

Morphine Juno

Active ingredient

Morphine hydrochloride trihydrate

Schedule

S8

 

1 Name of Medicine

Morphine hydrochloride trihydrate.

2 Qualitative and Quantitative Composition

Morphine Juno is a sterile solution containing morphine hydrochloride 10 milligrams/mL and 20 milligrams/mL in water for injections. The solution does not contain any antioxidant or preservative. The pH of the solution ranges between 3.0 and 5.0, 0.1 N hydrochloric acid is used to adjust the pH of the solution.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Morphine Juno is a clear, colourless to pale yellow, sterile solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Morphine hydrochloride trihydrate is indicated for:
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;
symptomatic relief of severe and intractable pains in terminal cancer patients;
use 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 after parenteral administration of morphine.
Morphine hydrochloride injection should be administered by subcutaneous, intramuscular or slow intravenous injection. The subcutaneous route is not suitable for oedematous patients.
Product is for single use in one patient only. Discard any residue.

Adults.

 The usual adult dose by intramuscular or subcutaneous injection is 5 to 20 milligrams. Doses may be repeated every 4 to 6 hours.
Morphine may be administered intravenously when a rapid onset of action is desired. The usual adult dose is 2.5 to 15 milligrams diluted in 4 to 5 mL of water for injections given slowly over 4 to 5 minutes.
The dose should be reduced in elderly patients, those with respiratory impairment and in patients receiving other CNS depressant medication. In severe or chronic pain, the dose may need to be adjusted according to the response and tolerance of the patient.
Dosage reduction may be necessary in patients with renal or hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment, Use in renal impairment).

Children.

Morphine is given by intramuscular or subcutaneous injection in doses of 0.1 to 0.2 milligrams/kg bodyweight to a maximum of 15 milligrams. Doses 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 milligrams/kg, incrementally over 5 to 15 minutes. Repeat intravenous dosing is unsubstantiated as a method of analgesia in children.
Morphine is not usually given preoperatively 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).

Note.

Morphine hydrochloride trihydrate contains almost an equivalent amount of morphine base per milligram as morphine sulphate and morphine tartrate, hence the preparations may be used interchangeably.

Continuous intravenous infusion.

Morphine may be administered by continuous intravenous infusion using a suitable controlled rate infusion pump or syringe driver. The dosage of morphine should be titrated according to the patient's analgesic requirements and previous opioid 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 milligrams/kg/hour after adequate analgesia has been established.
For children, the recommended dose by intravenous infusion is 0.01 to 0.05 milligrams/kg/hour of morphine, to a maximum of 4 milligrams/hour.
An opioid antagonist and equipment for artificial ventilation should 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, the patient depresses a button, and a dose of morphine is administered intravenously. If the patient depresses 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 milligrams morphine have been given via PCA using a lockout interval of 6 to 10 minutes. Some syringe pumps also deliver a background continuous infusion of morphine at a basal rate, along with the self administered dose of morphine. A dose of 1 milligram/hour morphine is often used in adults as a background infusion. 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 milligrams/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. A background infusion dose of 0.015 milligrams/kg/hour morphine has been 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.
Close monitoring is required, as the use of techniques such as PCA with background continuous infusion are associated with a higher rate of adverse effects.

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 may be inadequate or impractical in the terminally ill patient.
Patients being converted from oral morphine to parenteral 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 should be given regularly, in most instances every 4 hours. The basis of pain control with parenteral morphine should be regular scheduling rather than on an 'as required' or PRN 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 four to five 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.

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.

4.3 Contraindications

Morphine alkaloids are contraindicated in patients with a known hypersensitivity to morphine or other opioids.
Morphine is also contraindicated in the following situations:
premature infants or during labour or delivery of premature infants;
patients with severe respiratory disease, acute respiratory disease, respiratory depression or insufficiency, especially in the presence of cyanosis and/or excessive bronchial secretion;
acute or severe bronchial asthma or other obstructive airways disease;
other conditions where respiratory reserve is depleted, such as severe emphysema, chronic bronchitis or kyphoscoliosis;
cor pulmonale;
diabetic acidosis where there is a danger of coma;
acute alcoholism or delirium tremens;
heart failure secondary to chronic pulmonary disease;
cardiac arrhythmias;
head injuries;
raised cerebrospinal or intracranial pressure;
convulsive states such as status epilepticus, tetanus or strychnine poisoning (see Section 4.4 Special Warnings and Precautions for Use);
severe CNS depression;
brain tumour;
severe liver disease or incipient hepatic encephalopathy;
following operations on the biliary tract or surgical anastomosis;
gastrointestinal obstruction, paralytic ileus;
suspected surgical abdomen;
biliary colic;
acute diarrhoeal conditions associated with antibiotic-induced pseudomembranous colitis;
diarrhoea caused by poisoning (until the toxic material has been eliminated);
phaeochromocytoma (due to risk of pressor response to histamine release);
comatose patients.
Morphine should not be given to patients taking monoamine oxidase inhibitors or within fourteen days of stopping such treatment (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Continuous intravenous infusion of morphine is contraindicated in patients with hepatic or renal disease (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment, Use in renal impairment).
The administration of morphine via patient controlled analgesia to children less than six years of age and adults with poor cognitive function is contraindicated.

4.4 Special Warnings and Precautions for Use

Hazardous and harmful use.

Morphine Juno contains morphine hydrochloride trihydrate which is an opioid and a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed morphine at recommended doses.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed morphine.
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 6.4 Special Precautions for Storage; 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 with anyone.

Accidental ingestion/exposure.

Accidental ingestion or exposure of morphine, especially by children, can result in a fatal overdose of morphine. Patients and their caregivers should be given information on safe storage and disposal of unused morphine (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).

Head injury and increased intracranial pressure.

Morphine should be used with extreme caution in patients with head injuries, other intracranial lesions and raised intracranial pressure, as respiratory depression and potential to increase cerebrospinal fluid (CSF) pressure may be exaggerated, thereby complicating the clinical course. Morphine may produce confusion, miosis, vomiting and other side effects which obscure the clinical course in patients with head injuries. Morphine should only be used in these patients if it is considered essential.

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 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 hepatic and renal impairment. Morphine should therefore be used only in 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 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 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.

Convulsions.

High doses of morphine may cause seizures; therefore, patients with known seizure disorders should be carefully observed, especially if doses are increased in response to tolerance to the drug.

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 temperature elevation.

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.

Morphine administration may cause severe hypotension in patients whose ability to maintain adequate blood pressure has been compromised by a reduced blood volume or concurrent administration of other drugs with hypotensive effects such as phenothiazines or anaesthetics.
Morphine may produce orthostatic hypotension in ambulatory patients.

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.

Tolerance, dependence and withdrawal.

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid. 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 are usually mild or 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.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine). Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, palpitations, irritability, agitation, anxiety, hyperkinesia, tremor, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate, increased heart rate, piloerection, sneezing, convulsions, and unexplained fever.
When discontinuing morphine 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; 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 Tolerance, 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 using, 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 taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
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, Category C.

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 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 non-pharmacological 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). 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 analgesia 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-naive 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 tolerance (see Tolerance, 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, weakness, dizziness, and low blood pressure.

Delayed gastric emptying.

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.

Acute abdominal conditions.

The administration of morphine or other opioids may obscure the diagnosis and 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.

Biliary disorders and biliary surgery.

Morphine should be avoided in patients with biliary disorders (see Section 4.3 Contraindications). Morphine can cause an increase in intrabiliary pressure as a result of effects on the sphincter of Oddi. 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 disease (SCD) and acute chest syndrome (ACS).

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

Decreased sex hormones and increased prolactin.

Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or amenorrhea.

Other special risk patients.

Morphine should be given with caution or in reduced amounts to patients with adrenocortical insufficiency (e.g. Addison's disease), impaired liver function, shock, hypothyroidism, myxoedema, prostatic hypertrophy, urethral stricture, impaired pulmonary or renal function and in aged or debilitated patients. Caution should also be observed if morphine is administered to patients with toxic psychosis or myasthenia gravis. Patients with reduced circulating volume or impaired myocardial function should be carefully observed for orthostatic hypotension.

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 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 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 using morphine.
Morphine may cause drowsiness, 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 additional 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).

Use in hepatic impairment.

Morphine should be given with caution or in reduced amounts to patients with impaired hepatic function as morphine is principally metabolised in the liver. Continuous intravenous infusion of morphine is contraindicated in patients with hepatic impairment (see Section 4.3 Contraindications).

Use in renal impairment.

Morphine should be given with caution or in reduced amounts to patients with impaired renal function, as morphine is principally metabolised in the liver and excreted in the urine (see Section 5 Pharmacological Properties, Section 5.2 Pharmacokinetic Properties). Continuous intravenous infusion of morphine is contraindicated in patients with renal function.
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.

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.

Paediatric use.

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

Effect on laboratory tests.

Morphine delays gastric emptying, thereby invalidating test results in gastric emptying studies.
Morphine may interfere with hepatobiliary imaging using technetium Tc99m diosfenin. Morphine may constrict the sphincter of Oddi and increase biliary tract pressure, preventing delivery of Tc99m diosfenin 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 reducing 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, tranquillisers, 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 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 reduced plasma catecholamine levels.

Antihypertensive agents.

The hypotensive effects of antihypertensive drugs and hypotension producing drugs may be potentiated with the concurrent administration of morphine leading to increased risk of orthostatic hypotension.

Phenothiazines.

Concurrent administration of morphine with some phenothiazines may increase the risk of morphine induced hypotension. Chlorpromazine may enhance the analgesic effects of morphine.

Amphetamines.

Dexamphetamine and other amphetamines may enhance the analgesic effects, and decrease the sedation and lack of alertness caused by morphine.

Muscle relaxants.

Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants, and may 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 symptoms.

Monoamine oxidase inhibitors (MAOIs).

Non-selective monoamine oxidase inhibitors (MAOIs) enhance the effects of morphine, and can cause anxiety, confusion and significant respiratory depression, sometimes leading to coma. Morphine should not be given to patients taking MAOIs or within fourteen days of stopping such treatment (see Section 4.3 Contraindications). Caution is advised with selective MAOIs (e.g. moclobemide and selegeline), as it is not known whether these drugs interact with morphine.

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.

Anticoagulants.

Morphine may potentiate the anticoagulant activity of coumarin anticoagulant agents.

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.

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.

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 and P2Y12 inhibitors.

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.

Atropine.

Atropine may counteract morphine induced miosis.

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

Concurrent administration of morphine and antidiarrhoeal agents with antiperistaltic actions may increase the risk of severe constipation and CNS depression.

Doxapram.

Doxapram may antagonise morphine induced respiratory 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.

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 delay of gastric emptying.
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.

In a dominant lethal study, morphine treatment at 10 mg/kg/day (IP) in male mice over three consecutive days was associated with an increase in chromosomal aberration frequency in spermatocytes. In rats, decreased plasma and testicular levels of luteinising hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring, and decreased fertility in female offspring were observed. The clinical significance of these findings is not known.
Prolonged use of opioids may result in impaired reproductive function, including reduced fertility and sexual dysfunction in both sexes, and irregular menses in women.
(Category C)
Opioid analgesics may cause respiratory depression in the newborn infant. Withdrawal symptoms in newborn infants have been reported with prolonged use of this class of drugs.
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. As safety in pregnancy has not been established, morphine administration is not recommended during pregnancy unless the benefits clearly outweigh any potential risk to the foetus.
Long-term use of morphine during pregnancy may 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.
Use of morphine during and immediately before labour is not recommended, as its effects are unpredictable. Morphine may prolong labour by temporarily reducing the strength, duration and frequency of uterine contractions, or conversely, may tend to shorten labour by increasing the rate of cervical dilatation.
Morphine crosses the placenta and may produce respiratory depression in the neonate if it is administered during labour. Morphine should only be administered during the last 2 to 3 hours before expected delivery if the expected benefits to the mother outweigh the risk to the foetus.
Infants born to mothers who have received opioid analgesics during labour should be observed closely for signs of respiratory depression. Naloxone, a specific opioid antagonist, should be available for reversal of opioid induced respiratory depression if necessary.
Australian characterisation of pregnancy definition: 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 cause of malformations. These effects may be reversible.
 Morphine is excreted in breast milk; therefore, administration of morphine to women who are breastfeeding is not recommended. Withdrawal symptoms have been observed in breastfed infants following discontinuation of maternal morphine administration.

4.7 Effects on Ability to Drive and Use Machines

Morphine, in common with other opioids, has CNS depressant effects. Effects on the ability to drive or operate machinery have not been studied, but it is expected to have a major influence on the ability to drive or operate machines within 48 hours of administration. Patients should not drive or use heavy machinery until all adverse CNS effects have fully worn off. Ambulatory patients should be cautioned against driving or operating machinery.
This medication may cause drowsiness. If affected do not drive a vehicle or operate machinery. Avoid alcohol.

4.8 Adverse Effects (Undesirable Effects)

The major adverse effects associated with morphine include the following: respiratory depression, apnoea, and to a lesser degree circulatory depression. Respiratory arrest, shock and cardiac arrest have occurred following morphine administration.

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 clears in three to five days and is usually not a cause for concern unless it is excessive, or associated with unsteadiness or confusion. Excessive or persistent sedation should be investigated. Possible causes include concurrent sedative medications, the presence of hepatic or renal insufficiency or exacerbated respiratory failure, tolerance to the dose used, especially in older patients, and the patient's general condition and the severity of the disease. If it is necessary to reduce the dose of morphine, but the 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, the appropriate dosage may be lower in patients over 50 years of age.

Nausea and vomiting.

Nausea and vomiting frequently occur after single doses of morphine or as an early undesirable effect of regular opioid therapy. Routine administration of a suitable antiemetic should be considered if prolonged morphine therapy is to be instituted. The frequency of nausea and vomiting usually decreases within a week or so but may persist due to opioid induced gastric stasis.

Constipation.

Chronic morphine administration will cause constipation in virtually all patients. Some patients, particularly elderly, debilitated or bedridden patients, may become impacted. Patients must be cautioned accordingly. An appropriate regimen of bowel management should be initiated when opioid therapy is commenced.

Other adverse effects.

Cardiovascular.

Facial flushing, chills, tachycardia, bradycardia, palpitations, faintness, syncope, hypotension.

Central nervous system.

Weakness, headache, restlessness, anxiety, agitation, irritability, tremor, uncoordinated muscle movements, insomnia, dizziness, vertigo, delirium, confusion or disorientation, transient hallucinations, allodynia, hyperalgesia, mood changes including euphoria and dysphoria. The euphoric activity of morphine has led to its abuse.

Gastrointestinal.

Dry mouth, anorexia, constipation, cramps, laryngospasm, colic, taste alterations, biliary tract cramps and biliary spasm.

Genitourinary.

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

Endocrine.

A syndrome of inappropriate antidiuretic hormone secretion characterised by hyponatraemia secondary to decreased free water excretion may occur. If this occurs, electrolyte monitoring may be necessary. Morphine stimulates prolactin release, and may also cause hyperglycaemia.

Ocular.

Visual disturbances, blurred vision, nystagmus, diplopia, miosis.

Allergic.

Pruritus, urticaria, other skin rashes including contact dermatitis, 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 at injection site, local tissue irritation and induration following subcutaneous injection.

Dependence/ tolerance.

In long-term use, physical dependence and tolerance may develop. In drug dependence, “drug craving” is often involved.

Withdrawal (abstinence) syndrome.

Physical dependence, with or without psychological dependence, may occur as a result of chronic use of opioid analgesics. A withdrawal syndrome may be precipitated if opioid administration is discontinued suddenly, or if an opioid antagonist is administered.
Withdrawal symptoms include body aches, diarrhoea, piloerection, anorexia, nervousness or restlessness, runny nose, sneezing, tremors or shivering, restless legs syndrome, stomach cramps, nausea, flu-like symptoms, sleep disturbance, unusual increase in sweating and yawning, weakness, tachycardia, mydriasis and unexplained fever. 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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

Opioid analgesic overdosage usually produces central nervous system depression ranging from stupor to a profound coma; respiratory depression which may progress to Cheyne-Stokes respiration and/or cyanosis; pneumonia aspiration, pulmonary oedema, extreme somnolence progressing to stupor or coma, confusion, severe dizziness, severe drowsiness, severe nervousness or restlessness, hallucinations, convulsions (especially in infants and children), cold, clammy skin and/or hypothermia; flaccid skeletal muscles; bradycardia; and hypotension. Rhabdomyolysis, progressing to renal failure, has been reported in overdosage. In patients with severe overdosage, particularly following rapid intravenous opioid administration, apnoea, circulatory collapse, cardiac arrest, respiratory arrest and death may occur. Complications such as pneumonia, shock, and/or pulmonary oedema may also prove fatal. Although miosis is characteristic of overdosage with morphine, mydriasis may occur in terminal narcosis or severe hypoxia.
The triad of respiratory depression, coma and constricted pupils is considered indicative of opioid overdosage with dilatation of the pupils occurring as hypoxia develops. Death may occur from respiratory failure.
Overdosage may be caused inadvertently by delayed absorption when repeated doses of opioid analgesics are administered intramuscularly or subcutaneously to a patient with hypothermia, shock, hypotension, or any other condition that might impair circulation. When circulation is restored in these patients, large amounts of the opioid are absorbed into the blood stream. Therefore, such patients should receive intravenous rather than subcutaneous or intramuscular injections with the consideration that intravenous administration may increase the already severe cardiorespiratory impairment.

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.
Opioid induced respiratory depression may be treated with an opioid antagonist. Naloxone, a pure antagonist, is a specific antidote against the respiratory depression resulting from opioid overdose. Administer intravenous naloxone (e.g. 0.4 to 2 milligrams) which may be repeated at 2 to 3 minute intervals. A response should be seen after 2 to 3 doses.
For children, the recommended initial dose of naloxone is 0.01 milligrams/kg. 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 physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.
In severe toxicity the cardiovascular system is usually depressed and requires supportive treatment. If hypotension is due to vasodilatation, then plasma expansion or even vasopressors may be required. Additional measures include support of electrolyte balance, maintenance of normal temperature, catheterisation of the bladder to avoid distension and symptomatic treatment for itching, nausea, vomiting, headache and confusion during the recovery period.
Acidification of the urine will enhance excretion of absorbed drug.

Note.

In an individual physically dependent on opioids, the administration of the usual dose of an opioid antagonist (e.g. naloxone) will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of antagonist administered. The use of opioid antagonists in such individuals should be avoided if possible. If an opioid antagonist must be used to treat serious respiratory depression in the physically dependent patient, only 10% to 20% of the usual initial dose of the antagonist should be administered.
In case of overdose, immediately contact the Poisons Information Centre for advice. (In Australia, call 13 11 26; in New Zealand call 0800 764 766.)

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Morphine, the principal alkaloid of opium, is an opioid analgesic. It has agonist activity, binding to receptors in the brain, spinal cord and other tissues. Morphine is most active at the mu receptors, but is also active at the kappa receptors and may have some agonist activity at the delta receptors. The mu receptors are widely distributed throughout the central nervous system, particularly in the limbic system, thalamus, striatum, hypothalamus and midbrain, and in the dorsal horn of the spinal cord. Kappa receptors are localised primarily in the cerebral cortex and spinal cord, while delta receptors occur in the limbic system.
Morphine exerts its primary effect on the central nervous system (CNS) and on organs containing smooth muscle, including the intestines.
Morphine produces many pharmacological effects including analgesia, decreased gastrointestinal motility, respiratory depression, cough suppression, drowsiness, miosis, mood changes including euphoria and dysphoria, reduction in body temperature, and alterations in both the endocrine system and autonomic nervous system.
Cough suppression is mediated through a direct effect on the medullary centre. Respiratory depression results from reduced responsiveness of the respiratory centre to carbon dioxide.
Nausea and vomiting may occur through direct stimulation of the chemoreceptor trigger zone. Urinary retention may occur due to increased bladder sphincter tone. Biliary tract pressure may occur as a result of morphine induced spasm of the sphincter of Oddi. Constipation is secondary to the action of morphine on bowel wall nerve plexuses.
Morphine hydrochloride has the same pharmacological activity as other morphine salts.

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 after intramuscular and subcutaneous injection is fairly rapid, with peak analgesia occurring 30 to 60 minutes after intramuscular injection and 50 to 90 minutes after subcutaneous injection. Peak analgesia occurs within 20 minutes following intravenous administration.

Distribution.

Morphine is distributed throughout the body, but particularly to parenchymatous tissue such as the kidneys, lungs, 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. Only small quantities of morphine cross the blood brain barrier. About 35% is protein bound, mainly to albumin.

Elderly.

In older patients, the volume of distribution is considerably smaller and initial concentrations of morphine are correspondingly higher.

Metabolism.

Morphine is metabolised principally in the liver, by conjugation with glucuronic acid. The principal metabolites are morphine-3-glucuronide and morphine-6-glucuronide. Metabolism to morphine-3,6-diglucuronide occurs to a limited extent. Morphine-3-glucuronide is pharmacologically inactive and morphine-6-glucuronide is pharmacologically active. Other active metabolites include codeine, normorphine, and morphine-ethereal sulfate.

Excretion.

The serum elimination half-life is approximately 1.5 to 2 hours in healthy subjects. About 90% of the dose is excreted in the urine within 24 hours. Approximately 7 to 10% of the dose is recovered in the faeces, the majority after conjugation and excretion via bile. Morphine-6-glucuronide has a longer half-life then morphine. In patients with renal impairment, accumulation of morphine-6-glucuronide occurs, which can result in enhanced and prolonged opiate activity.

5.3 Preclinical Safety Data

Genotoxicity.

No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, the results of in vitro studies showed that morphine is non-mutagenic in the Drosophila melanogaster lethal mutation assay and produced no evidence of chromosomal aberrations when incubated with murine splenocytes. However, morphine was found to increase DNA fragmentation when incubated in vitro with a human lymphoma cell line. In vivo, morphine has been reported to produce an increase in the frequency of micronuclei in bone marrow cells and immature red blood cells in the mouse micronucleus test and to induce chromosomal aberrations in murine lymphocytes and spermatocytes.

Carcinogenicity.

Studies in animals to evaluate the carcinogenic potential of morphine sulfate have not been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

Water for injections, hydrochloric acid.

6.2 Incompatibilities

Incompatibilities/compatibilities.

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.
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.

6.4 Special Precautions for Storage

Store below 25°C, keep the ampoules in the outer carton in order to protect from light.
To reduce microbiological hazard, use as soon as practicable after dilution with 4 to 5 mL of water for injections. If storage is necessary, hold at 2-8°C for not more than 24 hours.

6.5 Nature and Contents of Container

Morphine Juno is available as a clear colourless solution or slightly yellow solution available in glass ampoules in the following presentations and pack sizes:
10 mg/1 mL, (AUST R 224246) 5 and 10 pack clear or yellow ampoules* .
50 mg/5 mL, (AUST R 224251) 5 and 10 pack yellow ampoules*.
20 mg/1 mL, (AUST R 224242) 5 and 10 pack yellow ampoules*.
100 mg/5 mL, (AUST R 224245) 5 and 10 pack yellow ampoules*.
*Not all pack sizes may be 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

Molecular weight.

375.83.

Molecular formula.

C17H19NO3.HCl.3H2O.

Chemical name.

(5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol hydrochloride trihydrate.

Chemical structure.


CAS number.

[6055-07-7].

7 Medicine Schedule (Poisons Standard)

Schedule 8 (Controlled Drug).

Summary Table of Changes