Consumer medicine information

Ordine

Morphine hydrochloride trihydrate

BRAND INFORMATION

Brand name

Ordine

Active ingredient

Morphine hydrochloride trihydrate

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ordine.

SUMMARY CMI

ORDINE® oral solution

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using ORDINE?

ORDINE contains the active ingredient morphine hydrochloride trihydrate. ORDINE is used for the short-term relief of severe pain for which other treatment options have failed, or otherwise unsuitable to provide sufficient management of pain.

For more information, see Section 1. Why am I using ORDINE? in the full CMI.

2. What should I know before I use ORDINE?

Do not use if you have ever had an allergic reaction to morphine or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ORDINE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ORDINE and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use ORDINE?

  • Your doctor will tell you exactly how much to take.
  • Measure the dose accurately with a medicine measure.
  • Follow the instructions given to you by your doctor or your pharmacist.
  • You must only take ORDINE by mouth.

More instructions can be found in Section 4. How do I use ORDINE? in the full CMI.

5. What should I know while using ORDINE?

Things you should do
  • Remind any doctor or dentist you visit that you are using ORDINE.
  • Tell your doctor or pharmacist if you are taking any other medicines that you use to help you relax, anything that contains alcohol (like cough syrup) or other medicines that treat pain.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not take more than your doctor tells you to.
Driving or using machines
  • ORDINE may cause drowsiness. If affected, do not drive a vehicle or operate machinery.
Drinking alcohol
  • Avoid alcohol. Alcohol may make you feel more sleepy and could increase the risk of serious side effects, such as shallow breathing with the risk of stopping breathing and loss of consciousness.
Looking after your medicine
  • Store below 30°C and protect from light.
  • Keep it where young children cannot reach it.

For more information, see Section 5. What should I know while using ORDINE? in the full CMI.

6. Are there any side effects?

ORDINE may cause constipation, nausea, vomiting, dizziness, drowsiness and be habit forming if taken frequently or over long periods.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING:

Limitations of use

ORDINE should only be used when your doctor decides that other treatment options are not able to effectively manage your pain or you cannot tolerate them.

Hazardous and harmful use

ORDINE poses risks of abuse, misuse and addiction which can lead to overdose and death. Your doctor will monitor you regularly during treatment.

Life threatening respiratory depression

ORDINE can cause life-threatening or fatal breathing problems (slow, shallow, unusual or no breathing) even when used as recommended. These problems can occur at any time during use, but the risk is higher when first starting ORDINE and after a dose increase, if you are older, or have an existing problem with your lungs. Your doctor will monitor you and change the dose as appropriate.

Use of other medicines while using ORDINE

Using ORDINE with other medicines that can make you feel drowsy such as sleeping tablets (e.g. benzodiazepines), other pain relievers, antihistamines, antidepressants, antipsychotics, gabapentinoids (e.g. gabapentin and pregabalin), cannabis and alcohol may result in severe drowsiness, decreased awareness, breathing problems, coma and death. 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 ORDINE.



FULL CMI

ORDINE® oral solution

Active ingredient: morphine hydrochloride trihydrate


Consumer Medicine Information (CMI)

This leaflet provides important information about using ORDINE. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ORDINE.

Where to find information in this leaflet:

1. Why am I using ORDINE?
2. What should I know before I use ORDINE?
3. What if I am taking other medicines?
4. How do I use ORDINE?
5. What should I know while using ORDINE?
6. Are there any side effects?
7. Product details

1. Why am I using ORDINE?

ORDINE contains the active ingredient morphine hydrochloride trihydrate. Morphine belongs to a group of medicines called opioid analgesics.

ORDINE is used to provide the short-term management of severe pain for which other treatment options have failed or are otherwise inappropriate to provide sufficient management of pain.

2. What should I know before I use ORDINE?

Warnings

Do not use ORDINE if:

  • you are allergic to morphine, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • you have acute breathing difficulties such as bronchitis or asthma
  • you have severe abdominal pain with bloating, cramps or vomiting
  • you have a condition where your small bowel does not work properly
  • you take medicine for depression called a 'monoamine oxidase inhibitor' or have taken any in the last two weeks
  • you are pregnant or in labour.

Check with your doctor if you:

  • are severely drowsy, have a reduced level of consciousness or are feeling faint or dizzy upon standing
  • have heart problems or heart disease
  • have low blood pressure
  • have chronic lung disease
  • suffer from sleep apnoea (temporarily stopping breathing while you sleep)
  • have just drunk a large amount of alcohol, regularly drink large amounts of alcohol or have confusion and shaking due to stopping drinking alcohol
  • suffer from convulsions, fits or seizures
  • have a head injury, brain tumour or increased pressure in your head
  • are about to have surgery, had recent gastrointestinal surgery or have had other surgery in the last 24 hours
  • have chronic liver or kidney disease
  • have increased prostate size or difficulty passing urine
  • have problems with your gall bladder
  • have problems with or recent surgery of your bile duct
  • have inflammation of the pancreas
  • have adrenal glands which are not working properly
  • have an underactive thyroid gland
  • have a severe mental condition involving losing contact with reality or an inability to think clearly
  • have an addiction or history of abuse of alcohol, opioids or other drugs.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

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

Talk to your doctor if you are breastfeeding or intend to breastfeed. Low levels of opioid analgesics have been detected in human milk.

Addiction

You can become addicted to ORDINE even if you take it exactly as prescribed. ORDINE 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 ORDINE. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking ORDINE suddenly, so it is important to take it exactly as directed by your doctor.

Tolerance

Tolerance to ORDINE 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 taking 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.

3. What if I am taking other medicines?

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

Some medicines may interfere with ORDINE and affect how it works.

Using ORDINE with medicines that can make you feel drowsy may result in severe drowsiness, decreased awareness, breathing problems, coma and death. These medicines include:

  • sleeping tablets and other sedatives (including benzodiazepines and barbiturates)
  • gabapentinoids
  • cannabis
  • antihistamines
  • anxiolytics
  • general anaesthetics
  • antiemetics
  • antidepressants (including tricyclic antidepressants)
  • antipsychotics (including phenothiazines)
  • neuroleptics
  • beta-blockers (medicines used to treat high blood pressure)
  • other opioids
  • alcohol.

ORDINE may enhance the action of neuromuscular blocking agents (medicines used to relax muscles) and affect your breathing.

ORDINE may increase the anticoagulant activity of coumarin and other anticoagulants (medicines used to prevent blood clots).

ORDINE should not be used if you are taking non-selective monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping such treatment.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ORDINE.

4. How do I use ORDINE?

How much to take

  • Your doctor will tell you how much to take.
  • Follow the instructions provided and use ORDINE until your doctor tells you to stop.

When to take ORDINE

  • Take ORDINE every 4 hours or as directed by your doctor.
  • Take ORDINE at about the same time each day.
  • ORDINE can be taken before or after food, but try to take it the same way every time.

If you begin to experience pain, tell your doctor as your dosage may have to be reviewed.

How to take ORDINE

  • Measure the dose accurately with a medicine measure. Using a medicine measure such as a measuring glass or oral syringe, will make sure that you get the correct dose. You can buy a medicine measure from your pharmacist.
  • Wipe the neck of the bottle and the cap after use to assist with re-opening.

If you forget to use ORDINE

If you are taking regular doses of ORDINE, you should take it at the same time each day. If you miss your dose at the usual time, you may take ORDINE as soon as you remember or think you need it.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

This may increase the chance of getting unwanted side effects including severe drowsiness, decreased awareness, breathing problems, coma and death.

If you use too much ORDINE (overdose)

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 ORDINE that was prescribed for you. If someone takes 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 ORDINE 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.

5. What should I know while using ORDINE?

Things you should do

Call your doctor straight away if you:

  • become pregnant
  • feel your pain is getting worse.

Remind any doctor or dentist or pharmacist you visit that you are using ORDINE.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

Things you should not do

Do not stop using this medicine suddenly. If you stop taking ORDINE suddenly, your pain may worsen and you may experience withdrawal symptoms.

Do not take ORDINE to treat any other complaint unless your doctor tells you to.

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

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ORDINE affects you.

ORDINE may cause drowsiness or impair mental and/or physical ability in some people.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may make you feel more sleepy, and could increase the risk of serious side effects, such as shallow breathing with the risk of stopping breathing and loss of consciousness.

Looking after your medicine

  • Store below 30°C

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

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

When to discard your medicine

ORDINE oral solution only lasts for 6 months once the bottle has been opened as long as the expiry date has not passed. Discard any remaining solution once the 6 months has passed.

To help you remember, write the date of opening on the label.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal and urinary related:
  • constipation
  • nausea or vomiting
  • difficulty urinating
Neurological and behavior related:
  • dizziness
  • drowsiness
  • headache
Allergy related:
  • sweating
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Breathing related:
  • difficulty breathing or shallow breathing
Neurological and behavior related:
  • light-headedness, fainting or dizziness especially when standing up
  • changes in mood
  • drowsiness or feeling extremely sedated
  • feeling disorientated and having nightmares
Heart related:
  • slow or noticeable heartbeats
Gastrointestinal and urinary related:
  • severe stomach pain with nausea or vomiting
  • difficulty urinating
Allergy related:
  • shortness of breath, swelling of the face, lips, tongue or other parts of the body
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What ORDINE contains

Active ingredient
(main ingredient)
Morphine hydrochloride trihydrate
Other ingredients
(inactive ingredients)
Citric acid
Disodium edetate
Glycerol
Sodium citrate dihydrate
Sodium methyl hydroxybenzoate (preservative)
Water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What ORDINE looks like

ORDINE is a clear, colourless or pale yellow aqueous solution in a 200 mL brown plastic bottle.

ORDINE 1 mg/mL oral solution (Aust R 150219)

ORDINE 2 mg/mL oral solution (Aust R 150220)

ORDINE 5 mg/mL oral solution (Aust R 150221)

ORDINE 10 mg/mL oral solution (Aust R 150222)

Who distributes ORDINE

Mundipharma Pty Limited
ABN 87 081 322 509
88 Phillip Street
SYDNEY NSW 2000
Phone: 1800 188 009

This leaflet was prepared in July 2020.

® ORDINE is a registered trade mark of Pfizer (Perth) Pty Ltd and is used under licence.
Orbis RA-0279-002

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Ordine

Active ingredient

Morphine hydrochloride trihydrate

Schedule

S8

 

1 Name of Medicine

Morphine hydrochloride trihydrate.

2 Qualitative and Quantitative Composition

Ordine oral solution (1 mg/mL) contains morphine hydrochloride trihydrate 1 mg/mL.
Ordine oral solution (2 mg/mL) contains morphine hydrochloride trihydrate 2 mg/mL.
Ordine oral solution (5 mg/mL) contains morphine hydrochloride trihydrate 5 mg/mL.
Ordine oral solution (10 mg/mL) contains morphine hydrochloride trihydrate 10 mg/mL.
Ordine oral solution (20 mg/mL) contains morphine hydrochloride trihydrate 20 mg/mL.*
Ordine oral solution (40 mg/mL) contains morphine hydrochloride trihydrate 40 mg/mL.*
* Not currently distributed in Australia.
Excipients of known effect: sodium methyl hydroxybenzoate. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ordine oral solution is a clear, colourless or pale yellow aqueous solution available in bottles of 200 mL.

4 Clinical Particulars

4.1 Therapeutic Indications

Ordine oral solution 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.

4.2 Dose and Method of Administration

Dosage must be titrated to the patient's needs because of the wide inter-individual variability in plasma concentration required to achieve analgesia. The usual adult dosage is 5-20 mg (2.5-10 mL of the 2 mg/mL mixture) every 4 hours. The initial dose will depend largely on the patient's previous treatment and should be the lowest compatible with pain control. Treatment should start at a dosage of 5 mg every 4 hours, with further increments as required. With repeated administration, tolerance may develop and the dose may need to be increased gradually in order to control the pain.
Dosage should be lower in elderly patients, those with respiratory, hepatic or renal impairment and in patients receiving CNS depressants.
Dosage in children should be adjusted according to body weight, 0.1-0.2 mg/kg every 4 hours.

4.3 Contraindications

Morphine is contraindicated in patients hypersensitive to opioids; known hypersensitivity to any of the excipients; in children under one year of age including premature infants or during labour or delivery of premature infants; following biliary tract surgery or surgical anastomosis; paralytic ileus; concomitant monoamine oxidase inhibitors (MAOIs), or within 14 days of such therapy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Morphine is contraindicated in severe respiratory disease, acute respiratory disease and respiratory depression.
Morphine should not be given to patients with acute bronchial asthma or other obstructive airway disease, heart failure secondary to chronic pulmonary disease (cor pulmonale), cardiac arrhythmias, severe CNS depression, acute alcoholism, delirium tremens, head injuries, brain tumour, raised cerebrospinal or intracranial pressure, suspected surgical and acute abdomen, paralytic ileus, delayed gastric emptying, severe liver and renal dysfunction, incipient hepatic encephalopathy and convulsive states such as status epilepticus, tetanus due to stimulatory effects on the spinal cord or strychnine poisoning.

4.4 Special Warnings and Precautions for Use

Hazardous and harmful use.

Ordine oral solution contains the opioid morphine and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Ordine oral solution 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 Ordine oral solution. 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 Ordine oral solution with anyone else.

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 Ordine oral solution, 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 renal and hepatic impairment and in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma). Opioids should be used with caution and with close monitoring in these patients (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).
Morphine should be used with extreme caution in patients with substantially decreased respiratory reserve, hypoxia or hypercapnia. Such patients are often less sensitive to the stimulatory effects of carbon dioxide on the respiratory centre and the respiratory depressant effects of morphine may reduce respiratory drive to the point of apnoea.
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 (see Section 4.2 Dose and Method of Administration), together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.
Opioids may cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use may increase the risk of CSA in a dose-dependent manner in some patients. Opioids may also cause worsening of pre-existing sleep apnoea (see Section 4.8 Adverse Effects (Undesirable Effects)). In patients who present with CSA, consider decreasing the total opioid dosage.
Resuscitative equipment and opioid antagonists must be readily available.

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 Ordine oral solution with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible. If a decision is made to prescribe Ordine oral solution concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. 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 Ordine oral solution.

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, 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 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 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).

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.
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, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate.
When discontinuing Ordine oral solution 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).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Ordine oral solution, 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 Ordine oral solution (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).

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.

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 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 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. 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.

Head injury and increased intracranial pressure.

Morphine should be used with extreme caution and only if it is judged essential, in patients with head injuries, brain tumour, and raised cerebrospinal or intracranial pressure. The respiratory depressant effects of morphine, and the capacity to elevate cerebrospinal fluid pressure, may be greatly increased in the presence of already elevated intracranial pressure. Also, morphine may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of such patients.

Hypotensive effect.

Morphine administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, impaired myocardial function or concurrent administration of drugs such as sympatholytics, phenothiazines or certain anaesthetics. Morphine should be used with caution and these patients should be carefully observed for orthostatic hypotension.

Abdominal conditions.

Morphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions. Morphine should be used with extreme caution in suspected surgical and acute abdomen, and in patients with obstructive bowel disorders. Where there is a possibility of paralytic ileus occurring, morphine should not be used. Should paralytic ileus be suspected or occur during use, Ordine oral solution should be discontinued immediately. As with all oral morphine preparations, Ordine oral solution should be used with caution post-operatively including, but not limited to, following abdominal surgery, as morphine impairs intestinal motility and should not be used until the physician is assured of normal bowel function.
Decreased gastric emptying associated with morphine may be expected to increase the risks of aspiration either associated with morphine-induced CNS depression/coma, or during or after general anaesthesia.

Biliary tract and sphincter of Oddi conditions.

Because of the spasmogenic properties of morphine in the biliary tract and sphincter of Oddi, it should be used only when necessary, and with caution in biliary colic, diseases of the biliary tract and pancreatitis.

Acute ulcerative colitis.

Ordine oral solution should be used with caution in patients with inflammatory bowel disorders (including constipation). Morphine may cause toxic dilation in patients with acute ulcerative colitis.

Cordotomy.

Severe pain antagonises the subjective and respiratory depressant actions of morphine. Should pain suddenly subside, these effects may rapidly become manifest. Patients who are scheduled for cordotomy or other pain-relieving surgical procedures should not receive Ordine oral solution within 24 hours of the procedure. Pain in the immediate pre-operative period, and any symptoms of opioid withdrawal, should be managed with short-acting analgesic agents. If further treatment with Ordine oral solution is then indicated, the dosage should be adjusted to the new post-operative requirement.

Special risk groups.

Morphine should be administered with caution and in reduced dosages to patients with adrenocortical insufficiency, hypothyroidism, prostatic hypertrophy or urethral stricture.
Seizures may result from high doses. Morphine may lower the seizure threshold in patients with a history of seizure. Patients with known seizure disorders should be carefully observed, especially when doses are increased in response to tolerance.
Morphine should be used with extreme caution, if benefits outweigh risks, in convulsive states such as status epilepticus.
Morphine should be used with caution pre-operatively or within the first 24 hours post-operatively.

Use in hepatic impairment.

Morphine should be administered with caution and in reduced dosages to patients with severely reduced hepatic function.

Use in renal impairment.

Morphine should be administered with caution and in reduced dosages to patients with severely reduced renal function.

Use in the elderly.

Morphine should be administered with extreme caution and in reduced dosages, to elderly or debilitated patients.

Paediatric use.

Safety and effectiveness in neonates have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Acidifying or alkalising agents.

The clearance of morphine may be increased by acidifying agents and decreased by alkalising agents. Morphine's actions on gastrointestinal motility may influence the absorption of other drugs.

Amphetamines, chlorpromazine and methocarbamol.

The analgesic effect of morphine is potentiated by amphetamines, chlorpromazine and methocarbamol.

Anticholinergics.

Medicinal products that block the action of acetylcholine, for example antihistamines, anti-parkinsonian drugs and anti-emetics, may interact with morphine to potentiate anti-cholinergic adverse events.

Cimetidine.

Cimetidine inhibits the metabolism of morphine. A potentially lethal interaction between morphine and cimetidine has been reported. The patient exhibited apnoea, significantly reduced respiratory rate and suffered a grand mal seizure. Naloxone increased the respiratory rate; however, confusion, disorientation, generalised twitching and periods of apnoea persisted for 80 hours.

CNS depressants.

CNS depressants including other opioids, anaesthetics, sedatives (including benzodiazepines), hypnotics, barbiturates, phenothiazines, tricyclic antidepressants, chloral hydrate, glutethimide, tranquilisers, muscle relaxants, antihypertensives, gabapentinoids, antihistamines, cannabis, centrally-acting anti-emetics and alcohol may enhance the depressant effects of morphine. Beta-blockers may also enhance the depressant effect of morphine. Interactive effects resulting in respiratory depression, hypotension, profound sedation and/or coma may result if these drugs are taken in combination with the usual doses of morphine (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).

Coumarin and other anticoagulants.

Morphine may increase the anticoagulant activity of coumarin and other anticoagulants.

Mixed agonist/antagonist opioid analgesics.

Mixed agonist/antagonist opioid analgesics (e.g. buprenorphine, nalbuphine, pentazocine) should not be administered to a patient who has received a course of therapy with a pure opioid agonist analgesic.

Monoamine oxidase inhibitors (MAOIs).

Non-selective MAOIs (including procarbazine hydrochloride) intensify the effects of morphine and other opioid drugs which can cause anxiety, confusion and significant respiratory depression, sometimes leading to coma. Morphine should not be given to patients taking non-selective MAOIs or within 14 days of stopping such treatment. It is unknown whether there is an interaction between the selective MAOIs (e.g. moclobemide, selegiline) and morphine, therefore, caution is advised with this drug combination.

Propranolol.

The combination of morphine and propranolol is potentially lethal. Propranolol increases the acute CNS toxicity of morphine.

Rifampicin.

Plasma concentrations of morphine may be reduced by rifampicin.

Ritonavir.

Available data indicate that ritonavir may increase the activity of glucuronyl transferases. Consequently, co-administration of ritonavir and morphine may result in decreased serum concentrations of morphine with possible loss of analgesic effectiveness.

Zidovudine.

Morphine may alter the metabolism of zidovudine by competitively inhibiting glucuronidation or directly inhibiting hepatic microsomal metabolism; therefore this combination should be used with caution.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Prolonged use of opioid drugs may result in impairment of reproductive function, including infertility and sexual dysfunction in both sexes and irregular menses in women.
Reduced fertility has been shown in male rats administered repeat doses of morphine subcutaneously.
(Category C)
Australian Pregnancy Categorisation 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.
Opioid analgesics may cause respiratory depression in the newborn infant. Morphine has been associated with foetal CNS defects in rodent studies.
In humans it is not known whether morphine can cause foetal harm when administered during pregnancy. Use of Ordine should be avoided to the extent possible in patients who are pregnant.
Infants born of mothers who have been taking morphine chronically may exhibit withdrawal symptoms.

Use during labour/delivery.

Morphine may prolong labour by reducing the strength and frequency of uterine contractions. Morphine crosses the placental barrier and its administration during labour may cause respiratory depression in the newborn infant.
Morphine has been detected in human breastmilk. Morphine administration to nursing mothers is not recommended.

4.7 Effects on Ability to Drive and Use Machines

Morphine may cause drowsiness and may impair the mental and/or physical abilities needed for certain potentially hazardous activities, such as driving a car or operating machinery. Patients should be cautioned accordingly.
Patients should also be cautioned about the combined effects of morphine with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics and alcohol.

4.8 Adverse Effects (Undesirable Effects)

The following frequencies are the basis for assessing adverse effects. Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).
The major hazards associated with morphine, as with other opioid analgesics, are respiratory depression and, to a lesser degree, circulatory depression. Respiratory arrest, shock and cardiac arrest have occurred following oral and parenteral use of morphine.

Very common adverse reactions requiring medical attention.

Frequently observed adverse reactions of opioid analgesics such as morphine are sedation, nausea and vomiting, constipation and sweating.

Sedation.

Most patients experience initial drowsiness, partly for pharmacokinetic reasons and partly because patients often recuperate from prolonged fatigue after the relief of persistent pain. Drowsiness usually clears in three to five days and is usually not a reason for concern providing that it is not excessive, or associated with unsteadiness or confusional symptoms. If excessive sedation persists, the reason for it must be sought. Some of these are: concomitant sedative medications, hepatic or renal failure, exacerbated respiratory failure, higher doses than tolerated in an older patient, or the patient is actually more severely ill than realised. If it is necessary to reduce the dose, it can be carefully increased again after three or four days if it is obvious that the pain is not being well controlled. Dizziness and unsteadiness may be caused by postural hypotension particularly in elderly or debilitated patients. It can be alleviated if the patient lies down. Because of the slower clearance in patients over 50 years of age, an appropriate dose in this age group may be as low as half or less the usual dose in the younger age group.

Nausea and vomiting.

Nausea and vomiting occur frequently after single doses of opioids or as an early unwanted effect of regular opioid therapy. When instituting prolonged therapy for chronic pain, the routine prescribing of an anti-emetic should be considered. Patients taking the equivalent of a single dose of 20 mg or more of morphine usually require an anti-emetic during early therapy. Small doses of prochlorperazine or haloperidol are frequently prescribed anti-emetics. Nausea and vomiting tend to lessen in a week or so but may persist due to opioid-induced gastric stasis. In such patients, metoclopramide is often useful.

Constipation.

As with all opioid analgesics, constipation is very common. In some instances, particularly the elderly or bedridden, patients may become impacted. It is essential to caution patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged opioid therapy. Dietary modification, suitable exercise, softeners, laxatives and other appropriate measures should be used as required.

Other adverse reactions.

Cardiac disorders.

Not known: bradycardia, palpitations, supra-ventricular tachycardia.

Ear and labyrinth disorders.

Uncommon: vertigo.

Endocrine disorders.

Uncommon: syndrome of inappropriate antidiuretic hormone secretion characterised by hyponatraemia secondary to decreased free water excretion may be prominent (monitoring of electrolytes may be necessary).

Eye disorders.

Uncommon: visual impairment. Not known: miosis.

Gastrointestinal disorders.

Common: abdominal pain, anorexia, dry mouth. Uncommon: dyspepsia, ileus, taste perversion. Not known: cramps, gastrointestinal disorders.

General disorders.

Common: asthenia, fatigue, malaise, pruritus. Uncommon: peripheral oedema. Not known: drug tolerance, oedema, drug withdrawal syndrome.

Hepato-biliary disorders.

Uncommon: increased hepatic enzyme. Not known: biliary pain, biliary spasm, biliary tract cramps.

Immune system disorders.

Uncommon: hypersensitivity. Not known: anaphylactic reaction, anaphylactoid reaction.

Nervous system disorders.

Common: dizziness, headache, involuntary muscle contractions, somnolence. Uncommon: convulsions, hypertonia, paraesthesia, syncope. Not known: hyperalgesia, weakness.

Psychiatric disorders.

Common: confusion, insomnia. Uncommon: agitation, euphoria, hallucinations, malaise, mood altered. Not known: drug dependence, dysphoria, thinking disturbances.

Renal and urinary disorders.

Uncommon: uretic spasm, urinary retention or hesitance. Not known: oliguria.

Reproductive system and breast disorders.

Not known: amenorrhoea, erectile dysfunction, reduced libido or potency.

Respiratory, thoracic and mediastinal disorders.

Uncommon: bronchospasm, pulmonary oedema, respiratory depression. Not known: cough decreased.

Skin and subcutaneous tissue disorders.

Common: hyperhidrosis, other skin rashes including contact dermatitis. Uncommon: urticaria.

Vascular disorders.

Uncommon: facial flushing, hypotension. Not known: faintness, postural hypotension.

Withdrawal (abstinence) syndrome.

Physical dependence with or without psychological dependence tends to occur with chronic administration. An abstinence syndrome may be precipitated when opioid administration is discontinued or opioid antagonists administered.
The following withdrawal symptoms may be observed after opioids are discontinued: body aches, diarrhoea, gooseflesh, loss of appetite, nervousness or restlessness, runny nose, sneezing, chills, tremors or shivering, stomach cramps, nausea, trouble with sleeping, unusual increase in sweating and yawning, weakness, tachycardia and unexplained fever. With appropriate medical use of opioids and gradual withdrawal from the drug, these symptoms are usually mild.

Post-marketing.

Nervous system disorders.

Not known: allodynia, sleep apnoea syndrome.

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

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

Symptoms and signs.

Serious morphine overdosage is characterised by respiratory depression (reduced respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, miotic pupils (dilated if hypoxia is severe), rhabdomyolysis progressing to renal failure, flaccidity of skeletal muscle, cold or clammy skin, and sometimes hypotension and bradycardia. Severe overdosage may result in apnoea, pulmonary oedema, circulatory collapse, cardiac arrest and death.

Treatment.

Primary attention should be given to the establishment of adequate respiratory exchange through the provision of a patent airway and controlled or assisted ventilation. The opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression due to overdosage or as a result of unusual sensitivity to morphine. (Please refer naloxone product information). An appropriate dose of one of the antagonists should therefore be administered, preferably by the intravenous route. The usual initial intravenous (I.V.) adult dose of naloxone is 0.4 mg or higher. Concomitant efforts at respiratory resuscitation should be carried out. Since the duration of action of morphine may exceed that of the antagonist, the patient should be under continued surveillance and doses of the antagonists should be repeated as needed to maintain adequate respiration.
An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Oxygen, intravenous fluids, vasopressors and other supportive measures should be used as indicated to manage circulatory shock accompanying an overdose. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Artificial ventilation should be applied if necessary and fluid and electrolyte metabolism maintained.
In an individual physically dependent on opioids, the administration of the usual dose of opioid antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of antagonist administered. The use of opioid antagonists in such individuals should be avoided if possible. If an opioid antagonist must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care by using dosage titration, commencing with 10 to 20% of the usual recommended initial dose.
Evacuation of gastric contents may be useful in removing unabsorbed drug.

Toxicity.

Morphine toxicity may result from overdosage but because of the great inter-individual variation in sensitivity to opioids it is difficult to determine an exact dose of any opioid that is toxic or lethal.
The presence of pain or tolerance tends to diminish the toxic effects of morphine. Published data suggest that in a morphine-naive, pain-free individual, the lethal dose would be in excess of 120 mg. Patients on chronic oral morphine therapy have been known to take in excess of 3000 mg/day with no apparent toxicity.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Morphine is the principal alkaloid of opium and is a phenanthrene derivative.
Morphine, like other opioids, acts as an agonist interacting with stereo-specific and saturable binding sites/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 (frontal and temporal cortex, amygdala and hippocampus), thalamus, striatum, hypothalamus, midbrain and laminae I, II, IV and V of the dorsal horn in the spinal cord. It has been postulated that exogenously administered morphine exerts its analgesic effect, in part, by altering the central release of neurotransmitter from afferent nerves sensitive to noxious stimuli. Peripheral threshold or responsiveness to noxious stimuli is unaffected, leaving monosynaptic reflexes such as the patella or the Achilles tendon reflex intact.
Morphine exerts its primary effects on the central nervous system and organs containing smooth muscle. Pharmacological effects include analgesia, drowsiness, alteration in mood (euphoria), reduction in body temperature, dose-related depression of respiration, interference with adrenocortical response to stress (at high doses), reduction in peripheral resistance with little or no effect on cardiac index, cough suppressions mediated through a direct effect on the medullary centre and miosis.
Direct stimulation of the chemoreceptor trigger zone may cause emesis and spasmogenic effects on the gastrointestinal tract resulting in decreased peristaltic activity. Urinary retention may occur due to increased bladder sphincter tone.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Morphine is readily absorbed from the gastrointestinal tract. Significant first pass metabolism occurs in the liver following oral administration; hence, the bioavailability of oral morphine is low and variable.
With repeated regular dosing, oral morphine is about 1/3 as potent as when given by intramuscular injection.

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 conjunction with glucuronic acid at the 3-hydroxyl group, and to a much lesser extent to the 3,6-diglucuronide.

Excretion.

Elimination half-life is approximately 1.5-2 hours in healthy subjects and 90% of the dose is recovered in urine within 24 hours. Approximately 7-10% of the dose is recovered in faeces, the majority after conjugation and excretion via bile.

5.3 Preclinical Safety Data

Genotoxicity.

No regulatory studies to assess the mutagenic potential of morphine have been conducted.

Carcinogenicity.

Regulatory studies in animals to evaluate the carcinogenic potential of morphine have not been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

The sugar and alcohol free vehicle contains the excipients anhydrous citric acid, sodium citrate, glycerol and disodium edetate with sodium methyl hydroxybenzoate 0.23% w/v as preservative and water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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.
Discard 6 months after opening. Do not exceed the stated expiry date printed on the label.

6.4 Special Precautions for Storage

Store below 30°C. Do not refrigerate. Protect from light.

6.5 Nature and Contents of Container

Polyethylene terephthalate bottle, 200 mL.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Morphine hydrochloride is a white, crystalline powder or colourless, silky crystals. It is soluble 1:21 in water and 1:10 in boiling alcohol. It is practically insoluble in chloroform or ether.
Morphine is liable to precipitate out of solution in an alkaline environment.

Chemical structure.

Morphine hydrochloride is 7,8-didehydro- 4,5-epoxy-17-methylmorphinan-3,6-diol hydrochloride trihydrate (molecular weight 375.8).
The structural formula of morphine hydrochloride is:

CAS number.

52-26-6 (anhydrous).

7 Medicine Schedule (Poisons Standard)

S8.

Summary Table of Changes