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.

What is in this leaflet

This leaflet answers some common questions about ORDINE oral solution.

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 taking this medicine against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What ORDINE oral solution is taken for

ORDINE oral solution contains morphine hydrochloride trihydrate. Morphine belongs to a group of medicines called opioid analgesics.

ORDINE oral solution is used to relieve severe pain when other forms of treatment have not been effective. It may also be used to improve sleep where sleeplessness is due to pain.

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

As with all strong painkillers, your body may become used to you taking ORDINE oral solution. Taking 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.

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

Before you take it

When you must not take it

Do not take ORDINE oral solution if you:

  • have any breathing problems such as acute asthma, respiratory depression (breathing slows or weakens) or other obstructive airways disease
  • are severely drowsy or have a reduced level of consciousness
  • suffer from irregular heart beats or changes in the way the heart beats
  • have heart problems or heart disease including if due to long-term lung disease
  • have just consumed a large amount of alcohol, regularly consume large amounts of alcohol or have confusion and shaking due to stopping drinking alcohol
  • suffer from convulsions, fits or seizures, tetanus caused by excitement of your spinal cord or strychnine poisoning
  • have a head injury, brain tumour, increased pressure in your head or spine
  • have severe abdominal pain
  • have a condition where your stomach empties more slowly than it should or your small bowel does not work properly
  • have an obstruction of the bowel or a condition where it could occur
  • have had recent surgery of your gall bladder or bile duct or to join two hollow organs together
  • are about to have surgery on your spine for pain relief in the next 24 hours
  • have severe kidney or liver disease or a disease of the brain caused by liver disease
  • take medicine for depression called a 'monoamine oxidase inhibitor' or you have taken any in the last two weeks.

Do not take ORDINE oral solution if you are allergic to morphine, opioid analgesics, or any of the ingredients listed at the end of this leaflet.

Do not take this medicine after the expiry date (EXP) printed on the pack. If you take it after the expiry date has passed, it may not work very well.

Do not take it if the packaging is torn or shows signs of tampering.

Do not take ORDINE oral solution if you are pregnant or planning to become pregnant whilst taking this medicine. Like most medicines of this kind, ORDINE oral solution is not recommended to be used during pregnancy. Your doctor will discuss the risks of taking it if you are pregnant.

Do not take this medicine during labour for the delivery of premature infants.

Do not give this medicine to a child under one year of age including premature infants. Safety and efficacy in children less than one year of age have not been established.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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

  • low blood pressure
  • increased prostate size or difficulty passing urine
  • problems with your gall bladder or bile duct
  • inflammation of the pancreas
  • chronic lung, liver or kidney disease
  • underactive adrenal glands
  • underactive thyroid gland
  • inflammatory bowel disease or recent abdominal surgery
  • are about to have an operation or have just had one within the last 24 hours
  • an addiction or history of abuse of alcohol or drugs.

This medicine is not recommended to be taken during labour. Morphine given to the mother during labour may cause breathing problems and signs of withdrawal in the newborn.

Tell your doctor if you are breastfeeding or are planning to breastfeed. Morphine can pass into the breast milk and can affect the baby. Your doctor can discuss with you the risks involved.

If you have not told your doctor about any of the above, tell them before you start taking ORDINE oral solution.

Taking other medicines

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

Some medicines and ORDINE oral solution may interfere with each other. These include:

  • medicines to treat depression, psychiatric or mental disorders
  • medicines to treat depression belonging to a group called 'monoamine oxidase inhibitors' must be stopped 14 days before ORDINE oral solution is taken
  • medicines to help you sleep, including medicines belonging to a group called 'benzodiazepines'
  • medicines to put you to sleep during an operation or procedure
  • medicines to relax your muscles
  • medicines to prevent or relieve the symptoms of allergy such as antihistamines
  • propranolol or other medicines to lower blood pressure
  • gabapentin or barbiturates, medicines to treat seizures
  • medicines to thin the blood e.g. coumarin derivatives such as warfarin
  • medicines used to relieve heartburn or treat stomach ulcers such as cimetidine or antacids
  • medicines to treat Parkinson's disease
  • medicines to stop nausea and vomiting e.g. metoclopramide or prochlorperazine
  • rifampicin, a medicine to treat tuberculosis
  • other pain relievers including other opioids
  • medicines to treat HIV infection and AIDs e.g. ritonavir or zidovudine
  • alcohol.

These medicines and alcohol may be affected by ORDINE oral solution, may affect how well ORDINE oral solution works or may increase side effects. You may need to use different amounts of your medicines, or take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking this medicine.

How to take ORDINE oral solution

How much to take

Your doctor will tell you exactly how much to take.

Follow the instructions given to you by your doctor or pharmacist exactly.

If you do not understand the instructions on the bottle, ask your doctor or pharmacist for help.

How to take it

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.

This medicine only lasts for 6 months once the bottle has been opened as long as the expiry date has not passed. Discard any remaining solution after the 6 months has passed. To help you remember, write the date you open the bottle on the label and check the expiry date.

You must only take ORDINE oral solution by mouth. ORDINE oral solution is only designed to work properly if taken by mouth. Taking this medicine in a manner other than that prescribed by your doctor can be harmful to your health.

When to take it

Take ORDINE oral solution every four hours, or as directed by your doctor, to control the pain. If your doctor has told you to take it routinely, take the doses at about the same time each day.

If you begin to experience pain and you are taking ORDINE oral solution as prescribed, contact your doctor as your dosage may have to be reviewed.

You can take this medicine before or after food.

If you are already taking other medications for your pain, your doctor may have recommended that you also take ORDINE oral solution as required for the relief of breakthrough pain.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

If you stop taking this medicine suddenly, your pain may worsen and you may experience withdrawal symptoms such as:

  • body aches
  • loss of appetite, nausea, stomach cramps or diarrhoea
  • fast heart rate
  • sneezing or runny nose
  • chills, tremors, shivering or fever
  • trouble sleeping
  • increased sweating and yawning
  • weakness
  • nervousness or restlessness.

If you forget to take it

If you forget to take a dose, contact your doctor or pharmacist for advice.

Do not take a double dose to make up for the dose that you missed. This will increase the chance of you getting unwanted side effects.

If you have trouble remembering when to take your medicine, ask your pharmacist for hints. For example, take your medicine at the same times each day.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much ORDINE oral solution.

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

Keep telephone numbers for these places handy.

You should also follow the above steps if someone other than you has accidently taken ORDINE oral solution that was prescribed for you.

If someone takes an overdose they may experience difficulties in breathing, become drowsy and tired, lack muscle tone, have cold or clammy skin, have constricted pupils, have very low blood pressure or slow heart rate, and possibly may even become unconscious and die.

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

While you are taking it

Things you must do

Take ORDINE oral solution exactly as your doctor has prescribed.

Before you start on a new medicine, remind your doctor and pharmacist that you are taking ORDINE oral solution.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon and anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all your doctor's appointments so that your progress can be checked.

Tell your doctor if your pain is getting worse. Also tell your doctor if you are having any problems or difficulties while you are being treated with ORDINE oral solution. Tolerance to morphine may develop which means that the effect of the medicine may decrease. If this happens, speak to your doctor.

Keep enough ORDINE oral solution with you to last over weekends and holidays.

Things you must not do

Do not drink alcohol while you are taking ORDINE oral solution. Drinking alcohol whilst taking ORDINE oral solution may make you feel more sleepy and increase the risk of serious side effects, such as shallow breathing with the risk of stopping breathing and loss of consciousness.

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

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

Do not stop taking your medicine, exceed the dose recommended or change the dosage without checking with your doctor. Over time your body may become used to you taking morphine. If you stop taking it suddenly, your pain may worsen and you may experience unwanted side effects such as withdrawal symptoms. This is called physical dependence.

If you need to stop taking this medicine, your doctor will gradually reduce the amount you take each day, if possible, before stopping the medicine completely.

Things to be careful of

Tell your doctor if you find that you cannot concentrate or that you feel more sleepy than normal when you start taking this medicine or when your dose is increased. This feeling should wear off after a few days.

Do not drive or operate machinery until you know how ORDINE oral solution affects you. ORDINE oral solution may cause drowsiness, dizziness, hallucinations, confusion, vision problems or may affect alertness. If you are affected, you should not drive or operate machinery. Discuss these effects with your doctor.

Be careful if you are elderly, unwell or taking other medicines. Some people may experience side effects such as unsteadiness, dizziness, drowsiness or confusion which may increase the risk of a fall.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. Standing up slowly will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Tell your doctor if you suffer from nausea or vomiting when taking ORDINE oral solution. If you vomit after taking your dose, your pain may come back as you may not have absorbed your morphine. If this happens, speak to your doctor. Your doctor may prescribe some medicine to help stop vomiting.

Tell your doctor if taking ORDINE oral solution causes constipation. Your doctor can advise you about your diet, the proper use of laxatives or alternative treatments and suitable exercise you can do to help manage this.

There is potential for abuse of morphine and the development of addiction to morphine. It is important that you discuss this issue with your doctor.

Side effects

All medicines may have some unwanted side effects. Sometimes they are serious but most of the time they are not. Your doctor has weighed the risks of using this medicine against the benefits they expect it will have for you.

Do not be alarmed by this list of possible side effects. Not everybody experiences them.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ORDINE oral solution. This medicine helps most people with severe pain, but it may have unwanted side effects in some people. Other side effects not listed here may also occur.

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

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

  • mild abdominal problems such as feeling sick (nausea), loss of appetite or constipation
  • dry mouth or changes in taste
  • sweating
  • facial flushing
  • trouble sleeping
  • trouble with your balance
  • new problems with your eyesight
  • skin rash or itching
  • absence of menstrual periods
  • sexual problems
  • muscle twitching or muscle stiffness
  • swelling, including but not only of the legs or ankles.

Tell your doctor as soon as possible if you notice any of the following and they worry you:

  • stomach discomfort or cramps, vomiting, indigestion or abdominal pain
  • abnormal thinking or changes in mood
  • drowsiness, feeling faint or fainting or dizziness especially when standing up
  • slow or noticeable heartbeats
  • headache, confusion or hallucinations
  • unusual weakness or loss of strength
  • changes in passing urine, such as the volume passed, pain or feeling the need to urinate urgently.

The above list includes serious side effects that may require medical attention.

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

  • your breathing slows or weakens
  • you have an allergic reaction: shortness of breath, wheezing, shallow or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin
  • seizures, fits or convulsions
  • fast or irregular heartbeats.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

When seeking medical attention, take this leaflet and any remaining solution with you to show the doctor.

After taking it

Storage

Keep your ORDINE oral solution in the bottle with the lid tightly fastened until it is time to take it. If you take the solution out of the bottle or leave the lid off it may not keep well.

Keep your medicine in a cool dry place, away from light, where the temperature stays below 30°C.

Do not store it in the refrigerator.

Do not store it or any other medicine in the bathroom, near a sink or leave it on a window sill.

Do not leave it in the car. Heat 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

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.

If your doctor tells you to stop taking this medicine or the expiry date has passed, return any unused medicine to your pharmacist.

Product description

What it looks like

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

ORDINE® oral solution is available in 4 strengths:

1 mg/mL

2 mg/mL

5 mg/mL

10 mg/mL

Ingredients

Active ingredient:
One mL of solution contains the following:

  • 1 mg morphine hydrochloride trihydrate in the 1 mg/mL solution
  • 2 mg morphine hydrochloride trihydrate in the 2 mg/mL solution
  • 5 mg morphine hydrochloride trihydrate in the 5 mg/mL solution
  • 10 mg morphine trihydrate hydrochloride in the 10 mg/mL solution.

Inactive ingredients:

  • anhydrous citric acid
  • sodium citrate
  • glycerol
  • disodium edetate
  • sodium methyl hydroxybenzoate (preservative)
  • water for injections.

ORDINE® oral solution does not contain sugar, alcohol, gluten, lactose, tartrazine or azo dyes.

Manufacturer / Sponsor

ORDINE® oral solution is made in Australia and distributed by:

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

® ORDINE is a registered trademark of Pfizer (Perth) Pty Ltd and is used under licence.

This leaflet was updated in January 2019.

Australian Register Numbers:

1 mg/mL: AUST R 150219

2 mg/mL: AUST R 150220

5 mg/mL: AUST R 150221

10 mg/mL: AUST R 150222

Orbis RA-0255

Published by MIMS March 2019

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